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Sample records for hypoxia-induced cardiac hypertrophy

  1. Chronic intermittent hypoxia induces cardiac hypertrophy by impairing autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway.

    PubMed

    Xie, Sheng; Deng, Yan; Pan, Yue-Ying; Ren, Jie; Jin, Meng; Wang, Yu; Wang, Zhi-Hua; Zhu, Die; Guo, Xue-Ling; Yuan, Xiao; Shang, Jin; Liu, Hui-Guo

    2016-09-15

    Autophagy is tightly regulated to maintain cardiac homeostasis. Impaired autophagy is closely associated with pathological cardiac hypertrophy. However, the relationship between autophagy and cardiac hypertrophy induced by chronic intermittent hypoxia (CIH) is not known. In the present study, we measured autophagy-related genes and autophagosomes during 10 weeks of CIH in rats, and 6 days in H9C2 cardiomyocytes, and showed that autophagy was impaired. This conclusion was confirmed by the autophagy flux assay. We detected significant hypertrophic changes in myocardium with impaired autophagy. Rapamycin, an autophagy enhancer, attenuated the cardiac hypertrophy induced by CIH. Moreover, silencing autophagy-related gene 5 (ATG5) exerted the opposite effect. The role of adenosine monophosphate-activated protein kinase (AMPK) in regulating autophagy under CIH was confirmed using AICAR to upregulate this enzyme and restore autophagy flux. Restoring autophagy by AICAR or rapamycin significantly reversed the hypertrophic changes in cardiomyocytes. To investigate the mechanism of autophagy impairment, we compared phospho (p)-AMPK, p-Akt, cathepsin D, and NFAT3 levels, along with calcineurin activity, between sham and CIH groups. CIH activated calcineurin, and inhibited AMPK and AMPK-mediated autophagy in an Akt- and NFAT3-independent manner. Collectively, these data demonstrated that impaired autophagy induced by CIH through the AMPK pathway contributed to cardiac hypertrophy. PMID:27412517

  2. Chronic intermittent hypoxia induces cardiac hypertrophy by impairing autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway.

    PubMed

    Xie, Sheng; Deng, Yan; Pan, Yue-Ying; Ren, Jie; Jin, Meng; Wang, Yu; Wang, Zhi-Hua; Zhu, Die; Guo, Xue-Ling; Yuan, Xiao; Shang, Jin; Liu, Hui-Guo

    2016-09-15

    Autophagy is tightly regulated to maintain cardiac homeostasis. Impaired autophagy is closely associated with pathological cardiac hypertrophy. However, the relationship between autophagy and cardiac hypertrophy induced by chronic intermittent hypoxia (CIH) is not known. In the present study, we measured autophagy-related genes and autophagosomes during 10 weeks of CIH in rats, and 6 days in H9C2 cardiomyocytes, and showed that autophagy was impaired. This conclusion was confirmed by the autophagy flux assay. We detected significant hypertrophic changes in myocardium with impaired autophagy. Rapamycin, an autophagy enhancer, attenuated the cardiac hypertrophy induced by CIH. Moreover, silencing autophagy-related gene 5 (ATG5) exerted the opposite effect. The role of adenosine monophosphate-activated protein kinase (AMPK) in regulating autophagy under CIH was confirmed using AICAR to upregulate this enzyme and restore autophagy flux. Restoring autophagy by AICAR or rapamycin significantly reversed the hypertrophic changes in cardiomyocytes. To investigate the mechanism of autophagy impairment, we compared phospho (p)-AMPK, p-Akt, cathepsin D, and NFAT3 levels, along with calcineurin activity, between sham and CIH groups. CIH activated calcineurin, and inhibited AMPK and AMPK-mediated autophagy in an Akt- and NFAT3-independent manner. Collectively, these data demonstrated that impaired autophagy induced by CIH through the AMPK pathway contributed to cardiac hypertrophy.

  3. Nanocurcumin protects cardiomyoblasts H9c2 from hypoxia-induced hypertrophy and apoptosis by improving oxidative balance.

    PubMed

    Nehra, Sarita; Bhardwaj, Varun; Kalra, Namita; Ganju, Lilly; Bansal, Anju; Saxena, Shweta; Saraswat, Deepika

    2015-06-01

    Hypoxia-induced cardiomyocyte hypertrophy is evident; however, the distinct molecular mechanism underlying the oxidative stress-mediated damages to cardiomyocytes remains unknown. Curcumin (diferuloylmethane) is known for anti-hypertrophic effects, but low bioavailability makes it unsuitable to exploit its pharmacological properties. We assessed the efficacy of nanotized curcumin, i.e. nanocurcumin, in ameliorating hypoxia-induced hypertrophy and apoptosis in H9c2 cardiomyoblasts and compared it to curcumin. H9c2 cardiomyoblasts were challenged with 0.5 % oxygen, for 24 h to assess hypoxia-induced oxidative damage, hypertrophy and consequent apoptosis. The molecular mechanism underlying the protective efficacy of nanocurcumin was evaluated in regulating Raf-1/Erk-1/2 apoptosis by caspase-3/-7 pathway and oxidative stress. Nanocurcumin ameliorated hypoxia-induced hypertrophy and apoptosis in H9c2 cells significantly (p ≤ 0.01), by downregulating atrial natriuretic factor expression, caspase-3/-7 activation, oxidative stress and stabilizing hypoxia-inducible factor-1α (HIF-1α) better than curcumin. Nanocurcumin provides insight into its use as a potential candidate in curing hypoxia-induced cardiac pathologies by restoring oxidative balance. PMID:25846484

  4. Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

    PubMed Central

    Hou, Jianglong; Kang, Y. James

    2012-01-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

  5. Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice

    PubMed Central

    Jin, Yuling; Wang, Wang; Chai, Sanbao; Liu, Jie

    2015-01-01

    Hypoxic pulmonary hypertension (HPH), which is characterized by pulmonary arteriolar remodeling and right ventricular hypertrophy, is still a life-threatening disease with the current treatment strategies. The underlying molecular mechanisms of HPH remain unclear. Our previously published study showed that Wnt5a, one of the ligands in the Wnt family, was critically involved in the inhibition of hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin/cyclin D1 in vitro. In this study, we investigated the possible functions and mechanisms of Wnt5a in HPH in vivo. Recombinant mouse Wnt5a (rmWnt5a) or phosphate buffered saline (PBS) was administered to male C57/BL6 mice weekly from the first day to the end of the two or four weeks after exposed to hypoxia (10% O2). Hypoxia-induced pulmonary hypertension was associated with a marked increase in β-catenin/cyclin D1 expression in lungs. Right ventricular systolic pressure and right ventricular hypertrophy index were reduced in animals treated with rmWnt5a compared with PBS. Histology showed less pulmonary vascular remodeling and right ventricular hypertrophy in the group treated with rmWnt5a than with PBS. Treatment with rmWnt5a resulted in a concomitant reduction in β-catenin/cyclin D1 levels in lungs. These data demonstrate that Wnt5a exerts its beneficial effects on HPH by regulating pulmonary vascular remodeling and right ventricular hypertrophy in a manner that is associated with reduction in β-catenin/cyclin D1 signaling. A therapy targeting the β-catenin/cyclin D1 signaling pathway might be a potential strategy for HPH treatment. PMID:25956683

  6. Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice.

    PubMed

    Jin, Yuling; Wang, Wang; Chai, Sanbao; Liu, Jie; Yang, Ting; Wang, Jun

    2015-12-01

    Hypoxic pulmonary hypertension (HPH), which is characterized by pulmonary arteriolar remodeling and right ventricular hypertrophy, is still a life-threatening disease with the current treatment strategies. The underlying molecular mechanisms of HPH remain unclear. Our previously published study showed that Wnt5a, one of the ligands in the Wnt family, was critically involved in the inhibition of hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin/cyclin D1 in vitro. In this study, we investigated the possible functions and mechanisms of Wnt5a in HPH in vivo. Recombinant mouse Wnt5a (rmWnt5a) or phosphate buffered saline (PBS) was administered to male C57/BL6 mice weekly from the first day to the end of the two or four weeks after exposed to hypoxia (10% O2). Hypoxia-induced pulmonary hypertension was associated with a marked increase in β-catenin/cyclin D1 expression in lungs. Right ventricular systolic pressure and right ventricular hypertrophy index were reduced in animals treated with rmWnt5a compared with PBS. Histology showed less pulmonary vascular remodeling and right ventricular hypertrophy in the group treated with rmWnt5a than with PBS. Treatment with rmWnt5a resulted in a concomitant reduction in β-catenin/cyclin D1 levels in lungs. These data demonstrate that Wnt5a exerts its beneficial effects on HPH by regulating pulmonary vascular remodeling and right ventricular hypertrophy in a manner that is associated with reduction in β-catenin/cyclin D1 signaling. A therapy targeting the β-catenin/cyclin D1 signaling pathway might be a potential strategy for HPH treatment.

  7. Glucose metabolism and cardiac hypertrophy

    PubMed Central

    Kolwicz, Stephen C.; Tian, Rong

    2011-01-01

    The most notable change in the metabolic profile of hypertrophied hearts is an increased reliance on glucose with an overall reduced oxidative metabolism, i.e. a reappearance of the foetal metabolic pattern. In animal models, this change is attributed to the down-regulation of the transcriptional cascades promoting gene expression for fatty acid oxidation and mitochondrial oxidative phosphorylation in adult hearts. Impaired myocardial energetics in cardiac hypertrophy also triggers AMP-activated protein kinase (AMPK), leading to increased glucose uptake and glycolysis. Aside from increased reliance on glucose as an energy source, changes in other glucose metabolism pathways, e.g. the pentose phosphate pathway, the glucosamine biosynthesis pathway, and anaplerosis, are also noted in the hypertrophied hearts. Studies using transgenic mouse models and pharmacological compounds to mimic or counter the switch of substrate preference in cardiac hypertrophy have demonstrated that increased glucose metabolism in adult heart is not harmful and can be beneficial when it provides sufficient fuel for oxidative metabolism. However, improvement in the oxidative capacity and efficiency rather than the selection of the substrate is likely the ultimate goal for metabolic therapies. PMID:21502371

  8. Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy.

    PubMed

    Bruns, Danielle R; Buttrick, Peter M; Walker, Lori A

    2016-03-15

    Interleukin-18 (IL-18), a proinflammatory cytokine, has been implicated in pathologic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies have been conflicting. The purpose of these experiments was to determine whether genetic ablation of IL-18 would protect mice against hypobaric hypoxia (HH)-induced right ventricular (RV) hypertrophy, a condition in which chamber-specific inflammation is prominent. We hypothesized that IL-18 knockout (KO) mice would be protected while wild-type (WT) mice would demonstrate RV hypertrophy in response to HH exposure. KO and WT mice were exposed to HH for 7 wk, and control mice were exposed to normoxic ambient air. Following echocardiography, the RV was dissected and flash-frozen for biochemical analyses. HH exposure increased IL-18 mRNA (P = 0.08) in RV from WT mice. Genetic ablation of IL-18 mildly attenuated RV hypertrophy as assessed by myocyte size. However, IL-18 KO mice were not protected against HH-induced organ-level remodeling, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared with normoxic KO mice. These RV changes were similar to those seen in HH-exposed WT mice. Compensatory upregulation of other proinflammatory cytokines IL-2 and stromal cell-derived factor-1 was seen in the HH-KO animals, suggesting that activation of parallel inflammatory pathways might mitigate the effect of IL-18 KO. These data suggest targeted blockade of IL-18 alone is not a viable therapeutic strategy in this model.

  9. The role of autophagy in cardiac hypertrophy.

    PubMed

    Li, Lanfang; Xu, Jin; He, Lu; Peng, Lijun; Zhong, Qiaoqing; Chen, Linxi; Jiang, Zhisheng

    2016-06-01

    Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy. PMID:27084518

  10. Regression of altitude-produced cardiac hypertrophy.

    NASA Technical Reports Server (NTRS)

    Sizemore, D. A.; Mcintyre, T. W.; Van Liere, E. J.; Wilson , M. F.

    1973-01-01

    The rate of regression of cardiac hypertrophy with time has been determined in adult male albino rats. The hypertrophy was induced by intermittent exposure to simulated high altitude. The percentage hypertrophy was much greater (46%) in the right ventricle than in the left (16%). The regression could be adequately fitted to a single exponential function with a half-time of 6.73 plus or minus 0.71 days (90% CI). There was no significant difference in the rates of regression for the two ventricles.

  11. Tripartite motif 32 prevents pathological cardiac hypertrophy

    PubMed Central

    Huang, Jia; Ji, Yanxiao; Zhang, Xiaojing; Wang, Pixiao; Deng, Keqiong; Jiang, Xi; Ma, Genshan

    2016-01-01

    TRIM32 (tripartite motif 32) is widely accepted to be an E3 ligase that interacts with and eventually ubiquitylates multiple substrates. TRIM32 mutants have been associated with LGMD-2H (limb girdle muscular dystrophy 2H). However, whether TRIM32 is involved in cardiac hypertrophy induced by biomechanical stresses and neurohumoral mediators remains unclear. We generated mice and isolated NRCMs (neonatal rat cardiomyocytes) that overexpressed or were deficient in TRIM32 to investigate the effect of TRIM32 on AB (aortic banding) or AngII (angiotensin II)-mediated cardiac hypertrophy. Echocardiography and both pathological and molecular analyses were used to determine the extent of cardiac hypertrophy and subsequent fibrosis. Our results showed that overexpression of TRIM32 in the heart significantly alleviated the hypertrophic response induced by pressure overload, whereas TRIM32 deficiency dramatically aggravated pathological cardiac remodelling. Similar results were also found in cultured NRCMs incubated with AngII. Mechanistically, the present study suggests that TRIM32 exerts cardioprotective action by interruption of Akt- but not MAPK (mitogen-dependent protein kinase)-dependent signalling pathways. Additionally, inactivation of Akt by LY294002 offset the exacerbated hypertrophic response induced by AB in TRIM32-deficient mice. In conclusion, the present study indicates that TRIM32 plays a protective role in AB-induced pathological cardiac remodelling by blocking Akt-dependent signalling. Therefore TRIM32 could be a novel therapeutic target for the prevention of cardiac hypertrophy and heart failure. PMID:26884348

  12. Hyperplasia and hypertrophy of pulmonary neuroepithelial bodies, presumed airway hypoxia sensors, in hypoxia-inducible factor prolyl hydroxylase-deficient mice

    PubMed Central

    Pan, Jie; Bishop, Tammie; Ratcliffe, Peter J; Yeger, Herman; Cutz, Ernest

    2016-01-01

    Pulmonary neuroepithelial bodies (NEBs), presumed polymodal airway sensors, consist of innervated clusters of amine (serotonin) and peptide-producing cells. While NEB responses to acute hypoxia are mediated by a membrane-bound O2 sensor complex, responses to sustained and/or chronic hypoxia involve a prolyl hydroxylase (PHD)–hypoxia-inducible factor-dependent mechanism. We have previously reported hyperplasia of NEBs in the lungs of Phd1−/− mice associated with enhanced serotonin secretion. Here we use a novel multilabel immunofluorescence method to assess NEB distribution, frequency, and size, together with the number and size of NEB cell nuclei, and to colocalize multiple cytoplasmic and nuclear epitopes in the lungs of Phd1−/−, Phd2+/−, and Phd3−/− mice and compare them with wild-type controls. To define the mechanisms of NEB cell hyperplasia, we used antibodies against Mash1 and Prox1 (neurogenic genes involved in NEB cell differentiation/maturation), hypoxia-inducible factor-1alpha, and the cell proliferation marker Ki67. Morphometric analysis of (% total lung area) immunostaining for synaptophysin (% synaptophysin), a cytoplasmic marker of NEB cells, was significantly increased in Phd1−/− and Phd3−/− mice compared to wild-type mice. In addition, NEB size and the number and size of NEB nuclei were also significantly increased, indicating that deficiency of Phds is associated with striking hyperplasia and hypertrophy of NEBs. In Phd2+/− mice, while mean % synaptophysin was comparable to wild-type controls, the NEB size was moderately increased, suggesting an effect even in heterozygotes. NEBs in all Phd-deficient mice showed increased expression of Mash1, Prox1, Ki67, and hypoxia-inducible factor-1alpha, in keeping with enhanced differentiation from precursor cells and a minor component of cell proliferation. Since the loss of PHD activity mimics chronic hypoxia, our data provide critical information on the potential role of PHDs in

  13. Exercise Attenuates Intermittent Hypoxia-Induced Cardiac Fibrosis Associated with Sodium-Hydrogen Exchanger-1 in Rats

    PubMed Central

    Chen, Tsung-I; Tu, Wei-Chia

    2016-01-01

    Purpose: To investigate the role of sodium–hydrogen exchanger-1 (NHE-1) and exercise training on intermittent hypoxia-induced cardiac fibrosis in obstructive sleep apnea (OSA), using an animal model mimicking the intermittent hypoxia of OSA. Methods: Eight-week-old male Sprague–Dawley rats were randomly assigned to control (CON), intermittent hypoxia (IH), exercise (EXE), or IH combined with exercise (IHEXE) groups. These groups were randomly assigned to subgroups receiving either a vehicle or the NHE-1 inhibitor cariporide. The EXE and IHEXE rats underwent exercise training on an animal treadmill for 10 weeks (5 days/week, 60 min/day, 24–30 m/min, 2–10% grade). The IH and IHEXE rats were exposed to 14 days of IH (30 s of hypoxia—nadir of 2–6% O2—followed by 45 s of normoxia) for 8 h/day. At the end of 10 weeks, rats were sacrificed and then hearts were removed to determine the myocardial levels of fibrosis index, oxidative stress, antioxidant capacity, and NHE-1 activation. Results: Compared to the CON rats, IH induced higher cardiac fibrosis, lower myocardial catalase, and superoxidative dismutase activities, higher myocardial lipid and protein peroxidation and higher NHE-1 activation (p < 0.05 for each), which were all abolished by cariporide. Compared to the IH rats, lower cardiac fibrosis, higher myocardial antioxidant capacity, lower myocardial lipid, and protein peroxidation and lower NHE-1 activation were found in the IHEXE rats (p < 0.05 for each). Conclusion: IH-induced cardiac fibrosis was associated with NHE-1 hyperactivity. However, exercise training and cariporide exerted an inhibitory effect to prevent myocardial NHE-1 hyperactivity, which contributed to reduced IH-induced cardiac fibrosis. Therefore, NHE-1 plays a critical role in the effect of exercise on IH-induced increased cardiac fibrosis. PMID:27790155

  14. Glucose Transporters in Cardiac Metabolism and Hypertrophy

    PubMed Central

    Shao, Dan; Tian, Rong

    2016-01-01

    The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. PMID:26756635

  15. Prenatal hypoxia induces increased cardiac contractility on a background of decreased capillary density

    PubMed Central

    Hauton, David; Ousley, Victoria

    2009-01-01

    Background Chronic hypoxia in utero (CHU) is one of the most common insults to fetal development and may be associated with poor cardiac recovery from ischaemia-reperfusion injury, yet the effects on normal cardiac mechanical performance are poorly understood. Methods Pregnant female wistar rats were exposed to hypoxia (12% oxygen, balance nitrogen) for days 10–20 of pregnancy. Pups were born into normal room air and weaned normally. At 10 weeks of age, hearts were excised under anaesthesia and underwent retrograde 'Langendorff' perfusion. Mechanical performance was measured at constant filling pressure (100 cm H2O) with intraventricular balloon. Left ventricular free wall was dissected away and capillary density estimated following alkaline phosphatase staining. Expression of SERCA2a and Nitric Oxide Synthases (NOS) proteins were estimated by immunoblotting. Results CHU significantly increased body mass (P < 0.001) compared with age-matched control rats but was without effect on relative cardiac mass. For incremental increases in left ventricular balloon volume, diastolic pressure was preserved. However, systolic pressure was significantly greater following CHU for balloon volume = 50 μl (P < 0.01) and up to 200 μl (P < 0.05). For higher balloon volumes systolic pressure was not significantly different from control. Developed pressures were correspondingly increased relative to controls for balloon volumes up to 250 μl (P < 0.05). Left ventricular free wall capillary density was significantly decreased in both epicardium (18%; P < 0.05) and endocardium (11%; P < 0.05) despite preserved coronary flow. Western blot analysis revealed no change to the expression of SERCA2a or nNOS but immuno-detectable eNOS protein was significantly decreased (P < 0.001) in cardiac tissue following chronic hypoxia in utero. Conclusion These data offer potential mechanisms for poor recovery following ischaemia, including decreased coronary flow reserve and impaired angiogenesis

  16. Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

    PubMed Central

    Boguslavskyi, Andrii; Pavlovic, Davor; Aughton, Karen; Clark, James E.; Howie, Jacqueline; Fuller, William; Shattock, Michael J.

    2014-01-01

    Aims Elevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force–frequency relationship, and arrhythmias. Although phospholemman (PLM) is recognized to form the link between signalling pathways and Na/K pump activity, the possibility that defects in its regulation contribute to elevation of intracellular Na has not been investigated. Our aim was to test the hypothesis that the prevention of PLM phosphorylation in a PLM3SA knock-in mouse (in which PLM has been rendered unphosphorylatable) will exacerbate cardiac hypertrophy and cellular Na overload. Testing this hypothesis should determine whether changes in PLM phosphorylation are simply bystander effects or are causally involved in disease progression. Methods and results In wild-type (WT) mice, aortic constriction resulted in hypophosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3 days post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na]i. Echocardiography, morphometry, and pressure-volume (PV) catheterization confirmed remodelling, dilation, and contractile dysfunction, respectively. In PLM3SA mice, expression of Na/K ATPase was increased and PLM decreased such that net Na/K pump current under quiescent conditions was unchanged (cf. WT myocytes); [Na+]i was increased and forward-mode Na/Ca exchanger was reduced in paced PLM3SA myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM3SA mice compared with banded WT. Conclusions Decreased phosphorylation of PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction, and adverse remodelling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure. PMID:25103111

  17. Raf-mediated cardiac hypertrophy in adult Drosophila

    PubMed Central

    Yu, Lin; Daniels, Joseph; Glaser, Alex E.; Wolf, Matthew J.

    2013-01-01

    SUMMARY In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK) signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFRA887T, Ras85DV12 and Ras85DV12S35, which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr) RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERKD334N, which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for

  18. Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy

    PubMed Central

    Li, Ran; Bai, Jian; Ding, Liang; Gu, Rong; Wang, Lian; Xu, Biao

    2016-01-01

    Pathological cardiomyocyte hypertrophy is associated with significantly increased risk of heart failure, one of the leading medical causes of mortality worldwide. MicroRNAs are known to be involved in pathological cardiac remodeling. However, whether miR-99a participates in the signaling cascade leading to cardiac hypertrophy is unknown. To evaluate the role of miR-99a in cardiac hypertrophy, we assessed the expression of miR-99a in hypertrophic cardiomyocytes induced by isoprenaline (ISO)/angiotensin-II (Ang II) and in mice model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Expression of miR-99a was evaluated in these hypertrophic cells and hearts. We also found that miR-99a expression was highly correlated with cardiac function of mice with heart failure (8 weeks after TAC surgery). Overexpression of miR-99a attenuated cardiac hypertrophy in TAC mice and cellular hypertrophy in stimuli treated cardiomyocytes through down-regulation of expression of mammalian target of rapamycin (mTOR). These results indicate that miR-99a negatively regulates physiological hypertrophy through mTOR signaling pathway, which may provide a new therapeutic approach for pressure-overload heart failure. PMID:26914935

  19. Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy

    PubMed Central

    Fang, Xi; Stroud, Matthew J.; Ouyang, Kunfu; Fang, Li; Zhang, Jianlin; Dalton, Nancy D.; Gu, Yusu; Wu, Tongbin; Peterson, Kirk L.; Huang, Hsien-Da; Wang, Nanping

    2016-01-01

    Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ. However, candidate cell types responsible for RSG-induced cardiomyocyte hypertrophy remain unexplored. Utilizing cocultures of adipocytes and cardiomyocytes, we found that stimulation of PPARγ signaling in adipocytes increased miR-200a expression and secretion. Delivery of miR-200a in adipocyte-derived exosomes to cardiomyocytes resulted in decreased TSC1 and subsequent mTOR activation, leading to cardiomyocyte hypertrophy. Treatment with an antagomir to miR-200a blunted this hypertrophic response in cardiomyocytes. In vivo, specific ablation of PPARγ in adipocytes was sufficient to blunt hypertrophy induced by RSG treatment. By delineating mechanisms by which RSG elicits cardiac hypertrophy, we have identified pathways that mediate the crosstalk between adipocytes and cardiomyocytes to regulate cardiac remodeling. PMID:27734035

  20. Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II.

    PubMed

    Peng, Kesong; Tian, Xinqiao; Qian, Yuanyuan; Skibba, Melissa; Zou, Chunpeng; Liu, Zhiguo; Wang, Jingying; Xu, Zheng; Li, Xiaokun; Liang, Guang

    2016-03-01

    Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)-induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal-regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II-induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II-induced EGFR activation is mediated by c-Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c-Src-dependent EGFR activation may play an important role in Ang II-induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II-associated cardiac diseases. PMID:26762600

  1. Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis

    PubMed Central

    Samak, Mostafa; Fatullayev, Javid; Sabashnikov, Anton; Zeriouh, Mohamed; Schmack, Bastian; Farag, Mina; Popov, Aron-Frederik; Dohmen, Pascal M.; Choi, Yeong-Hoon; Wahlers, Thorsten; Weymann, Alexander

    2016-01-01

    Ventricular hypertrophy is an ominous escalation of hemodynamically stressful conditions such as hypertension and valve disease. The pathophysiology of hypertrophy is complex and multifactorial, as it touches on several cellular and molecular systems. Understanding the molecular background of cardiac hypertrophy is essential in order to protect the myocardium from pathological remodeling, or slow down the destined progression to heart failure. In this review we highlight the most important molecular aspects of cardiac hypertrophic growth in light of the currently available published research data. PMID:27450399

  2. Shensongyangxin protects against pressure overload‑induced cardiac hypertrophy.

    PubMed

    Shen, Di-Fei; Wu, Qing-Qing; Ni, Jian; Deng, Wei; Wei, Cong; Jia, Zhen-Hua; Zhou, Heng; Zhou, Meng-Qiao; Bian, Zhou-Yan; Tang, Qi-Zhu

    2016-01-01

    Shensongyangxin (SSYX) is a medicinal herb, which has long been used in traditional Chinese medicine. Various pharmacological activities of SSYX have been identified. However, the role of SSYX in cardiac hypertrophy remains to be fully elucidated. In present study, aortic banding (AB) was performed to induce cardiac hypertrophy in mice. SSYX (520 mg/kg) was administered by daily gavage between 1 and 8 weeks following surgery. The extent of cardiac hypertrophy was then evaluated by pathological and molecular analyses of heart tissue samples. In addition, in vitro experiments were performed to confirm the in vivo results. The data of the present study demonstrated that SSYX prevented the cardiac hypertrophy and fibrosis induced by AB, as assessed by measurements of heart weight and gross heart size, hematoxylin and eosin staining, cross‑sectional cardiomyocyte area and the mRNA expression levels of hypertrophic markers. SSYX also inhibited collagen deposition and suppressed the expression of transforming growth factor β (TGFβ), connective tissue growth factor, fibronectin, collagen Ⅰα and collagen Ⅲα, which was mediated by the inhibition of the TGFβ/small mothers against decapentaplegic (Smad) signaling pathway. The inhibitory action of SSYX on cardiac hypertrophy was mediated by the inhibition of Akt signaling. In vitro investigations in the rat H9c2 cardiac cells also demonstrated that SSYX attenuated angiotensin II‑induced cardiomyocyte hypertrophy. These findings suggested that SSYX attenuated cardiac hypertrophy and fibrosis in the pressure overloaded mouse heart. Therefore, the cardioprotective effect of SSYX is associated with inhibition of the Akt and TGFβ/Smad signaling pathways. PMID:26648261

  3. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension in broilers.

    PubMed

    Yang, Y; Zhang, B K; Liu, D; Nie, W; Yuan, J M; Wang, Z; Guo, Y M

    2012-01-01

    1. The aim of the study was to determine if H(2)S is involved in the development of hypoxia-induced pulmonary hypertension in broilers, a condition frequently observed in a variety of cardiac and pulmonary diseases. 2. Two-week-old broilers were reared under normoxic conditions or exposed to normobaric hypoxia (6 h/day) with tissue levels of H(2)S adjusted by administering sodium hydrosulfide (NaHS, 10 µmol/kg body weight/day). Mean pulmonary arterial pressure, right ventricular mass, plasma and tissue H(2)S levels, the expression of cystathionine-β-synthase (CSE) and vascular remodeling were determined at 35 d of age. 3. Exposure to hypoxia-induced pulmonary arterial hypertension was characterized by elevated pulmonary pressure, right ventricular hypertrophy and vascular remodeling. This was accompanied by decreased expression of CSE and decreased concentrations of plasma and tissue H(2)S. 4. Hypoxia-induced pulmonary hypertension was significantly reduced by administration of NaHS but this protective effect was largely abolished by D, L-propargylglycerine, an inhibitor of CSE. 5. The results indicate that H(2)S is involved in the development of hypoxia-induced pulmonary hypertension. Supplementing NaHS or H(2)S could be a strategy for reducing hypoxia-induced hypertension in broilers.

  4. The transcription factor GATA-6 regulates pathological cardiac hypertrophy

    PubMed Central

    van Berlo, Jop H.; Elrod, John W.; van den Hoogenhof, Maarten M.G.; York, Allen J.; Aronow, Bruce J.; Duncan, Stephen A.; Molkentin, Jeffery D.

    2010-01-01

    Rationale The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown. Objective To determine the role of GATA-6 in cardiac hypertrophy and homeostasis. Methods and Results Here we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, while deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with greater than 95% loss of GATA-6 protein in the heart. These later mice were subjected to pressure overload induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure while control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes. Conclusions These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4. PMID:20705924

  5. Investigating the Mechanism of Hyperglycemia-Induced Fetal Cardiac Hypertrophy.

    PubMed

    Han, Sha-sha; Wang, Guang; Jin, Ya; Ma, Zheng-lai; Jia, Wei-jing; Wu, Xia; Wang, Xiao-yu; He, Mei-yao; Cheng, Xin; Li, Wei-jing; Yang, Xuesong; Liu, Guo-sheng

    2015-01-01

    Hyperglycemia in diabetic mothers enhances the risk of fetal cardiac hypertrophy during gestation. However, the mechanism of high-glucose-induced cardiac hypertrophy is not largely understood. In this study, we first demonstrated that the incidence rate of cardiac hypertrophy dramatically increased in fetuses of diabetic mothers using color ultrasound examination. In addition, human fetal cardiac hypertrophy was successfully mimicked in a streptozotocin (STZ)-induced diabetes mouse model, in which mouse cardiac hypertrophy was diagnosed using type-M ultrasound and a histological assay. PH3 immunofluorescent staining of mouse fetal hearts and in vitro-cultured H9c2 cells indicated that cell proliferation decreased in E18.5, E15.5 and E13.5 mice, and cell apoptosis in H9c2 cells increased in the presence of high glucose in a dose-dependent manner. Next, we found that the individual cardiomyocyte size increased in pre-gestational diabetes mellitus mice and in response to high glucose exposure. Meanwhile, the expression of β-MHC and BMP-10 was up-regulated. Nkx2.5 immunofluorescent staining showed that the expression of Nkx2.5, a crucial cardiac transcription factor, was suppressed in the ventricular septum, left ventricular wall and right ventricular wall of E18.5, E15.5 and E13.5 mouse hearts. However, cardiac hypertrophy did not morphologically occur in E13.5 mouse hearts. In cultured H9c2 cells exposed to high glucose, Nkx2.5 expression decreased, as detected by both immunostaining and western blotting, and the expression of KCNE1 and Cx43 was also restricted. Taken together, alterations in cell size rather than cell proliferation or apoptosis are responsible for hyperglycemia-induced fetal cardiac hypertrophy. The aberrant expression of Nkx2.5 and its regulatory target genes in the presence of high glucose could be a principal component of pathogenesis in the development of fetal cardiac hypertrophy. PMID:26418041

  6. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress.

    PubMed

    Ma, Yuedong; Huang, Huiling; Jiang, Jingzhou; Wu, Lingling; Lin, Chunxi; Tang, Anli; Dai, Gang; He, Jiangui; Chen, Yili

    2016-06-10

    AVE 0991, the nonpeptide angiotensin-(1-7) (Ang-(1-7)) analog, is recognized as having beneficial cardiovascular effects. However, the mechanisms have not been fully elucidated. This study was designed to investigate the effects of AVE 0991 on cardiac hypertrophy and the mechanisms involved. Mice were underwent aortic banding to induce cardiac hypertrophy followed by the administration of AVE 0991 (20 mg kg·day (-1)) for 4 weeks. It was shown that AVE 0991 reduced left ventricular hypertrophy and improved heart function, characterized by decreases in left ventricular weight and left ventricular end-diastolic diameter, and increases in ejection fraction. Moreover, AVE 0991 significantly down-regulated mean myocyte diameter and attenuate the gene expression of the hypertrophic markers. Furthermore, AVE 0991 inhibited the expression of NOX 2 and NOX 4, meaning that AVE 0991 reduced oxidative stress of cardiac hypertrophy mice. Our data showed that AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress. PMID:26403967

  7. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy.

    PubMed

    Pirompol, Prapawadee; Teekabut, Vassana; Weerachatyanukul, Wattana; Bupha-Intr, Tepmanas; Wattanapermpool, Jonggonnee

    2016-04-01

    Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports on cardiac sudden death. Although physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supra-physiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In this study, dose- and time-dependent effects of high-testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into four groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both percentage heart:body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-week-treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-week testosterone-treated groups, as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-week testosterone-treated group, eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness, but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependent but is rather relied on the factor of exposure to duration in inducing maladaptive responses of the heart. PMID:26850730

  8. Cardiomyocyte specific deletion of PP2A causes cardiac hypertrophy

    PubMed Central

    Li, Lei; Fang, Chao; Xu, Di; Xu, Yidan; Fu, Heling; Li, Jianmin

    2016-01-01

    Cardiac hypertrophy is a common pathological alteration in heart disease, which has been reported to be connected with serine/threonine protein phosphatases that control the dephosphorylation of a variety of cardiac proteins. Herein, we generated protein phosphatase type 2A knockout expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer) under the control of the a-myosin heavy chain promoter. Cardiac function of mice was determined by echocardiography. Decrease in PP2A activity leads to increased cardiomyocyte hypertrophy and fibrosis. Loss of PP2ACα leads to the heart failure, including the changes of EF, FS, LV, ANP and BNP. On the molecular level, knockout mice shows increased expression of B55a and B56e at 60 days after tamoxifen injection. Additionally, the regulation of the Akt/GSK3β/β-catenin pathway is severely disturbed in knockout mice. In conclusion, cardiomyocyte specific deletion of PP2A gene causes the cardiac hypertrophy. We will use the knockout mice to generate a type of cardiomyocyte hypertrophy mouse model with myocardial fibrosis. PMID:27186301

  9. Dance band on the Titanic: biomechanical signaling in cardiac hypertrophy.

    PubMed

    Sussman, Mark A; McCulloch, Andrew; Borg, Thomas K

    2002-11-15

    Biomechanical signaling is a complex interaction of both intracellular and extracellular components. Both passive and active components are involved in the extracellular environment to signal through specific receptors to multiple signaling pathways. This review provides an overview of extracellular matrix, specific receptors, and signaling pathways for biomechanical stimulation in cardiac hypertrophy.

  10. Genistein prevents isoproterenol-induced cardiac hypertrophy in rats.

    PubMed

    Maulik, Subir Kumar; Prabhakar, Pankaj; Dinda, Amit Kumar; Seth, Sandeep

    2012-08-01

    Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150-200 g, 10-12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)(-1)) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg(-1), subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities. PMID:22808991

  11. Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats...

  12. Protein kinase cascades in the regulation of cardiac hypertrophy

    PubMed Central

    Dorn, Gerald W.; Force, Thomas

    2005-01-01

    In broad terms, there are 3 types of cardiac hypertrophy: normal growth, growth induced by physical conditioning (i.e., physiologic hypertrophy), and growth induced by pathologic stimuli. Recent evidence suggests that normal and exercise-induced cardiac growth are regulated in large part by the growth hormone/IGF axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive cardiac growth is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phospholipase C pathway, leading to an increase in cytosolic calcium and activation of PKC. Here we review recent developments in the area of these cardiotrophic kinases, highlighting the utility of animal models that are helping to identify molecular targets in the human condition. PMID:15765134

  13. Cytoskeletal mechanics in pressure-overload cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Tagawa, H.; Wang, N.; Narishige, T.; Ingber, D. E.; Zile, M. R.; Cooper, G. 4th

    1997-01-01

    We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on

  14. Speckle Tracking Based Strain Analysis Is Sensitive for Early Detection of Pathological Cardiac Hypertrophy

    PubMed Central

    An, Xiangbo; Wang, Jingjing; Li, Hao; Lu, Zhizhen; Bai, Yan; Xiao, Han; Zhang, Youyi; Song, Yao

    2016-01-01

    Cardiac hypertrophy is a key pathological process of many cardiac diseases. However, early detection of cardiac hypertrophy is difficult by the currently used non-invasive method and new approaches are in urgent need for efficient diagnosis of cardiac malfunction. Here we report that speckle tracking-based strain analysis is more sensitive than conventional echocardiography for early detection of pathological cardiac hypertrophy in the isoproterenol (ISO) mouse model. Pathological hypertrophy was induced by a single subcutaneous injection of ISO. Physiological cardiac hypertrophy was established by daily treadmill exercise for six weeks. Strain analysis, including radial strain (RS), radial strain rate (RSR) and longitudinal strain (LS), showed marked decrease as early as 3 days after ISO injection. Moreover, unlike the regional changes in cardiac infarction, strain analysis revealed global cardiac dysfunction that affects the entire heart in ISO-induced hypertrophy. In contrast, conventional echocardiography, only detected altered E/E’, an index reflecting cardiac diastolic function, at 7 days after ISO injection. No change was detected on fractional shortening (FS), E/A and E’/A’ at 3 days or 7 days after ISO injection. Interestingly, strain analysis revealed cardiac dysfunction only in ISO-induced pathological hypertrophy but not the physiological hypertrophy induced by exercise. Taken together, our study indicates that strain analysis offers a more sensitive approach for early detection of cardiac dysfunction than conventional echocardiography. Moreover, multiple strain readouts distinguish pathological cardiac hypertrophy from physiological hypertrophy. PMID:26871457

  15. Speckle Tracking Based Strain Analysis Is Sensitive for Early Detection of Pathological Cardiac Hypertrophy.

    PubMed

    An, Xiangbo; Wang, Jingjing; Li, Hao; Lu, Zhizhen; Bai, Yan; Xiao, Han; Zhang, Youyi; Song, Yao

    2016-01-01

    Cardiac hypertrophy is a key pathological process of many cardiac diseases. However, early detection of cardiac hypertrophy is difficult by the currently used non-invasive method and new approaches are in urgent need for efficient diagnosis of cardiac malfunction. Here we report that speckle tracking-based strain analysis is more sensitive than conventional echocardiography for early detection of pathological cardiac hypertrophy in the isoproterenol (ISO) mouse model. Pathological hypertrophy was induced by a single subcutaneous injection of ISO. Physiological cardiac hypertrophy was established by daily treadmill exercise for six weeks. Strain analysis, including radial strain (RS), radial strain rate (RSR) and longitudinal strain (LS), showed marked decrease as early as 3 days after ISO injection. Moreover, unlike the regional changes in cardiac infarction, strain analysis revealed global cardiac dysfunction that affects the entire heart in ISO-induced hypertrophy. In contrast, conventional echocardiography, only detected altered E/E', an index reflecting cardiac diastolic function, at 7 days after ISO injection. No change was detected on fractional shortening (FS), E/A and E'/A' at 3 days or 7 days after ISO injection. Interestingly, strain analysis revealed cardiac dysfunction only in ISO-induced pathological hypertrophy but not the physiological hypertrophy induced by exercise. Taken together, our study indicates that strain analysis offers a more sensitive approach for early detection of cardiac dysfunction than conventional echocardiography. Moreover, multiple strain readouts distinguish pathological cardiac hypertrophy from physiological hypertrophy.

  16. Resistance training and cardiac hypertrophy: unravelling the training effect.

    PubMed

    Haykowsky, Mark J; Dressendorfer, Rudolph; Taylor, Dylan; Mandic, Sandra; Humen, Dennis

    2002-01-01

    Resistance training (RT) is a popular method of conditioning to enhance sport performance as well as an effective form of exercise to attenuate the age-mediated decline in muscle strength and mass. Although the benefits of RT on skeletal muscle morphology and function are well established, its effect on left ventricular (LV) morphology remains equivocal. Some investigations have found that RT is associated with an obligatory increase in LV wall thickness and mass with minimal alteration in LV internal cavity dimension, an effect called concentric hypertrophy. However, others report that short- (<5 years) to long-term (>18 years) RT does not alter LV morphology, arguing that concentric hypertrophy is not an obligatory adaptation secondary to this form of exertion. This disparity between studies on whether RT consistently results in cardiac hypertrophy could be caused by: (i) acute cardiopulmonary mechanisms that minimise the increase in transmural pressure (i.e. ventricular pressure minus intrathoracic pressure) and LV wall stress during exercise; (ii) the underlying use of anabolic steroids by the athletes; or (iii) the specific type of RT performed. We propose that when LV geometry is altered after RT, the pattern is usually concentric hypertrophy in Olympic weightlifters. However, the pattern of eccentric hypertrophy (increased LV mass secondary to an increase in diastolic internal cavity dimension and wall thickness) is not uncommon in bodybuilders. Of particular interest, nearly 40% of all RT athletes have normal LV geometry, and these athletes are typically powerlifters. RT athletes who use anabolic steroids have been shown to have significantly higher LV mass compared with drug-free sport-matched athletes. This brief review will sort out some of the factors that may affect the acute and chronic outcome of RT on LV morphology. In addition, a conceptual framework is offered to help explain why cardiac hypertrophy is not always found in RT athletes. PMID

  17. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  18. Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3β phosphorylation.

    PubMed

    Liu, Ningning; Chai, Renjie; Liu, Bin; Zhang, Zhenhui; Zhang, Shuangwei; Zhang, Jingzhi; Liao, Yuning; Cai, Jianyu; Xia, Xiaohong; Li, Aiqun; Liu, Jinbao; Huang, Hongbiao; Liu, Shiming

    2016-09-23

    Cardiac hypertrophy, a compensatory response to various stimuli in the heart, independently predicts cardiovascular ailments and related deaths. Increasing evidence indicates ubiquitin-proteasome signaling contributes to cardiac hypertrophy regulation. Here, we identified ubiquitin-specific protease 14 (USP14), a 19S proteasome associated deubiquitinase (DUB), as a novel target for cardiac hypertrophy therapy via inhibition of the GSK-3β pathway. Indeed, USP14 expression was increased in an animal model of abdominal aorta constriction. In an angiotensin II (AngII) induced primary neonatal rat cardiomyocyte hypertrophy model, USP14 expression was increased in a time-dependent manner, and reduced USP14 deubiquitinase activity or USP14 knockdown resulted in lower expression levels of the myocardial hypertrophy specific marker β-MHC, and subsequent decreased GSK-3β phosphorylation. In conclusion, USP14 mediates the development of cardiac hypertrophy by promoting GSK-3β phosphorylation, suggesting that USP14 might represent a novel therapeutic target for cardiac hypertrophy treatment.

  19. Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway

    PubMed Central

    Yang, Hao; Luo, Fangbo; Chen, Lihong; Cai, Huawei; Li, Yajiao; You, Guiying; Long, Dan; Li, Shengfu; Zhang, Qiuping; Rao, Li

    2016-01-01

    Aims Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. Methods and Results In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Conclusions Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials. PMID:27438013

  20. HIF-1α and PPARγ during physiological cardiac hypertrophy induced by pregnancy: Transcriptional activities and effects on target genes.

    PubMed

    Soñanez-Organis, José G; Godoy-Lugo, José A; Hernández-Palomares, Magally L E; Rodríguez-Martínez, Daniel; Rosas-Rodríguez, Jesús A; González-Ochoa, Guadalupe; Virgen-Ortiz, Adolfo; Ortiz, Rudy M

    2016-10-15

    Hypoxia inducible factor 1-α (HIF-1α) and peroxisome proliferator-activated receptor γ (PPARγ) are transcription factors that activate genes involved in cellular metabolism. Physiological cardiac hypertrophy induced by pregnancy initiates compensatory changes in metabolism. However, the contributions of HIF-1α and PPARγ to this physiological status and to its reversible, metabolic process (postpartum) in the heart are not well-defined. Therefore, the aim of the present study was to evaluate the transcriptional activities of HIF-1α and PPARγ in the left ventricle of rats before, during, and after pregnancy. Furthermore, the effects of pregnancy on target genes of glycolysis and glycerol-lipid biosynthesis, key regulatory enzymes, and metabolic intermediates were evaluated. The activities of HIF-1α and PPARγ increased 1.2- and 1.6-fold, respectively, during pregnancy, and decreased to basal levels during postpartum. Expressions of mRNA for glucose transport 1 (GLUT1), enzymes of glycolysis (HK2, PFKM, and GAPDH) and glycerol-lipid biosynthesis (GPAT and GPD1) increased 1.6- to 14-fold during pregnancy and returned to basal levels postpartum. The increase in GPD1 expression translated to an increase in its activity, but such was not the case for GAPDH suggesting that post-translational regulation of these proteins is differential during pregnancy. Glycolytic (glucose, lactate, and DHAP) and glycerol-lipid biosynthesis (G3P and FFA) intermediates increased with pregnancy and were maintained postpartum. The results demonstrate that pregnancy-induced, physiological cardiac hypertrophy activates the expression of genes involved in glycolytic and glycerol-lipid biosynthesis suggesting that the shift in cardiac metabolism is mediated by the activation of HIF-1α and PPARγ.

  1. The role of frataxin in doxorubicin-mediated cardiac hypertrophy.

    PubMed

    Mouli, Shravanthi; Nanayakkara, Gayani; AlAlasmari, Abdullah; Eldoumani, Haitham; Fu, Xiaoyu; Berlin, Avery; Lohani, Madhukar; Nie, Ben; Arnold, Robert D; Kavazis, Andreas; Smith, Forrest; Beyers, Ronald; Denney, Thomas; Dhanasekaran, Muralikrishnan; Zhong, Juming; Quindry, John; Amin, Rajesh

    2015-09-01

    Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy. PMID:26209053

  2. Ultrastructural features of degenerated cardiac muscle cells in patients with cardiac hypertrophy.

    PubMed Central

    Maron, B. J.; Ferrans, V. J.; Roberts, W. C.

    1975-01-01

    Degenerated cardiac muscle cells were present in hypertrophied ventricular muscle obtained at operation from 12 (38%) of 32 patients with asymmetric septal hypertrophy (hypertrophic cardiomyopathy) or aortic valvular disease. Degenerated cells demonstrated a wide variety of ultrastructural alterations. Mildly altered cells were normal-sized or hypertrophied and showed focal changes, including preferential loss of thick (myosin) filaments, streaming and clumping of Z band material, and proliferation of the tubules of sarcoplasmic reticulum. Moderately and severely degenerated cells were normal-sized or atrophic and showed additional changes, including extensive myofibrillar lysis and loss of T tubules. The appearance of the most severely degenerated cells usually reflected the cytoplasmic organelle (sarcoplasmic reticulum, glycogen, or mitochondria) which underwent proliferation and filled the myofibril-free areas of these cells. Moderately and severely degenerated cells were present in areas of fibrosis, had thickened basement membranes, and had lost their intercellular connections. These observations suggest that degenerated cardiac muscle cells have poor contractile function and may be responsible for impaired cardiac performance in some patients with chronic ventricular hypertrophy. Images Fig 1 Fig 2 Fig 3 Figs 4-6 Figs 7-8 Fig 9 Fig 10 Fig 11 Figs 12-15 Fig 16 Fig 17 Figs 18-21 Figs 22-23 Fig 24 Fig 25 Fig 26 Fig 27 Figs 28-29 Fig 30 Figs 31-32 Fig 33 PMID:124533

  3. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling.

    PubMed

    Gitau, Samuel Chege; Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Liang, Haihai; Qian, Ming; Lv, Lifang; Li, Tianshi; Xu, Bozhi; Wang, Zhiguo; Zhang, Yong; Xu, Chaoqian; Lu, Yanjie; Du, Zhiming; Shan, Hongli; Yang, Baofeng

    2015-12-01

    Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg(-1)·d(-1)); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L(-1)) was treated with the human equivalent of low (10 or 100 μmol·L(-1)) and high (1000 μmol·L(-1)) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin. PMID:26626190

  4. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling.

    PubMed

    Gitau, Samuel Chege; Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Liang, Haihai; Qian, Ming; Lv, Lifang; Li, Tianshi; Xu, Bozhi; Wang, Zhiguo; Zhang, Yong; Xu, Chaoqian; Lu, Yanjie; Du, Zhiming; Shan, Hongli; Yang, Baofeng

    2015-12-01

    Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg(-1)·d(-1)); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L(-1)) was treated with the human equivalent of low (10 or 100 μmol·L(-1)) and high (1000 μmol·L(-1)) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

  5. Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure.

    PubMed

    Heger, J; Schulz, R; Euler, G

    2016-01-01

    Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.

  6. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy.

    PubMed

    Shahid, Mohd; Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A; Leyton, Patricio A; Cheng, Juan; Tainsh, Robert E T; Mayeur, Claire; Rhee, David K; Wu, Mei X; Scherrer-Crosbie, Marielle; Buys, Emmanuel S; Zapol, Warren M; Bloch, Kenneth D; Bloch, Donald B

    2016-04-15

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

  7. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis.

    PubMed

    Taniguchi, Takuya; Maruyama, Naoki; Ogata, Takehiro; Kasahara, Takeru; Nakanishi, Naohiko; Miyagawa, Kotaro; Naito, Daisuke; Hamaoka, Tetsuro; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF-/-) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF-/- mice. PTRF-/- mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF-/- mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF-/- hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF-/- hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF-/- hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart. PMID:27612189

  8. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis

    PubMed Central

    Ogata, Takehiro; Kasahara, Takeru; Nakanishi, Naohiko; Miyagawa, Kotaro; Naito, Daisuke; Hamaoka, Tetsuro; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF−/−) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF−/− mice. PTRF−/− mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF−/− mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF−/− hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF−/− hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF−/− hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart. PMID:27612189

  9. Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

    PubMed Central

    Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

    2016-01-01

    Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

  10. Proteasome inhibitors attenuated cholesterol-induced cardiac hypertrophy in H9c2 cells.

    PubMed

    Lee, Hyunjung; Park, Jinyoung; Kim, Eunice EunKyeong; Yoo, Young Sook; Song, Eun Joo

    2016-05-01

    The Ubiquitin proteasome system (UPS) plays roles in protein degradation, cell cycle control, and growth and inflammatory cell signaling. Dysfunction of UPS in cardiac diseases has been seen in many studies. Cholesterol acts as an inducer of cardiac hypertrophy. In this study, the effect of proteasome inhibitors on the cholesterol-induced hypertrophic growth in H9c2 cells is examined in order to observe whether UPS is involved in cardiac hypertrophy. The treatment of proteasome inhibitors MG132 and Bortezomib markedly reduced cellular surface area and mRNA expression of β-MHC in cholesterol-induced cardiac hypertrophy. In addition, activated AKT and ERK were significantly attenuated by MG132 and Bortezomib in cholesterol- induced cardiac hypertrophy. We demonstrated that cholesterol- induced cardiac hypertrophy was suppressed by proteasome inhibitors. Thus, regulatory mechanism of cholesterol- induced cardiac hypertrophy by proteasome inhibitors may provide a new therapeutic strategy to prevent the progression of heart failure. [BMB Reports 2016; 49(5): 270-275]. PMID:26592933

  11. Proteasome inhibitors attenuated cholesterol-induced cardiac hypertrophy in H9c2 cells

    PubMed Central

    Lee, Hyunjung; Park, Jinyoung; Kim, Eunice EunKyeong; Yoo, Young Sook; Song, Eun Joo

    2016-01-01

    The Ubiquitin proteasome system (UPS) plays roles in protein degradation, cell cycle control, and growth and inflammatory cell signaling. Dysfunction of UPS in cardiac diseases has been seen in many studies. Cholesterol acts as an inducer of cardiac hypertrophy. In this study, the effect of proteasome inhibitors on the cholesterol-induced hypertrophic growth in H9c2 cells is examined in order to observe whether UPS is involved in cardiac hypertrophy. The treatment of proteasome inhibitors MG132 and Bortezomib markedly reduced cellular surface area and mRNA expression of β-MHC in cholesterol-induced cardiac hypertrophy. In addition, activated AKT and ERK were significantly attenuated by MG132 and Bortezomib in cholesterol-induced cardiac hypertrophy. We demonstrated that cholesterol-induced cardiac hypertrophy was suppressed by proteasome inhibitors. Thus, regulatory mechanism of cholesterol-induced cardiac hypertrophy by proteasome inhibitors may provide a new therapeutic strategy to prevent the progression of heart failure. [BMB Reports 2016; 49(5): 270-275] PMID:26592933

  12. Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy

    PubMed Central

    Cao, Buqing; Yu, Qing; Zhao, Wei; Tang, Zhiping; Cong, Binghai; Du, Jiankui; Lu, Jianqiang; Zhu, Xiaoyan; Ni, Xin

    2016-01-01

    The tissue kallikrein-related peptidase family (KLK) is a group of trypsin- and chymotrypsin-like serine proteases that share a similar homology to parent tissue kallikrein (KLK1). KLK1 is identified in heart and has anti-hypertrophic effects. However, whether other KLK family members play a role in regulating cardiac function remains unknown. In the present study, we demonstrated for the first time that KLK8 was expressed in myocardium. KLK8 expression was upregulated in left ventricle of cardiac hypertrophy models. Both intra-cardiac adenovirus-mediated and transgenic-mediated KLK8 overexpression led to cardiac hypertrophy in vivo. In primary neonatal rat cardiomyocytes, KLK8 knockdown inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas KLK8 overexpression promoted cardiomyocyte hypertrophy via a serine protease activity-dependent but kinin receptor-independent pathway. KLK8 overexpression increased epidermal growth factor (EGF) production, which was blocked by the inhibitors of serine protease. EGF receptor (EGFR) antagonist and EGFR knockdown reversed the hypertrophy induced by KLK8 overexpression. KLK8-induced cardiomyocyte hypertrophy was also significantly decreased by blocking the protease-activated receptor 1 (PAR1) or PAR2 pathway. Our data suggest that KLK8 may promote cardiomyocyte hypertrophy through EGF signaling- and PARs-dependent but a kinin receptor-independent pathway. It is implied that different KLK family members can subtly regulate cardiac function and remodeling. PMID:26823023

  13. Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy.

    PubMed

    He, Ben; Zhao, Yi-Chao; Gao, Ling-Chen; Ying, Xiao-Ying; Xu, Long-Wei; Su, Yuan-Yuan; Ji, Qing-Qi; Lin, Nan; Pu, Jun

    2016-06-01

    Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy.

  14. Aberrant Glycosylation in the Left Ventricle and Plasma of Rats with Cardiac Hypertrophy and Heart Failure

    PubMed Central

    Nagai-Okatani, Chiaki; Minamino, Naoto

    2016-01-01

    Targeted proteomics focusing on post-translational modifications, including glycosylation, is a useful strategy for discovering novel biomarkers. To apply this strategy effectively to cardiac hypertrophy and resultant heart failure, we aimed to characterize glycosylation profiles in the left ventricle and plasma of rats with cardiac hypertrophy. Dahl salt-sensitive hypertensive rats, a model of hypertension-induced cardiac hypertrophy, were fed a high-salt (8% NaCl) diet starting at 6 weeks. As a result, they exhibited cardiac hypertrophy at 12 weeks and partially impaired cardiac function at 16 weeks compared with control rats fed a low-salt (0.3% NaCl) diet. Gene expression analysis revealed significant changes in the expression of genes encoding glycosyltransferases and glycosidases. Glycoproteome profiling using lectin microarrays indicated upregulation of mucin-type O-glycosylation, especially disialyl-T, and downregulation of core fucosylation on N-glycans, detected by specific interactions with Amaranthus caudatus and Aspergillus oryzae lectins, respectively. Upregulation of plasma α-l-fucosidase activity was identified as a biomarker candidate for cardiac hypertrophy, which is expected to support the existing marker, atrial natriuretic peptide and its related peptides. Proteomic analysis identified cysteine and glycine-rich protein 3, a master regulator of cardiac muscle function, as an O-glycosylated protein with altered glycosylation in the rats with cardiac hypertrophy, suggesting that alternations in O-glycosylation affect its oligomerization and function. In conclusion, our data provide evidence of significant changes in glycosylation pattern, specifically mucin-type O-glycosylation and core defucosylation, in the pathogenesis of cardiac hypertrophy and heart failure, suggesting that they are potential biomarkers for these diseases. PMID:27281159

  15. Aberrant Glycosylation in the Left Ventricle and Plasma of Rats with Cardiac Hypertrophy and Heart Failure.

    PubMed

    Nagai-Okatani, Chiaki; Minamino, Naoto

    2016-01-01

    Targeted proteomics focusing on post-translational modifications, including glycosylation, is a useful strategy for discovering novel biomarkers. To apply this strategy effectively to cardiac hypertrophy and resultant heart failure, we aimed to characterize glycosylation profiles in the left ventricle and plasma of rats with cardiac hypertrophy. Dahl salt-sensitive hypertensive rats, a model of hypertension-induced cardiac hypertrophy, were fed a high-salt (8% NaCl) diet starting at 6 weeks. As a result, they exhibited cardiac hypertrophy at 12 weeks and partially impaired cardiac function at 16 weeks compared with control rats fed a low-salt (0.3% NaCl) diet. Gene expression analysis revealed significant changes in the expression of genes encoding glycosyltransferases and glycosidases. Glycoproteome profiling using lectin microarrays indicated upregulation of mucin-type O-glycosylation, especially disialyl-T, and downregulation of core fucosylation on N-glycans, detected by specific interactions with Amaranthus caudatus and Aspergillus oryzae lectins, respectively. Upregulation of plasma α-l-fucosidase activity was identified as a biomarker candidate for cardiac hypertrophy, which is expected to support the existing marker, atrial natriuretic peptide and its related peptides. Proteomic analysis identified cysteine and glycine-rich protein 3, a master regulator of cardiac muscle function, as an O-glycosylated protein with altered glycosylation in the rats with cardiac hypertrophy, suggesting that alternations in O-glycosylation affect its oligomerization and function. In conclusion, our data provide evidence of significant changes in glycosylation pattern, specifically mucin-type O-glycosylation and core defucosylation, in the pathogenesis of cardiac hypertrophy and heart failure, suggesting that they are potential biomarkers for these diseases. PMID:27281159

  16. Integrin activation and focal complex formation in cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  17. Ghrelin and its promoter variant associated with cardiac hypertrophy.

    PubMed

    Ukkola, O; Pääkkö, T; Kesäniemi, Y A

    2012-07-01

    The roles of ghrelin, a peptide hormone that has a role in regulating food intake and energy homeostasis, in the cardiovascular system have not yet been unambiguously established. We evaluated the association between plasma ghrelin concentrations and -501A>C single-nucleotide polymorphism (SNP) in the ghrelin gene 5' flanking area and echocardiographic measurements in 1037 middle-aged subjects. Left ventricular mass index (LVMI) was calculated according to Devereux's method. The ambulatory blood pressure (BP) was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Results suggested that plasma ghrelin was not related to mean ambulatory BP values. However, the highest plasma ghrelin tertile was associated with increased intraventricular septum (P=0.043) and posterior ventricular wall (P=0.002) thicknesses as well as left ventricular mass (P=0.05). After adjustment for age, sex, body mass index and systolic BP, the association persisted between ghrelin tertiles and intraventricular septum (P=0.05) and posterior ventricular wall (P=0.001) thicknesses. The SNP -501A>C polymorphism was associated with LVMI after adjustments for age, sex and systolic BP. In conclusion, ghrelin and its promoter variant are associated with cardiac hypertrophy indexes independent of BP. Positive correlation between ghrelin levels and increased wall thickness parameters may reflect compensatory up-regulation of ghrelin concentrations or direct effects of ghrelin on myocardium. The effects of the SNP seem not to be mediated through its effects on ghrelin plasma levels. PMID:21614024

  18. Identification of genes regulated during mechanical load-induced cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

    2000-01-01

    Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

  19. Reduction of blood oxygen levels enhances postprandial cardiac hypertrophy in Burmese python (Python bivittatus).

    PubMed

    Slay, Christopher E; Enok, Sanne; Hicks, James W; Wang, Tobias

    2014-05-15

    Physiological cardiac hypertrophy is characterized by reversible enlargement of cardiomyocytes and changes in chamber architecture, which increase stroke volume and via augmented convective oxygen transport. Cardiac hypertrophy is known to occur in response to repeated elevations of O2 demand and/or reduced O2 supply in several species of vertebrate ectotherms, including postprandial Burmese pythons (Python bivittatus). Recent data suggest postprandial cardiac hypertrophy in P. bivittatus is a facultative rather than obligatory response to digestion, though the triggers of this response are unknown. Here, we hypothesized that an O2 supply-demand mismatch stimulates postprandial cardiac enlargement in Burmese pythons. To test this hypothesis, we rendered animals anemic prior to feeding, essentially halving blood oxygen content during the postprandial period. Fed anemic animals had heart rates 126% higher than those of fasted controls, which, coupled with a 71% increase in mean arterial pressure, suggests fed anemic animals were experiencing significantly elevated cardiac work. We found significant cardiac hypertrophy in fed anemic animals, which exhibited ventricles 39% larger than those of fasted controls and 28% larger than in fed controls. These findings support our hypothesis that those animals with a greater magnitude of O2 supply-demand mismatch exhibit the largest hearts. The 'low O2 signal' stimulating postprandial cardiac hypertrophy is likely mediated by elevated ventricular wall stress associated with postprandial hemodynamics.

  20. Cardiac Biomarkers and Left Ventricular Hypertrophy in Asymptomatic Hemodialysis Patients

    PubMed Central

    Koycheva, Reneta Yovcheva; Cholakov, Vasil; Andreev, Jivko; Penev, Margarit; Iliev, Rosen; Nancheva, Krasimira; Tsoneva, Vanya

    2016-01-01

    BACKGROUND: Cardiac biomarkers are often elevated in dialysis patients showing the presence of left ventricular dysfunction. The aim of the study is to establish the plasma levels of high-sensitivity cardiac troponin T (hs TnT), precursor of B-natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hs CRP) and their relation to the presence of left ventricular hypertrophy (LVH) in patients undergoing hemodialysis without signs of acute coronary syndrome or heart failure. MATERIAL AND METHODS: We studied 48 patients - 26 men and 22 women. Pre and postdialysis levels of hs cTnT, NT-proBNP and hs CRP were measured at week interim procedure. Patients were divided in two groups according to the presence of echocardiographic evidence of LVH - gr A - 40 patients (with LVH), and gr B - 8 patients (without LVH). RESULTS: In the whole group of patients was found elevated predialysis levels of all three biomarkers with significant increase (p < 0.05) after dialysis with low-flux dialyzers. Predialysis values of NT-proBNP show moderate positive correlation with hs cTnT (r = 0.47) and weaker with hs CRP (r = 0.163). Such dependence is observed in postdialysis values of these biomarkers. There is a strong positive correlation between the pre and postdialysis levels: for hs cTnT (r = 0.966), for NT-proBNP (r = 0.918) and for hs CRP (r = 0.859). It was found a significant difference in the mean values of hs cTnT in gr. A and gr. B (0.07 ± 0.01 versus 0.03 ± 0.01 ng/mL, p < 0.05) and NT-proBNP (15,605.8 ± 2,072.5 versus 2,745.5 ± 533.55 pg/mL, p < 0.05). Not find a significant difference in hs CRP in both groups. CONCLUSIONS: The results indicate the relationship of the studied cardiac biomarkers with LVH in asymptomatic patients undergoing hemodialysis treatment. PMID:27275331

  1. The mechanosensitive APJ internalization via clathrin-mediated endocytosis: A new molecular mechanism of cardiac hypertrophy.

    PubMed

    He, Lu; Chen, Linxi; Li, Lanfang

    2016-05-01

    The G protein-coupled receptor APJ elicits cellular response to diverse extracellular stimulus. Accumulating evidence reveals that APJ receptor plays a prominent role in the cardiomyocyte adapting to hypertrophic stimulation. At present, it remains obscure that the regulatory mechanism of APJ receptor in myocardial hypertrophy. The natural endogenous ligands apelin and Elabela as well as agonists maintain high affinity for the APJ receptor and drive its internalization. Ligand-activated receptor internalization is mainly performed by clathrin-mediated endocytic pathway. Simultaneously, clathrin-mediated endocytosis takes participate in the occurrence and development of cardiac hypertrophy. In this study, we hypothesize that natural ligands and agonists induce the mechanosensitive APJ internalization via clathrin-mediated endocytosis. APJ internalization may contribute to the development of cardiac hypertrophy. The mechanosensitive APJ internalization via clathrin-mediated endocytosis may be a new molecular mechanism of cardiac hypertrophy. PMID:27063076

  2. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment.

    PubMed

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy.

  3. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment.

    PubMed

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. PMID:26612707

  4. Mechanisms of cardiac hypertrophy in canine volume overload

    NASA Technical Reports Server (NTRS)

    Matsuo, T.; Carabello, B. A.; Nagatomo, Y.; Koide, M.; Hamawaki, M.; Zile, M. R.; McDermott, P. J.

    1998-01-01

    This study tested whether the modest hypertrophy that develops in dogs in response to mitral regurgitation is due to a relatively small change in the rate of protein synthesis or, alternatively, is due to a decreased rate of protein degradation. After 3 mo of severe experimental mitral regurgitation, the left ventricular (LV) mass-to-body weight ratio increased by 23% compared with baseline values. This increase in LV mass occurred with a small, but not statistically significant, increase in the fractional rate of myosin heavy chain (MHC) synthesis (Ks), as measured using continuous infusion with [3H]leucine in dogs at 2 wk, 4 wk, and 3 mo after creation of severe mitral regurgitation. Translational efficiency was unaffected by mitral regurgitation as measured by the distribution of MHC mRNA in polysome gradients. Furthermore, there was no detectable increase in translational capacity as measured by either total RNA content or the rate of ribosome formation. These data indicate that translational mechanisms that accelerate the rate of cardiac protein synthesis are not responsive to the stimulus of mitral regurgitation. Most of the growth after mitral regurgitation was accounted for by a decrease in the fractional rate of protein degradation, calculated by subtracting fractional rates of protein accumulation at each time point from the corresponding Ks values. We conclude that 1) volume overload produced by severe mitral regurgitation does not trigger substantial increases in the rate of protein synthesis and 2) the modest increase in LV mass results primarily from a decrease in the rate of protein degradation.

  5. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy.

    PubMed

    Feng, H J; Ouyang, W; Liu, J H; Sun, Y G; Hu, R; Huang, L H; Xian, J L; Jing, C F; Zhou, M J

    2014-05-01

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  6. Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

    SciTech Connect

    Guo, Haipeng; Zhang, Xin; Cui, Yuqian; Zhou, Heng; Xu, Dachun; Shan, Tichao; Zhang, Fan; Guo, Yuan; Chen, Yuguo; Wu, Dawei

    2015-09-01

    Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. - Highlights: • We focus on the protective effect of taxifolin on cardiac remodeling. • Taxifolin inhibited cardiac hypertrophy and attenuated ventricular fibrosis. • Taxifolin

  7. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy

    PubMed Central

    Mohamed, Tamer M. A.; Abou-Leisa, Riham; Stafford, Nicholas; Maqsood, Arfa; Zi, Min; Prehar, Sukhpal; Baudoin-Stanley, Florence; Wang, Xin; Neyses, Ludwig; Cartwright, Elizabeth J.; Oceandy, Delvac

    2016-01-01

    The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically in fibroblasts, reduces the hypertrophic response to pressure overload; however, knocking out Pmca4 specifically in cardiomyocytes does not produce this effect. Mechanistically, cardiac fibroblasts lacking PMCA4 produce higher levels of secreted frizzled related protein 2 (sFRP2), which inhibits the hypertrophic response in neighbouring cardiomyocytes. Furthermore, we show that treatment with the PMCA4 inhibitor aurintricarboxylic acid (ATA) inhibits and reverses cardiac hypertrophy induced by pressure overload in mice. Our results reveal that PMCA4 regulates the development of cardiac hypertrophy and provide proof of principle for a therapeutic approach to treat this condition. PMID:27020607

  8. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    SciTech Connect

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α{sub 1}-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy.

  9. Myocardial stress and hypertrophy: a complex interface between biophysics and cardiac remodeling.

    PubMed

    Grossman, William; Paulus, Walter J

    2013-09-01

    Pressure and volume overload results in concentric and eccentric hypertrophy of cardiac ventricular chambers with, respectively, parallel and series replication of sarcomeres. These divergent patterns of hypertrophy were related 40 years ago to disparate wall stresses in both conditions, with systolic wall stress eliciting parallel replication of sarcomeres and diastolic wall stress, series replication. These observations are relevant to clinical practice, as they relate to the excessive hypertrophy and contractile dysfunction regularly observed in patients with aortic stenosis. Stress-sensing mechanisms in cardiomyocytes and activation of cardiomyocyte death by elevated wall stress continue to intrigue cardiovascular scientists.

  10. Acute Targeting of General Transcription Factor IIB Restricts Cardiac Hypertrophy via Selective Inhibition of Gene Transcription

    PubMed Central

    Sayed, Danish; Yang, Zhi; He, Minzhen; Pfleger, Jessica M.; Abdellatif, Maha

    2014-01-01

    Background We previously reported that specialized and housekeeping genes are differentially regulated via de novo recruitment and pause-release of RNA polymerase II (pol II), respectively, during cardiac hypertrophy. However, the significance of this finding remains to be examined. Therefore, the purpose of this study was to determine the mechanisms that differentially regulate these gene groups and exploit them for therapeutic targeting. Methods and Results Here we show that general transcription factor IIB (TFIIB) and cyclin-dependent kinase 9 are upregulated during hypertrophy, both targeted by miR-1, and play preferential roles in regulating those two groups of genes. Chromatin immunoprecipitation-sequencing reveals that TFIIB is constitutively bound to all paused, housekeeping, promoters, whereas, de novo recruitment of TFIIB and pol II is required for specialized genes that are induced during hypertrophy. We exploited this dichotomy to acutely inhibit induction of the latter set, which encompasses cardiomyopathy, immune reaction, and extracellular matrix genes, using locked nucleic acid (LNA)-modified antisense TFIIB oligonucleotide treatment. This resulted in suppression of all specialized genes, while sparing the housekeeping ones, and, thus, attenuated pathological hypertrophy. Conclusions The data for the first time reveal distinct general transcription factor IIB dynamics that regulate specialized vs. housekeeping genes during cardiac hypertrophy. Thus, by acutely targeting TFIIB we were able to selectively inhibit the former set of genes and ameliorate pressure overload hypertrophy. We also demonstrate the feasibility of acutely and reversibly targeting cardiac mRNA for therapeutic purposes using LNA-modified antisense oligonucleotides. PMID:25398966

  11. Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

    PubMed Central

    Deng, Ke-Qiong; Wang, Aibing; Ji, Yan-Xiao; Zhang, Xiao-Jing; Fang, Jing; Zhang, Yan; Zhang, Peng; Jiang, Xi; Gao, Lu; Zhu, Xue-Yong; Zhao, Yichao; Gao, Lingchen; Yang, Qinglin; Zhu, Xue-Hai; Wei, Xiang; Pu, Jun; Li, Hongliang

    2016-01-01

    Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure. PMID:27249321

  12. Neuroglobin protects cardiomyocytes against apoptosis and cardiac hypertrophy induced by isoproterenol in rats.

    PubMed

    Liu, Zhen-Fang; Zhang, Xiao; Qiao, Yan-Xiang; Xu, Wan-Qun; Ma, Cheng-Tai; Gu, Hua-Li; Zhou, Xiu-Mei; Shi, Lei; Cui, Chang-Xing; Xia, Di; Chen, Yu-Guo

    2015-01-01

    Neuroglobin (Ngb) is well known as a physiological role in oxygen homeostasis of neurons and perhaps a protective role against hypoxia and oxidative stress. In this study, we found that Ngb is expressed in rat heart tissues and it is related to isoproterenol induced cardiac hypertrophy. Moreover, overexpression or knock-down of Ngb influences the expression of hypertrophic markers ANP and BNP and the ratio of hypertrophic cells in rat H9c2 myoblasts when isoproterenol treatment. The Annexin V-FITC/PI Staining, Western blot and qPCR analysis showed that the involvement in p53-mediated apoptosis of cardiomyocytes of Ngb is might be the mechanism. This protein could prevent the cells against ROS and POS-induced apoptosis not only in nervous systems but also in cardiomyocytes. From the results, it is concluded that Ngb is a promising protectant in the cardiac hypertrophy, it may be a candidate target to cardiac hypertrophy for clinic treatment. PMID:26131111

  13. Phenanthrene exposure induces cardiac hypertrophy via reducing miR-133a expression by DNA methylation.

    PubMed

    Huang, Lixing; Xi, Zhihui; Wang, Chonggang; Zhang, Youyu; Yang, Zhibing; Zhang, Shiqi; Chen, Yixin; Zuo, Zhenghong

    2016-01-01

    Growing evidence indicates that there is an emerging link between environmental pollution and cardiac hypertrophy, while the mechanism is unclear. The objective of this study was to examine whether phenanthrene (Phe) could cause cardiac hypertrophy, and elucidate the molecular mechanisms involved. We found that: 1) Phe exposure increased the heart weight and cardiomyocyte size of rats; 2) Phe exposure led to enlarged cell size, and increased protein synthesis in H9C2 cells; 3) Phe exposure induced important markers of cardiac hypertrophy, such as atrial natriuretic peptide, B-type natriuretic peptide, and c-Myc in H9C2 cells and rat hearts; 4) Phe exposure perturbed miR-133a, CdC42 and RhoA, which were key regulators of cardiac hypertrophy, in H9C2 cells and rat hearts; 5) Phe exposure induced DNA methyltransferases (DNMTs) in H9C2 cells and rat hearts; 6) Phe exposure led to methylation of CpG sites within the miR-133a locus and reduced miR-133a expression in H9C2 cells; 7) DNMT inhibition and miR-133a overexpression could both alleviate the enlargement of cell size and perturbation of CdC42 and RhoA caused by Phe exposure. These results indicated that Phe could induce cardiomyocyte hypertrophy in the rat and H9C2 cells. The mechanism might involve reducing miR-133a expression by DNA methylation. PMID:26830171

  14. Phenanthrene exposure induces cardiac hypertrophy via reducing miR-133a expression by DNA methylation

    PubMed Central

    Huang, Lixing; Xi, Zhihui; Wang, Chonggang; Zhang, Youyu; Yang, Zhibing; Zhang, Shiqi; Chen, Yixin; Zuo, Zhenghong

    2016-01-01

    Growing evidence indicates that there is an emerging link between environmental pollution and cardiac hypertrophy, while the mechanism is unclear. The objective of this study was to examine whether phenanthrene (Phe) could cause cardiac hypertrophy, and elucidate the molecular mechanisms involved. We found that: 1) Phe exposure increased the heart weight and cardiomyocyte size of rats; 2) Phe exposure led to enlarged cell size, and increased protein synthesis in H9C2 cells; 3) Phe exposure induced important markers of cardiac hypertrophy, such as atrial natriuretic peptide, B-type natriuretic peptide, and c-Myc in H9C2 cells and rat hearts; 4) Phe exposure perturbed miR-133a, CdC42 and RhoA, which were key regulators of cardiac hypertrophy, in H9C2 cells and rat hearts; 5) Phe exposure induced DNA methyltransferases (DNMTs) in H9C2 cells and rat hearts; 6) Phe exposure led to methylation of CpG sites within the miR-133a locus and reduced miR-133a expression in H9C2 cells; 7) DNMT inhibition and miR-133a overexpression could both alleviate the enlargement of cell size and perturbation of CdC42 and RhoA caused by Phe exposure. These results indicated that Phe could induce cardiomyocyte hypertrophy in the rat and H9C2 cells. The mechanism might involve reducing miR-133a expression by DNA methylation. PMID:26830171

  15. Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy

    PubMed Central

    Yasuno, Shinji; Kuwahara, Koichiro; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakagawa, Yasuaki; Usami, Satoru; Kuwabara, Yoshihiro; Ueshima, Kenji; Harada, Masaki; Nishikimi, Toshio; Nakao, Kazuwa

    2013-01-01

    BACKGROUND AND PURPOSE Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. EXPERIMENTAL APPROACH We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. KEY RESULTS As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. CONCLUSIONS AND IMPLICATIONS Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. PMID:23937445

  16. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling

    PubMed Central

    Ji, Yan-Xiao; Zhang, Peng; Zhang, Xiao-Jing; Zhao, Yi-Chao; Deng, Ke-Qiong; Jiang, Xi; Wang, Pi-Xiao; Huang, Zan; Li, Hongliang

    2016-01-01

    Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6–TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner. PMID:27249171

  17. Asiatic Acid Protects against Cardiac Hypertrophy through Activating AMPKα Signalling Pathway

    PubMed Central

    Ma, Zhen-Guo; Dai, Jia; Wei, Wen-Ying; Zhang, Wen-Bin; Xu, Si-Chi; Liao, Hai-Han; Yang, Zheng; Tang, Qi-Zhu

    2016-01-01

    Background: AMPactivated protein kinase α (AMPKα) is closely involved in the process of cardiac hypertrophy. Asiatic acid (AA), a pentacyclic triterpene, was found to activate AMPKα in our preliminary experiment. However, its effects on the development of cardiac hypertrophy remain unclear. The present study was to determine whether AA could protect against cardiac hypertrophy. Methods: Mice subjected to aortic banding were orally given AA (10 or 30mg/kg) for 7 weeks. In the inhibitory experiment, Compound C was intraperitoneally injected for 3 weeks after surgery. Results: Our results showed that AA markedly inhibited hypertrophic responses induced by pressure overload or angiotensin II. AA also suppressed cardiac fibrosis in vivo and accumulation of collagen in vitro. The protective effects of AA were mediated by activation of AMPKα and inhibition of the mammalian target of rapamycin (mTOR) pathway and extracellular signal-regulated kinase (ERK) in vivo and in vitro. However, AA lost the protective effects after AMPKα inhibition or gene deficiency. Conclusions: AA protects against cardiac hypertrophy by activating AMPKα, and has the potential to be used for the treatment of heart failure. PMID:27313499

  18. Flavonoids Extraction from Propolis Attenuates Pathological Cardiac Hypertrophy through PI3K/AKT Signaling Pathway

    PubMed Central

    Sun, Guang-wei; Qiu, Zhi-dong; Wang, Wei-nan; Sui, Xin

    2016-01-01

    Propolis, a traditional medicine, has been widely used for a thousand years as an anti-inflammatory and antioxidant drug. The flavonoid fraction is the main active component of propolis, which possesses a wide range of biological activities, including activities related to heart disease. However, the role of the flavonoids extraction from propolis (FP) in heart disease remains unknown. This study shows that FP could attenuate ISO-induced pathological cardiac hypertrophy (PCH) and heart failure in mice. The effect of the two fetal cardiac genes, atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), on PCH was reversed by FP. Echocardiography analysis revealed cardiac ventricular dilation and contractile dysfunction in ISO-treated mice. This finding is consistent with the increased heart weight and cardiac ANF protein levels, massive replacement fibrosis, and myocardial apoptosis. However, pretreatment of mice with FP could attenuate cardiac dysfunction and hypertrophy in vivo. Furthermore, the cardiac protection of FP was suppressed by the pan-PI3K inhibitor wortmannin. FP is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorder, such as fibrosis. The effects may be closely correlated with PI3K/AKT signaling. FP may be clinically used to inhibit PCH progression and heart failure. PMID:27213000

  19. Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: detrimental role of Na(+)-Ca(2+) exchanger.

    PubMed

    Magi, Simona; Nasti, Annamaria Assunta; Gratteri, Santo; Castaldo, Pasqualina; Bompadre, Stefano; Amoroso, Salvatore; Lariccia, Vincenzo

    2015-01-01

    Several molecular pathways involved in the development of cardiac hypertrophy are triggered by perturbation of intracellular Ca(2+) homeostasis. Within the heart, Na(+)/Ca(2+) exchanger 1 (NCX1) is one of the main determinant in controlling Ca(2+) homeostasis. In cardiac hypertrophy and heart failure NCX1 expression and activity have been reported to be altered. It has been shown that chronic bacterial infections (sepsis, endocarditis, and myocarditis) can promote cardiac hypertrophy. Bacterial stressors, such as the Gram-negative endotoxin lipopolysaccharide (LPS), can directly or indirectly affect intracellular Ca(2+) homeostasis in the heart and induce the development of cardiac hypertrophy. The present study aimed at evaluating the potential link between the signal pathways activated in LPS-exposed myocytes and NCX1. In the whole rat heart, LPS perfusion induced an early hypertrophy response during which NCX1 expression significantly increased. Notably, all these changes were completely prevented by the NCX inhibitor SN-6. We further dissect the role of NCX1 in the LPS-induced hypertrophic response in an in vitro cardiac model based on two H9c2 cardiomyoblast clones, namely H9c2-WT (lacking endogenous NCX1 expression) and H9c2-NCX1 (stably transfected with a functional NCX1). H9c2-NCX1 were more susceptible than H9c2-WT to develop a hypertrophic phenotype, and they displayed a significant increase in NCX1 expression and function after LPS treatment. SN-6 completely counteracted both hypertrophic response and exchanger alterations induced by LPS in H9c2-NCX1 cells, but it had no effects on H9c2-WT. Collectively, our results suggest that NCX1 plays a critical role in promoting myocardial hypertrophy triggered by LPS. PMID:25445045

  20. Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway

    PubMed Central

    Gu, Jun; Hu, Wei; Song, Zhi-Ping; Chen, Yue-Guang; Zhang, Da-Dong; Wang, Chang-Qian

    2016-01-01

    Rapamycin, also known as sirolimus, is an antifungal agent and immunosuppressant drug used to prevent organ rejection in transplantation. However, little is known about the role of rapamycin in cardiac hypertrophy and the signaling pathways involved. Here, the effect of rapamycin was examined using phenylephrine (PE) induced cardiomyocyte hypertrophy in vitro and in a rat model of aortic banding (AB) - induced hypertrophy in vivo. Inhibition of MEK/ERK signaling reversed the effect of rapamycin on the up-regulation of LC3-II, Beclin-1 and Noxa, and the down-regulation of Mcl-1 and p62. Silencing of Noxa or Beclin-1 suppressed rapamycin-induced autophagy, and co-immunoprecipitation experiments showed that Noxa abolishes the inhibitory effect of Mcl-1 on Beclin-1, promoting autophagy. In vivo experiments showed that rapamycin decreased AB-induced cardiac hypertrophy in a MEK/ERK dependent manner. Taken together, our results indicate that rapamycin attenuates cardiac hypertrophy by promoting autophagy through a mechanism involving the modulation of Noxa and Beclin-1 expression by the MEK/ERK signaling pathway. PMID:27047390

  1. Stargazing microRNA maps a new miR-21 star for cardiac hypertrophy

    PubMed Central

    Indolfi, Ciro; Curcio, Antonio

    2014-01-01

    Left ventricular hypertrophy is an initial compensatory mechanism in response to cardiac stress that can degenerate into heart failure and sudden cardiac death. Recent studies have shown that microRNAs (miRs) regulate several aspects of cardiovascular diseases. In this issue of the JCI, Bang and colleagues identified an exosome-mediated communication mechanism between cardiac fibroblasts and cardiomyocytes. Specifically, cardiac fibroblasts secrete miR-enriched exosomes, which are subsequently taken up by cardiomyocytes, in which they alter gene expression. In particular, a passenger strand miR, miR-21*, was identified as a potent paracrine factor that induces cardiomyocyte hypertrophy when shuttled through exosomes. These advanced comprehensive analyses represent a major step forward in our understanding of cardiovascular physiopathology, providing a promising adjunctive target for possible therapeutic approaches, namely the miR-mediated paracrine signaling network. PMID:24743143

  2. Stargazing microRNA maps a new miR-21 star for cardiac hypertrophy.

    PubMed

    Indolfi, Ciro; Curcio, Antonio

    2014-05-01

    Left ventricular hypertrophy is an initial compensatory mechanism in response to cardiac stress that can degenerate into heart failure and sudden cardiac death. Recent studies have shown that microRNAs (miRs) regulate several aspects of cardiovascular diseases. In this issue of the JCI, Bang and colleagues identified an exosome-mediated communication mechanism between cardiac fibroblasts and cardiomyocytes. Specifically, cardiac fibroblasts secrete miR-enriched exosomes, which are subsequently taken up by cardiomyocytes, in which they alter gene expression. In particular, a passenger strand miR, miR-21*, was identified as a potent paracrine factor that induces cardiomyocyte hypertrophy when shuttled through exosomes. These advanced comprehensive analyses represent a major step forward in our understanding of cardiovascular physiopathology, providing a promising adjunctive target for possible therapeutic approaches, namely the miR-mediated paracrine signaling network. PMID:24743143

  3. SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension.

    PubMed

    Mehrotra, Aanchal; Joe, Bina; de la Serna, Ivana L

    2013-12-01

    Pathological cardiac hypertrophy is characterized by a sustained increase in cardiomyocyte size and re-activation of the fetal cardiac gene program. Previous studies implicated SWI/SNF chromatin remodeling enzymes as regulators of the fetal cardiac gene program in surgical models of cardiac hypertrophy. Although hypertension is a common risk factor for developing cardiac hypertrophy, there has not yet been any investigation into the role of SWI/SNF enzymes in cardiac hypertrophy using genetic models of hypertension. In this study, we tested the hypothesis that components of the SWI/SNF complex are activated and recruited to promoters that regulate the fetal cardiac gene program in hearts that become hypertrophic as a result of salt induced hypertension. Utilizing the Dahl salt-sensitive (S) rat model, we found that the protein levels of several SWI/SNF subunits required for heart development, Brg1, Baf180, and Baf60c, are elevated in hypertrophic hearts from S rats fed a high salt diet compared with normotensive hearts from Dahl salt-resistant (R) rats fed the same diet. Furthermore, we detected significantly higher levels of SWI/SNF subunit enrichment as well as evidence of more accessible chromatin structure on two fetal cardiac gene promoters in hearts from S rats compared with R rats. Our data implicate SWI/SNF chromatin remodeling enzymes as regulators of gene expression in cardiac hypertrophy resulting from salt induced hypertension. Thus we provide novel insights into the epigenetic mechanisms by which salt induced hypertension leads to cardiac hypertrophy.

  4. Three 4-Letter Words of Hypertension-Related Cardiac Hypertrophy: TRPC, mTOR, and HDAC

    PubMed Central

    Kurdi, Mazen; Booz, George W.

    2011-01-01

    Left ventricular hypertrophy due to hypertension represents a major risk factor for adverse cardiovascular events and death. In recent years, the prevalence of cardiac hypertrophy has increased due to obesity and an aging population. Notably, a significant number of individuals have persistent cardiac hypertrophy in the face of blood pressure that is normalized by drug treatment. Thus, a better understanding of the processes underlying the cardiac remodeling events that are set into play by hypertension is needed. At the level of the cardiac myocytes, hypertrophic growth is often described as physiological, as occurs with exercise, or pathological, as seen with hypertension. Here we discuss recent developments in three areas that are fundamental to pathological hypertrophic growth of cardiac myocytes. These areas are the transient receptor potential canonical (TRPC) channels, mammalian target of rapamycin (mTOR) complexes, and histone deacetylase (HDAC) enzymes. In the last several years, studies in each of these areas have yielded new and exciting discoveries into the genesis of pathological growth of cardiac myocytes. The phosphoinositide 3-kinase – Akt signaling network may be the common denominator that links these areas together. Defining the interrelationship among TRPC channels, mTOR signaling, and HDAC enzymes is a promising, but challenging area of research. Such knowledge will undoubtedly lead to new drugs that better prevent or reverse left ventricular hypertension. PMID:21320507

  5. Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation

    PubMed Central

    Tan, Yingying; Zhang, Nan; Yao, Fanrong

    2015-01-01

    Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [3H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin. PMID:25488910

  6. Comparison of Nigella sativa- and exercise-induced models of cardiac hypertrophy: structural and electrophysiological features.

    PubMed

    Al-Asoom, Lubna Ibrahim; Al-Shaikh, Basil Abdulrahman; Bamosa, Abdullah Omar; El-Bahai, Mohammad Nabil

    2014-09-01

    Exercise training is employed as supplementary therapeutic intervention for heart failure, due to its ability to induce physiological cardiac hypertrophy. In parallel, supplementation with Nigella sativa (N. sativa) was found to enhance myocardial function and induce cardiac hypertrophy. In this study, we aim to compare the morphological and electrophysiological changes associated with these patterns of cardiac hypertrophy and the possible changes upon administration of N. sativa to exercise-trained animals. Fifty-six adult Wistar rats were divided into: control, Nigella-treated (N), exercise-trained (E), and Nigella-treated-exercise-trained (NE) rats. Daily 800 mg/kg N. sativa was administered orally to N and NE. E and NE ran on treadmill, 2 h/day. At the end of 8 weeks ECG, body weight (BW), heart weight (HW), and left ventricular weight (LVW) were recorded. Hematoxylin and Eosin and periodic acid-Schiff sections were prepared to study the histology of left ventricles and to measure diameter of cardiomyocytes (Cdia). HW/BW, LVW/BW, and mean Cdia were significantly higher in all experimental animals compared to the controls. Histology showed normal cardiomyocytes with no fibrosis. ECG showed significantly lower heart rates, higher QRS amplitude, and ventricular specific potential in NE group compared to control group. Supplementation of N. sativa demonstrated a synergistic effect with exercise training as Nigella-exercise-induced cardiac hypertrophy had lower heart rate and well-matched electrical activity of the heart to its mass. Therefore, this model of cardiac hypertrophy might be introduced as a new therapeutic strategy for treatment for heart failure with superior advantages to exercise training.

  7. Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis.

    PubMed

    Schneider, Johanna; Lother, Achim; Hein, Lutz; Gilsbach, Ralf

    2011-06-01

    Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

  8. Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy.

    PubMed

    Sorriento, Daniela; Santulli, Gaetano; Franco, Antonietta; Cipolletta, Ersilia; Napolitano, Luigi; Gambardella, Jessica; Gomez-Monterrey, Isabel; Campiglia, Pietro; Trimarco, Bruno; Iaccarino, Guido; Ciccarelli, Michele

    2015-11-01

    G protein coupled receptor kinase type 2 (GRK2) plays an important role in the development and maintenance of cardiac hypertrophy and heart failure even if its exact role is still unknown. In this study, we assessed the effect of GRK2 on the regulation of cardiac hypertrophy. In H9C2 cells, GRK2 overexpression increased atrial natriuretic factor (ANF) activity and enhanced phenylephrine-induced ANF response, and this is associated with an increase of NFκB transcriptional activity. The kinase dead mutant and a synthetic inhibitor of GRK2 activity exerted the opposite effect, suggesting that GRK2 regulates hypertrophy through upregulation of NFκB activity in a phosphorylation-dependent manner. In two different in vivo models of left ventricle hypertrophy (LVH), the selective inhibition of GRK2 activity prevented hypertrophy and reduced NFκB transcription activity. Our results suggest a previously undisclosed role for GRK2 in the regulation of hypertrophic responses and propose GRK2 as potential therapeutic target for limiting LVH. PMID:26224342

  9. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling.

    PubMed

    Oka, Toru; Xu, Jian; Kaiser, Robert A; Melendez, Jaime; Hambleton, Michael; Sargent, Michelle A; Lorts, Angela; Brunskill, Eric W; Dorn, Gerald W; Conway, Simon J; Aronow, Bruce J; Robbins, Jeffrey; Molkentin, Jeffery D

    2007-08-01

    The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn(-/-) mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn(-/-) hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn(-/-) hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy. PMID:17569887

  10. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    PubMed Central

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  11. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

    PubMed

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J; Lipskaia, Larissa; Chemaly, Elie R

    2015-11-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy.

  12. Cardiac hypertrophy, arrhythmogenicity and the new myocardial phenotype. II. The cellular adaptational process.

    PubMed

    Swynghedauw, B; Chevalier, B; Charlemagne, D; Mansier, P; Carré, F

    1997-07-01

    Ventricular fibrosis is not the only structural determinant of arrhythmias in left ventricular hypertrophy. In an experimental model of compensatory cardiac hypertrophy (CCH) the degree of cardiac hypertrophy is also independently linked to ventricular arrhythmias. Cardiac hypertrophy reflects the level of adaptation, and matches the adaptational modifications of the myocardial phenotype. We suggest that these modifications have detrimental aspects. The increased action potential (AP) and QT duration and the prolonged calcium transient both favour spontaneous calcium oscillations, and both are potentially arrhythmogenic and linked to phenotypic changes in membrane proteins. To date, only two ionic currents have been studied in detail: Ito is depressed (likely the main determinant in AP durations), and If, the pacemaker current, is induced in the overloaded ventricular myocytes. In rat CCH, the two components of the sarcoplasmic reticulum, namely Ca(2+)-ATPase and ryanodine receptors, are down-regulated in parallel. Nevertheless, while the inward calcium current is unchanged, the functionally linked duo composed of the Na+/Ca2+ exchanged and (Na+, K+)-ATPase, is less active. Such an imbalance may explain the prolonged calcium transient. The changes in heart rate variability provide information about the state of the autonomic nervous system and has prognostic value even in CCH. Transgenic studies have demonstrated that the myocardial adrenergic and muscarinic receptor content is also a determining factor. During CCH, several phenotypic membrane changes participate in the slowing of contraction velocity and are thus adaptational. They also have a detrimental counterpart and, together with fibrosis, favour arrhythmias. PMID:9302342

  13. The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy.

    PubMed

    Ooi, Jenny Y Y; Bernardo, Bianca C; McMullen, Julie R

    2014-02-01

    Cardiac hypertrophy is broadly defined as an increase in heart mass. Heart enlargement in a setting of cardiac disease is referred to as pathological hypertrophy and often progresses to heart failure. Physiological hypertrophy refers to heart growth in response to postnatal development, exercise training and pregnancy, and is an adaptive response associated with the activation of cardioprotective signaling cascades. miRNAs have emerged as novel therapeutic targets for numerous pathologies, and miRNA-based therapies have already entered clinical trials. The identification of miRNAs differentially regulated during physiological growth may open up new therapeutic approaches for heart failure. In this review, we present information on miRNAs regulated in models of physiological hypertrophy, describe preclinical cardiac disease studies that have successfully targeted miRNAs regulated in settings of physiological growth (miR-34, miR-15, miR-199b, miR-208a and miR-378), and discuss challenges to overcome for the safe entry of miRNA-based therapies into the clinic for heart failure patients. PMID:24467244

  14. Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway

    PubMed Central

    Al-rasheed, Nouf M; Al-Oteibi, Maha M; Al-Manee, Reem Z; Al-shareef, Sarah A; Al-Rasheed, Nawal M; Hasan, Iman H; Mohamad, Raeesa A; Mahmoud, Ayman M

    2015-01-01

    Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180–200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals. PMID:26150695

  15. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines

    PubMed Central

    Lauriol, Jessica; Cabrera, Janel R.; Roy, Ashbeel; Keith, Kimberly; Hough, Sara M.; Damilano, Federico; Wang, Bonnie; Segarra, Gabriel C.; Flessa, Meaghan E.; Miller, Lauren E.; Das, Saumya; Bronson, Roderick; Lee, Kyu-Ho; Kontaridis, Maria I.

    2016-01-01

    Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy. PMID:27348588

  16. Impact of L-NAME on the cardiopulmonary reflex in cardiac hypertrophy.

    PubMed

    Buckley, Maria M; Johns, Edward J

    2011-11-01

    There is evidence that in cardiac failure, there is defective baroreceptor reflex control of sympathetic nerve activity. Often, cardiac failure is preceded by a state of cardiac hypertrophy in which there may be enhanced performance of the heart. This study investigated whether in two different models of cardiac hypertrophy, there was an increased contribution of nitric oxide (NO) to the low-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and nerve-dependent excretory function. Administration of a volume load, 0.25* body wt/min saline for 30 min, in normal rats decreased RSNA by 40* and increased urine flow by some 9-fold. Following nitro-L-arginine methyl ester (L-NAME) administration, 10 μg·kg(-1)·min(-1) for 60 min, which had no effect on blood pressure, heart rate, or RSNA, the volume load-induced renal sympathoinhibitory and excretory responses were markedly enhanced. In cardiac hypertrophy states induced by 2 wk of isoprenaline/caffeine or 1 wk thyroxine administration, the volume challenge failed to suppress RSNA, and there were blunted increases in urine flow in the innervated kidneys, but following L-NAME infusion, the volume load decreased RSNA by 30-40* and increased urine flow by some 20-fold in the innervated kidneys, roughly to the same extent as observed in normal rats. These findings suggest that the blunted renal sympathoinhibition and nerve-dependent diuresis to the volume load in cardiac hypertrophy are related to a heightened production or activity of NO within either the afferent or central arms of the reflex. PMID:21865544

  17. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines.

    PubMed

    Lauriol, Jessica; Cabrera, Janel R; Roy, Ashbeel; Keith, Kimberly; Hough, Sara M; Damilano, Federico; Wang, Bonnie; Segarra, Gabriel C; Flessa, Meaghan E; Miller, Lauren E; Das, Saumya; Bronson, Roderick; Lee, Kyu-Ho; Kontaridis, Maria I

    2016-08-01

    Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy. PMID:27348588

  18. Construction and analysis of cardiac hypertrophy-associated lncRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in cardiac hypertrophy

    PubMed Central

    Liu, Yan; Pan, Hao; Qi, Han-ping; Cao, Yong-gang; Zhao, Jian-mei; Li, Shang; Guo, Jing; Sun, Hong-li; Li, Chun-quan

    2016-01-01

    Cardiac hypertrophy (CH) could increase cardiac after-load and lead to heart failure. Recent studies have suggested that long non-coding RNA (lncRNA) played a crucial role in the process of the cardiac hypertrophy, such as Mhrt, TERMINATOR. Some studies have further found a new interacting mechanism, competitive endogenous RNA (ceRNA), of which lncRNA could interact with micro-RNAs (miRNA) and indirectly interact with mRNAs through competing interactions. However, the mechanism of ceRNA regulated by lncRNA in the CH remained unclear. In our study, we generated a global triple network containing mRNA, miRNA and lncRNA, and extracted a CH related lncRNA-mRNA network (CHLMN) through integrating the data from starbase, miRanda database and gene expression profile. Based on the ceRNA mechanism, we analyzed the characters of CHLMN and found that 3 lncRNAs (SLC26A4-AS1, RP11-344E13.3 and MAGI1-IT1) were high related to CH. We further performed cluster module analysis and random walk with restart for the CHLMN, finally 14 lncRNAs had been discovered as the potential CH related disease genes. Our results showed that lncRNA played an important role in the CH and could shed new light to the understanding underlying mechanisms of the CH. PMID:26872060

  19. Repression of Cardiac Hypertrophy by KLF15: Underlying Mechanisms and Therapeutic Implications

    PubMed Central

    Leenders, Joost J.; Wijnen, Wino J.; van der Made, Ingeborg; Hiller, Monika; Swinnen, Melissa; Vandendriessche, Thierry; Chuah, Marinee; Pinto, Yigal M.; Creemers, Esther E.

    2012-01-01

    The Kruppel-like factor (KLF) family of transcription factors regulates diverse cell biological processes including proliferation, differentiation, survival and growth. Previous studies have shown that KLF15 inhibits cardiac hypertrophy by repressing the activity of pivotal cardiac transcription factors such as GATA4, MEF2 and myocardin. We set out this study to characterize the interaction of KLF15 with putative other transcription factors. We first show that KLF15 interacts with myocardin-related transcription factors (MRTFs) and strongly represses the transcriptional activity of MRTF-A and MRTF-B. Second, we identified a region within the C-terminal zinc fingers of KLF15 that contains the nuclear localization signal. Third, we investigated whether overexpression of KLF15 in the heart would have therapeutic potential. Using recombinant adeno-associated viruses (rAAV) we have overexpressed KLF15 specifically in the mouse heart and provide the first evidence that elevation of cardiac KLF15 levels prevents the development of cardiac hypertrophy in a model of Angiotensin II induced hypertrophy. PMID:22586493

  20. Myeloid Mineralocorticoid Receptor Deficiency Inhibits Aortic Constriction-Induced Cardiac Hypertrophy in Mice

    PubMed Central

    Zheng, Xiao Jun; Zhang, Wu Chang; Sun, Xue Nan; Yang, Qing Zhen; Ma, Shu Min; Huang, Baozhuan; Berger, Stefan; Wang, Wang; Wu, Yong; Yu, Ying; Duan, Sheng Zhong; Mortensen, Richard M.

    2014-01-01

    Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation. PMID:25354087

  1. Suppression of calcium-sensing receptor ameliorates cardiac hypertrophy through inhibition of autophagy

    PubMed Central

    LIU, LEI; WANG, CHAO; LIN, YAN; XI, YUHUI; LI, HONG; SHI, SA; LI, HONGZHU; ZHANG, WEIHUA; ZHAO, YAJUN; TIAN, YE; XU, CHANGQING; WANG, LINA

    2016-01-01

    The calcium-sensing receptor (CaSR) releases intracellular calcium ([Ca2+]i) by accumulating inositol phosphate. Changes in [Ca2+]i initiate myocardial hypertrophy. Furthermore, autophagy associated with [Ca2+]i. Autophagy has previously been demonstrated to participate in the hypertrophic process. The current study investigated whether suppression of CaSR affects the hypertrophic response via modulating autophagy. Isoproterenol (ISO) was used to induce cardiac hypertrophy in Wistar rats. Hypertrophic status was determined by echocardiographic assessment, hematoxylin and eosin, and Masson's staining. The protein expression levels of CaSR and autophagy level were observed. Changes of hypertrophy and autophagy indicators were observed following intravenous injection of a CaSR inhibitor. An ISO-induced cardiomyocyte hypertrophy model was established and used determine the involvement of GdCl3. [Ca2+]i was determined using Fluo-4/AM dye followed by confocal microscopy. The expression levels of various active proteins were analyzed by western blotting. The size of the heart, expression levels of CaSR and autophagy level were markedly increased in hypertrophic myocardium. In addition, the present study demonstrated that the indicators of hypertrophy and autophagy were effectively suppressed by CaSR inhibitor. Furthermore, similar effects were demonstrated in neonatal rat hypertrophic cardiomyocytes treated with ISO. It was also observed that CaSR regulates the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway induced by ISO in cardiomyocytes. Furthermore, the AMPK inhibition significantly reduced the autophagy level following CaSR stimulation (P<0.05). The results of the present demonstrated that inhibition of CaSR may ameliorate cardiac hypertrophy induced by ISO and the effect may be associated with the inhibition of autophagy and suppression of the Ca

  2. Endogenous antioxidant defense induction by melon superoxide dismutase reduces cardiac hypertrophy in spontaneously hypertensive rats.

    PubMed

    Carillon, Julie; Rugale, Caroline; Rouanet, Jean-Max; Cristol, Jean-Paul; Lacan, Dominique; Jover, Bernard

    2014-08-01

    We assessed the influence of SODB, a melon superoxide dismutase (SOD), on left ventricular (LV) hypertrophy in SHR. SODB (4 or 40U SOD) was given orally for 4 or 28 days to SHR. For each treatment period, LV weight index (LVWI) and cardiomyocytes size were measured. SOD, glutathione peroxidase (GPx) and catalase expressions, and LV production and presence of superoxide anion were determined. Pro-inflammatory markers were also measured. SODB reduced LVWI and cardiomyocytes size after 4 or 28 days. Cardiac SOD and GPx increased by 30-40% with SODB. The presence but not production of superoxide anion was significantly reduced by SODB. No effect of SODB was detected on inflammatory status in any group. The beneficial effect of SODB on cardiac hypertrophy seems to be related to the stimulation of endogenous antioxidant defense, suggesting that SODB may be of interest as a dietary supplementation during conventional antihypertensive therapy.

  3. Upregulation of M3 muscarinic receptor inhibits cardiac hypertrophy induced by angiotensin II

    PubMed Central

    2013-01-01

    Background M3 muscarinic acetylcholine receptor (M3-mAChR) is stably expressed in the myocardium, but its pathophysiological role remains largely undefined. This study aimed to investigate the role of M3-mAChR in cardiac hypertrophy induced by angiotensin II (Ang II) and elucidate the underlying mechanisms. Methods Cardiac-specific M3-mAChR overexpression transgenic (TG) mice and rat H9c2 cardiomyoblasts with ectopic expression of M3-mAChR were established. Models of cardiac hypertrophy were induced by transverse aortic constriction (TAC) or Ang II infusion in the mice in vivo, and by isoproterenol (ISO) or Ang II treatment of H9c2 cells in vitro. Cardiac hypertrophy was evaluated by electrocardiography (ECG) measurement, hemodynamic measurement and histological analysis. mRNA and protein expression were detected by real-time RT-PCR and Western blot analysis. Results M3-mAChR was upregulated in hypertrophic heart, while M2-mAChR expression did not change significantly. M3-mAChR overexpression significantly attenuated the increased expression of atrial natriuretic peptide and β-myosin heavy chain induced by Ang II both in vivo and in vitro. In addition, M3-mAChR overexpression downregulated AT1 receptor expression and inhibited the activation of MAPK signaling in the heart. Conclusion The upregulation of M3-mAChR during myocardial hypertrophy could relieve the hypertrophic response provoked by Ang II, and the mechanism may involve the inhibition of MAPK signaling through the downregulation of AT1 receptor. PMID:24028210

  4. DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

    PubMed Central

    Jurado-López, Raquel; Martínez-Martínez, Ernesto; Gómez-Hurtado, Nieves; Delgado, Carmen; Visitación Bartolomé, Maria; San Román, José Alberto; Cordova, Claudia; Lahera, Vicente; Nieto, Maria Luisa; Cachofeiro, Victoria

    2012-01-01

    Background The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. Methodology/Principal Findings The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. Conclusions/Significance Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac

  5. Cardiac hypertrophy in chick embryos induced by hypothermia

    SciTech Connect

    Boehm, C.; Johnson, T.R.; Caston, J.D.; Przybylski, R.J.

    1987-01-01

    A decrease in incubation temperature from 38 to 32/sup 0/C elicits a decrease in chicken embryo size and weight with concomitant heart enlargement if done after day 10 of incubation. When assayed at day 18 of incubation with the hypothermia started on day 11 or 14, evidence is presented that the heart enlargement is an hypertrophy with no detectable hyperplasia. Supporting data are presented for various physical parameters showing increases in heart wet and dry weight, volume, area, wall thickness, and cell size. There was little difference in DNA content and nuclear (/sup 3/H)thymidine labeling index between hearts of control and hypothermic embryos. Hearts of hypothermic embryos showed a slight increase in water content and considerable increases in RNA, protein, and glycogen content per unit DNA. The average size of polysomes isolated from hypothermic hearts was larger than that of polysomes isolated from controls. Microscopic studies showed no obvious increase in amount of capillary beds, connective tissue, and myocardial cells. Annulate lamellae were found only in myocardial cells of hypothermic embryos in sparse amounts and low frequency but always associated with large deposits of glycogen.

  6. Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway.

    PubMed

    Ding, Wenwen; Dong, Ming; Deng, Jianxin; Yan, Dewen; Liu, Yun; Xu, Teng; Liu, Jie

    2014-09-01

    Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and β-myosin heavy chain (β-MHC) were significantly increased. The amplitude of systolic Ca(2+) transient was increased, and sarcoplasmic reticulum Ca(2+) recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca(2+) handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca(2+) transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca(2+)-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca(2+) transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca(2+)-calcineurin pathway without compromising cardiac contractility. PMID:25015961

  7. Activation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy

    PubMed Central

    Lin, Qun; Huang, Yan; Booth, Carmen J.; Haase, Volker H.; Johnson, Randall S.; Celeste Simon, M.; Giordano, Frank J.; Yun, Zhong

    2013-01-01

    Background Obesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia‐signaling pathway plays an essential role in the development of obesity‐associated cardiomyopathy. Methods and Results Using a mouse model in which the hypoxia‐inducible factor (HIF) pathway is activated by deletion of the von Hippel–Lindau gene specifically in adipocytes, we found that mice with adipocyte–von Hippel–Lindau deletion developed lethal cardiac hypertrophy. HIF activation in adipocytes results in overexpression of key cardiomyopathy‐associated genes in adipose tissue, increased serum levels of several proinflammatory cytokines including interleukin‐1β and monocyte chemotactic protein‐1, and activation of nuclear factor–κB and nuclear factor of activated T cells in the heart. Interestingly, genetic deletion of Hif2a, but not Hif1a, was able to rescue cardiac hypertrophy and abrogate adipose inflammation. Conclusion We have discovered a previously uncharacterized mechanism underlying a critical and direct role of the adipocyte HIF‐2 transcription factor in the development of adipose inflammation and pathological cardiac hypertrophy. PMID:24326162

  8. Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3β and MAPK Signaling Pathways

    PubMed Central

    Wei, Wen-Ying; Ma, Zhen-Guo; Xu, Si-Chi; Zhang, Ning; Tang, Qi-Zhu

    2016-01-01

    Peroxisome proliferator activated receptor γ (PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγ agonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3β and MAPK pathways. PMID:27110236

  9. Diuretics Prevent Thiazolidinedione-Induced Cardiac Hypertrophy without Compromising Insulin-Sensitizing Effects in Mice

    PubMed Central

    Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming; Chen, Ju-Yi; Ho, Li-Chun; Pandya, Kumar; Maeda, Nobuyo; Tsai, Yau-Sheng

    2015-01-01

    Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg+/−) mice, but not in mice defective for ligand binding (PpargP465L/+). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity. PMID:24287404

  10. AMP-Activated Protein Kinase Signalling in Cancer and Cardiac Hypertrophy

    PubMed Central

    Lipovka, Yulia; Konhilas, John P

    2015-01-01

    The AMP-protein kinase (AMPK) pathway is very versatile as it regulates cellular energetic homeostasis in many different tissue types. An appreciation for the importance of AMPK signalling and regulation in cardiovascular and tumor biology is increasing. Recently, a link has been established between anti-cancer therapy and susceptibility to cardiac disease. It has been shown that some anti-cancer drugs lead to an increased risk of cardiac disease, underlined by de-regulation of AMPK signalling. This review explores the AMPK signalling axis in both cardiac and tumor metabolism. We then examine off-target AMPK inhibition by cancer drugs and how this may translate into increased risk of cardiovascular disease. Finally, we discuss the implication of deregulated AMPK signalling during different stages of cardiac hypertrophy. Better understanding of the molecular pathways behind pathological processes will lead to the development of more effective therapeutics for cancer and cardiovascular diseases. PMID:26798768

  11. Influence of natriuretic peptide receptor-1 on survival and cardiac hypertrophy during development

    PubMed Central

    Scott, Nicola J.A.; Ellmers, Leigh. J.; Lainchbury, John G.; Maeda, Nobuyo; Smithies, Oliver; Richards, A. Mark; Cameron, Vicky A.

    2010-01-01

    The heart adapts to an increased workload through the activation of a hypertrophic response within the cardiac ventricles. This response is characterized by both an increase in the size of the individual cardiomyocytes and an induction of a panel of genes normally expressed in the embryonic and neonatal ventricle, such as atrial natriuretic peptide (ANP). ANP and brain natriuretic peptide (BNP) exert their biological actions through activation of the natriuretic peptide receptor-1 (Npr1). The current study examined mice lacking Npr1 (Npr1−/−) activity and investigated the effects of the absence of Npr1 signaling during cardiac development on embryo viability, cardiac structure and gene and protein expression. Npr1−/−embryos were collected at embryonic day (ED) 12.5, 15.5 and neonatal day 1 (ND 1). Npr1−/−embryos occurred at the expected Mendelian frequency at ED 12.5, but knockout numbers were significantly decreased at ED 15.5 and ND 1. There was no indication of cardiac structural abnormalities in surviving embryos. However, Npr1−/−embryos exhibited cardiac enlargement (without fibrosis) from ED 15.5 as well as significantly increased ANP mRNA and protein expression compared to wild-type (WT) mice, but no concomitant increase in expression of the hypertrophy-related transcription factors, Mef2A, Mef2C, GATA-4, GATA-6 or serum response factor (SRF). However, there was a significant decrease in Connexin-43 (Cx43) gene and protein expression at mid-gestation in Npr1−/−embryos. Our findings suggest that the mechanism by which natriuretic peptide signaling influences cardiac development in Npr1−/− mice is distinct from that seen during the development of pathological cardiac hypertrophy and fibrosis. The decreased viability of Npr1−/−embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility. PMID:19782130

  12. Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story.

    PubMed

    Elnakish, Mohammad T; Ahmed, Amany A E; Mohler, Peter J; Janssen, Paul M L

    2015-01-01

    Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models. PMID:26146529

  13. Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

    PubMed Central

    Elnakish, Mohammad T.; Ahmed, Amany A. E.; Mohler, Peter J.; Janssen, Paul M. L.

    2015-01-01

    Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models. PMID:26146529

  14. NMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy.

    PubMed

    Yue, Zhongbao; Ma, Yunzi; You, Jia; Li, Zhuoming; Ding, Yanqing; He, Ping; Lu, Xia; Jiang, Jianmin; Chen, Shaorui; Liu, Peiqing

    2016-10-01

    Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease (OHD), which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in Angiotension II (Ang II)-treated cardiomyocytes and in hearts of Ang II-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy. In particular, SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3. Specifically, SIRT3 physically interacts with and deacetylates NMNAT3, thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects. Moreover, NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD. Taken together, these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.

  15. Puerarin prevents cardiac hypertrophy induced by pressure overload through activation of autophagy.

    PubMed

    Liu, Bei; Wu, Zhiye; Li, Yunpeng; Ou, Caiwen; Huang, Zhenjun; Zhang, Jianwu; Liu, Peng; Luo, Chengfeng; Chen, Minsheng

    2015-08-28

    This study aimed to explore the effects of puerarin on autophagy in cardiac hypertrophy. Decreased 5'-adenosine monophosphate kinase (AMPK) activity alone with inhibited autophagy could be detected in rats within 3 weeks after aortic banding (AB). Puerarin treatment for 3 weeks in AB rats significantly restored autophagy. Administration of puerarin for 6 weeks effectively restricted cardiomyocyte hypertrophy and apoptosis. In an in vitro study, similar anti-hypertrophy and anti-apoptosis effects of puerarin on isoprenaline-induced H9c2 cells were also observed. After inhibition of autophagy by pretreatment with 3-methyladenine, the protective effects of puerarin were blocked. Further in vivo study demonstrated that puerarin significantly enabled phosphorylation of 5'-AMPK to be activated, subsequently inhibiting expression of the mammalian target of rapamycin (mTOR) target proteins S6 ribosomal protein and 4E-binding protein 1. All these data indicate that puerarin exerts protective effects against cardiomyocyte hypertrophy and apoptosis, partly by restoration of autophagy through AMPK/mTOR-mediated signaling. PMID:26188094

  16. Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy.

    PubMed

    Xu, Xihui; Hua, Yinan; Nair, Sreejayan; Bucala, Richard; Ren, Jun

    2014-03-01

    The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be cardioprotective under various pathological conditions. However, the underlying mechanisms still remain elusive. In this study, we revealed that MIF deficiency overtly exacerbated abdominal aorta constriction-induced cardiac hypertrophy and contractile anomalies. MIF deficiency interrupted myocardial autophagy in hypertrophied hearts. Rapamycin administration mitigated the exacerbated hypertrophic responses in MIF(-/-) mice. Using the phenylephrine-induced hypertrophy in vitro model in H9C2 myoblasts, we confirmed that MIF governed the activation of AMP-activated protein kinase-mammalian target of rapamycin-autophagy cascade. Confocal microscopic examination demonstrated that MIF depletion prevented phenylephrine-induced mitophagy in H9C2 myoblasts. Myocardial Parkin, an E3 ubiquitin ligase and a marker for mitophagy, was significantly upregulated after sustained pressure overload, the effect of which was prevented by MIF knockout. Furthermore, our data exhibited that levels of MIF, AMP-activated protein kinase activation, and autophagy were elevated concurrently in human failing hearts. These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses. PMID:24366076

  17. Whole transcriptome microarrays identify long non-coding RNAs associated with cardiac hypertrophy

    PubMed Central

    Zhang, Lu; Hamad, Eman A.; Vausort, Mélanie; Funakoshi, Hajime; Nicot, Nathalie; Nazarov, Petr V.; Vallar, Laurent; Feldman, Arthur M.; Wagner, Daniel R.; Devaux, Yvan

    2015-01-01

    Long non-coding RNAs (lncRNAs) have recently emerged as a novel group of non-coding RNAs able to regulate gene expression. While their role in cardiac disease is only starting to be understood, their involvement in cardiac hypertrophy is poorly known. We studied the association between lncRNAs and left ventricular hypertrophy using whole transcriptome microarrays. Wild-type mice and mice overexpressing the adenosine A2A receptor were subjected to transverse aortic constriction (TAC) to induce left ventricular hypertrophy. Expression profiles of lncRNAs in the heart were characterized using genome-wide microarrays. An analytical pipeline was specifically developed to extract lncRNA data from microarrays. We identified 2 lncRNAs up-regulated and 3 lncRNAs down-regulated in the hearts of A2A-receptor overexpressing-mice subjected to TAC compared to wild-type mice. Differential expression of these 2 lncRNAs was validated by quantitative PCR. Complete microarray dataset is available at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE45423. Here, we describe in details the experimental design, microarray performance and analysis. PMID:26484228

  18. Whole transcriptome microarrays identify long non-coding RNAs associated with cardiac hypertrophy.

    PubMed

    Zhang, Lu; Hamad, Eman A; Vausort, Mélanie; Funakoshi, Hajime; Nicot, Nathalie; Nazarov, Petr V; Vallar, Laurent; Feldman, Arthur M; Wagner, Daniel R; Devaux, Yvan

    2015-09-01

    Long non-coding RNAs (lncRNAs) have recently emerged as a novel group of non-coding RNAs able to regulate gene expression. While their role in cardiac disease is only starting to be understood, their involvement in cardiac hypertrophy is poorly known. We studied the association between lncRNAs and left ventricular hypertrophy using whole transcriptome microarrays. Wild-type mice and mice overexpressing the adenosine A2A receptor were subjected to transverse aortic constriction (TAC) to induce left ventricular hypertrophy. Expression profiles of lncRNAs in the heart were characterized using genome-wide microarrays. An analytical pipeline was specifically developed to extract lncRNA data from microarrays. We identified 2 lncRNAs up-regulated and 3 lncRNAs down-regulated in the hearts of A2A-receptor overexpressing-mice subjected to TAC compared to wild-type mice. Differential expression of these 2 lncRNAs was validated by quantitative PCR. Complete microarray dataset is available at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE45423. Here, we describe in details the experimental design, microarray performance and analysis. PMID:26484228

  19. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.

    PubMed

    McDermott-Roe, Chris; Ye, Junmei; Ahmed, Rizwan; Sun, Xi-Ming; Serafín, Anna; Ware, James; Bottolo, Leonardo; Muckett, Phil; Cañas, Xavier; Zhang, Jisheng; Rowe, Glenn C; Buchan, Rachel; Lu, Han; Braithwaite, Adam; Mancini, Massimiliano; Hauton, David; Martí, Ramon; García-Arumí, Elena; Hubner, Norbert; Jacob, Howard; Serikawa, Tadao; Zidek, Vaclav; Papousek, Frantisek; Kolar, Frantisek; Cardona, Maria; Ruiz-Meana, Marisol; García-Dorado, David; Comella, Joan X; Felkin, Leanne E; Barton, Paul J R; Arany, Zoltan; Pravenec, Michal; Petretto, Enrico; Sanchis, Daniel; Cook, Stuart A

    2011-10-05

    Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

  20. Hypoxic Preconditioning Inhibits Hypoxia-induced Apoptosis of Cardiac Progenitor Cells via the PI3K/Akt-DNMT1-p53 Pathway

    PubMed Central

    Xu, Rongfeng; Sun, Yuning; Chen, Zhongpu; Yao, Yuyu; Ma, Genshan

    2016-01-01

    Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen–serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3β were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3β did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3β, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus. PMID:27488808

  1. Attenuation of the hypoxia-induced protein kinase Cdelta interaction with the 'd' subunit of F1Fo-ATP synthase in neonatal cardiac myocytes: implications for energy preservation and survival.

    PubMed

    Nguyen, Tiffany T; Ogbi, Mourad; Yu, Qilin; Johnson, John A

    2010-07-15

    The F1Fo-ATP synthase provides most of the heart's energy, yet events that alter its function during injury are poorly understood. Recently, we described a potent inhibitory effect on F1Fo-ATP synthase function mediated by the interaction of PKCdelta (protein kinase Cdelta) with dF1Fo ('d' subunit of the F1Fo-ATPase/ATP synthase). We have now developed novel peptide modulators which facilitate or inhibit the PKCdelta-dF1Fo interaction. These peptides include HIV-Tat (transactivator of transcription) protein transduction and mammalian mitochondrial-targeting sequences. Pre-incubation of NCMs (neonatal cardiac myocyte) with 10 nM extracellular concentrations of the mitochondrial-targeted PKCdelta-dF1Fo interaction inhibitor decreased Hx (hypoxia)-induced co-IP (co-immunoprecipitation) of PKCdelta with dF1Fo by 40+/-9%, abolished Hx-induced inhibition of F1Fo-ATPase activity, attenuated Hx-induced losses in F1Fo-derived ATP and protected against Hx- and reperfusion-induced cell death. A scrambled-sequence (inactive) peptide, which contained HIV-Tat and mitochondrial-targeting sequences, was without effect. In contrast, the cell-permeant mitochondrial-targeted PKCdelta-dF1Fo facilitator peptide, which we have shown previously to induce the PKCdelta-dF1Fo co-IP, was found to inhibit F1Fo-ATPase activity to an extent similar to that caused by Hx alone. The PKCdelta-dF1Fo facilitator peptide also decreased ATP levels by 72+/-18% under hypoxic conditions in the presence of glycolytic inhibition. None of the PKCdelta-dF1Fo modulatory peptides altered the inner mitochondrial membrane potential. Our studies provide the first evidence that disruption of the PKCdelta-dF1Fo interaction using cell-permeant mitochondrial-targeted peptides attenuates cardiac injury resulting from prolonged oxygen deprivation.

  2. Reversible cardiac hypertrophy induced by PEG-coated gold nanoparticles in mice

    PubMed Central

    Yang, Chengzhi; Tian, Aiju; Li, Zijian

    2016-01-01

    Gold nanoparticles (GNPs) are attracting more and more attention for their great potential value in biomedical application. Currently, no study has been reported on the chronic cardiac toxicity of GNPs after repeated administration. Here we carried out a comprehensive evaluation of the chronic cardiac toxicity of GNPs to the heart. Polyethylene glycol (PEG) -coated GNPs at three different sizes (10, 30 and 50 nm) or PBS was administrated to mice via tail vein for 14 consecutive days. Then the mice were euthanized at 2 weeks, 4 weeks or 12 weeks after the first injection. The accumulation of GNPs in the mouse heart and their effects on cardiac function, structure, fibrosis and inflammation were analysized. GNPs with smaller size showed higher accumulation and faster elimination. None of the three sizes of GNPs affected cardiac systolic function. The LVIDd (left ventricular end-diastolicinner-dimension), LVMass (left ventricular mass) and HW/BW (heart weight/body weight) were significantly increased in the mice receiving 10 nm PEG-GNPs for 2 weeks, but not for 4 weeks or 12 weeks. These results indicated that the accumulation of small size GNPs can induce reversible cardiac hypertrophy. Our results provide the basis for the further biomedical applications of GNPs in cardiac diseases. PMID:26830764

  3. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

    PubMed Central

    Lee, Eunjo; Song, Min-ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung

    2016-01-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

  4. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

    PubMed Central

    Lee, Eunjo; Song, Min-ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung

    2016-01-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats. PMID:27610034

  5. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

    PubMed

    Lee, Eunjo; Song, Min-Ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

    2016-09-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats. PMID:27610034

  6. Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice.

    PubMed

    Han, Jung Woo; Lee, Young Ho; Yoen, Su-In; Abramowitz, Joel; Birnbaumer, Lutz; Lee, Min Goo; Kim, Joo Young

    2016-10-01

    Sustained elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) reprograms cardiovascular cell fate, leading to cellular hypertrophy via Ca(2+)-calmodulin/calcineurin (Cn)/NFAT activation. Accumulating evidence suggests that transient receptor potential canonical (Trpc) channels play important roles in the development of pathologic cardiac hypertrophy. Here, we demonstrated that Trpc3 mediates pathologic cardiac hypertrophy in neurohumoral elevation via direct regulation of CaV1.2 expressions. Elevated PE (phenylephrine) was maintained in mice by continuous infusion using an osmotic pump. Wild-type (WT) mice, but not Trpc3 (-/-) showed a sudden decrease in blood pressure (BP) or death following elevation of BP under conditions of elevated PE. Trpc3 (-/-) mesenteric artery showed decreased PE-stimulated vasoconstriction. Analysis of morphology, function, and pathologic marker expression revealed that PE elevation caused pathologic cardiac hypertrophy in WT mice, which was prevented by deletion of Trpc3. Interestingly, protection by Trpc3 deletion seemed to be a result of reduced cardiac CaV1.2 expressions. Basal and PE induced increased expression of protein and mRNA of CaV1.2 was decreased in Trpc3 (-/-) heart. Accordingly, altered expression of CaV1.2 was observed by knockdown or stimulation of Trpc3 in cardiomyocytes. These findings suggest that Trpc3 is a mediator of pathologic cardiac hypertrophy not only through mediating part of the Ca(2+) influx, but also through control of CaV1.2 expressions.

  7. Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor.

    PubMed

    Mishra, S; Bedja, D; Amuzie, C; Foss, C A; Pomper, M G; Bhattacharya, R; Yarema, K J; Chatterjee, S

    2015-09-01

    D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with (125)I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using γ-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE-/- mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism.

  8. Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy.

    PubMed

    Giordano, Emanuele; Hillary, Rebecca A; Vary, Thomas C; Pegg, Anthony E; Sumner, Andrew D; Caldarera, Claudio M; Zhang, Xue-Qian; Song, Jianliang; Wang, JuFang; Cheung, Joseph Y; Shantz, Lisa M

    2012-02-01

    Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to β-adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC-ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl-isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to β-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility.

  9. Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor

    PubMed Central

    Foss, C.A.; Pomper, M.G.; Bhattacharya, R.; Yarema, K.J.; Chatterjee, S.

    2015-01-01

    D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with 125I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using γ-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE−/− mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism. PMID:26111596

  10. Aging reduces the efficacy of estrogen substitution to attenuate cardiac hypertrophy in female spontaneously hypertensive rats.

    PubMed

    Jazbutyte, Virginija; Hu, Kai; Kruchten, Patricia; Bey, Emmanuel; Maier, Sebastian K G; Fritzemeier, Karl-Heinrich; Prelle, Katja; Hegele-Hartung, Christa; Hartmann, Rolf W; Neyses, Ludwig; Ertl, Georg; Pelzer, Theo

    2006-10-01

    Clinical trials failed to show a beneficial effect of postmenopausal hormone replacement therapy, whereas experimental studies in young animals reported a protective function of estrogen replacement in cardiovascular disease. Because these diverging results could in part be explained by aging effects, we compared the efficacy of estrogen substitution to modulate cardiac hypertrophy and cardiac gene expression among young (age 3 months) and senescent (age 24 months) spontaneously hypertensive rats (SHRs), which were sham operated or ovariectomized and injected with placebo or identical doses of 17beta-estradiol (E2; 2 microg/kg body weight per day) for 6 weeks (n=10/group). Blood pressure was comparable among sham-operated senescent and young SHRs and not altered by ovariectomy or E2 treatment among young or among senescent rats. Estrogen substitution inhibited uterus atrophy and gain of body weight in young and senescent ovariectomized SHRs, but cardiac hypertrophy was attenuated only in young rats. Cardiac estrogen receptor-alpha expression was lower in intact and in ovariectomized senescent compared with young SHRs and increased with estradiol substitution in aged rats. Plasma estradiol and estrone levels were lower not only in sham-operated but surprisingly also in E2-substituted senescent SHRs and associated with a reduction of hepatic 17beta-hydroxysteroid dehydrogenase type 1 enzyme activity, which converts weak (ie, estrone) into potent estrogens, such as E2. Aging attenuates the antihypertrophic effect of estradiol in female SHRs and is associated with profound alterations in cardiac estrogen receptor-alpha expression and estradiol metabolism. These observations contribute to explain the lower efficiency of estrogen substitution in senescent SHRs.

  11. Cardiac effects of anabolic steroids: hypertrophy, ischemia and electrical remodelling as potential triggers of sudden death.

    PubMed

    Nascimento, J H M; Medei, E

    2011-05-01

    Anabolic-androgenic steroids (AAS) are synthetic testosterone derivatives developed to maximise anabolic activity and minimise androgenic activity. AAS abuse is widespread among both athletes and non-athletes at fitness centres and is becoming a public health issue. In addition to their atherogenic, thrombogenic and spastic effects, AAS have direct cardiotoxic effects by causing hypertrophy, electrical and structural remodelling, and contractile dysfunction and by increasing the susceptibility to ischemic injuries. All of these factors contribute to an increased risk of ventricular arrhythmias and sudden cardiac death.

  12. MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy.

    PubMed

    Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian; Walsh, Aaron; Liu, Lijun; Williams, Kandace; Joe, Bina; de la Serna, Ivana L

    2015-11-01

    The transcriptional regulation of pathological cardiac hypertrophy involves the interplay of transcription factors and chromatin remodeling enzymes. The Microphthalmia-Associated Transcription Factor (MITF) is highly expressed in cardiomyocytes and is required for cardiac hypertrophy. However, the transcriptional mechanisms by which MITF promotes cardiac hypertrophy have not been elucidated. In this study, we tested the hypothesis that MITF promotes cardiac hypertrophy by activating transcription of pro-hypertrophy genes through interactions with the SWI/SNF chromatin remodeling complex. In an in vivo model of cardiac hypertrophy, expression of MITF and the BRG1 subunit of the SWI/SNF complex increased coordinately in response to pressure overload. Expression of MITF and BRG1 also increased in vitro when cardiomyocytes were stimulated with angiotensin II or a β-adrenergic agonist. Both MITF and BRG1 were required to increase cardiomyocyte size and activate expression of hypertrophy markers in response to β-adrenergic stimulation. We detected physical interactions between MITF and BRG1 in cardiomyocytes and found that they cooperate to regulate expression of a pro-hypertrophic transcription factor, GATA4. Our data show that MITF binds to the E box element in the GATA4 promoter and facilitates recruitment of BRG1. This is associated with enhanced expression of the GATA4 gene as evidenced by increased Histone3 lysine4 tri-methylation (H3K4me3) on the GATA4 promoter. Thus, in hypertrophic cardiomyoctes, MITF is a key transcriptional activator of a pro-hypertrophic gene, GATA4, and this regulation is dependent upon the BRG1 component of the SWI/SNF complex. PMID:26388265

  13. Hypertrophy of Neurons Within Cardiac Ganglia in Human, Canine, and Rat Heart Failure: The Potential Role of Nerve Growth Factor

    PubMed Central

    Singh, Sanjay; Sayers, Scott; Walter, James S.; Thomas, Donald; Dieter, Robert S.; Nee, Lisa M.; Wurster, Robert D.

    2013-01-01

    Background Autonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hypertrophied in human, canine, and rat heart failure and that nerve growth factor, which we hypothesize is elevated in the failing heart, contributes to this neuronal hypertrophy. Methods and Results Somal morphology of neurons from human (579.54±14.34 versus 327.45±9.17 μm2; P<0.01) and canine hearts (767.80±18.37 versus 650.23±9.84 μm2; P<0.01) failing secondary to ischemia and neurons from spontaneously hypertensive rat hearts (327.98±3.15 versus 271.29±2.79 μm2; P<0.01) failing secondary to hypertension reveal significant hypertrophy of neurons in cardiac ganglia compared with controls. Western blot analysis shows that nerve growth factor levels in the explanted, failing human heart are 250% greater than levels in healthy donor hearts. Neurons from cardiac ganglia cultured with nerve growth factor are significantly larger and have greater dendritic arborization than neurons in control cultures. Conclusions Hypertrophied neurons are significantly less excitable than smaller ones; thus, hypertrophy of vagal postganglionic neurons in cardiac ganglia would help to explain the parasympathetic withdrawal that accompanies heart failure. Furthermore, our observations suggest that nerve growth factor, which is elevated in the failing human heart, causes hypertrophy of neurons in cardiac ganglia. PMID:23959444

  14. MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy.

    PubMed

    Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian; Walsh, Aaron; Liu, Lijun; Williams, Kandace; Joe, Bina; de la Serna, Ivana L

    2015-11-01

    The transcriptional regulation of pathological cardiac hypertrophy involves the interplay of transcription factors and chromatin remodeling enzymes. The Microphthalmia-Associated Transcription Factor (MITF) is highly expressed in cardiomyocytes and is required for cardiac hypertrophy. However, the transcriptional mechanisms by which MITF promotes cardiac hypertrophy have not been elucidated. In this study, we tested the hypothesis that MITF promotes cardiac hypertrophy by activating transcription of pro-hypertrophy genes through interactions with the SWI/SNF chromatin remodeling complex. In an in vivo model of cardiac hypertrophy, expression of MITF and the BRG1 subunit of the SWI/SNF complex increased coordinately in response to pressure overload. Expression of MITF and BRG1 also increased in vitro when cardiomyocytes were stimulated with angiotensin II or a β-adrenergic agonist. Both MITF and BRG1 were required to increase cardiomyocyte size and activate expression of hypertrophy markers in response to β-adrenergic stimulation. We detected physical interactions between MITF and BRG1 in cardiomyocytes and found that they cooperate to regulate expression of a pro-hypertrophic transcription factor, GATA4. Our data show that MITF binds to the E box element in the GATA4 promoter and facilitates recruitment of BRG1. This is associated with enhanced expression of the GATA4 gene as evidenced by increased Histone3 lysine4 tri-methylation (H3K4me3) on the GATA4 promoter. Thus, in hypertrophic cardiomyoctes, MITF is a key transcriptional activator of a pro-hypertrophic gene, GATA4, and this regulation is dependent upon the BRG1 component of the SWI/SNF complex.

  15. Cardiac hypertrophy and failure--a disease of adaptation. Modifications in membrane proteins provide a molecular basis for arrhythmogenicity.

    PubMed

    Moalic, J M; Charlemagne, D; Mansier, P; Chevalier, B; Swynghedauw, B

    1993-05-01

    Cardiac hypertrophy is the physiological adaptation of the heart to chronic mechanical overload. Cardiac failure indicates the limits of the process. Cardiac hypertrophy is only one example of biological adaptation and results from the induction of several changes in gene expression, mostly of the fetal type, including those coding for the myosin heavy chain or the alpha-subunit of the Na+,K(+)-ATPase. From a thermodynamic point of view, the decrease in Vmax allows the heart to produce a normal tension at a lower cost. This process results from changes both in the sarcomere and in the expression of certain membrane proteins. The decrease in calcium transient is determined by several changes in membrane proteins that result in a rather fragile equilibrium in terms of calcium homeostasis. Any abnormal input in calcium will have exaggerated detrimental consequences on a hypertrophied myocyte and may cause automaticity and arrhythmias or an exaggerated response to anoxia in terms of compliance. PMID:8485830

  16. The effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone on the pressure overload-induced progression of cardiac hypertrophy to cardiac failure.

    PubMed

    Huang, Jianchun; Tang, XiaoJun; Liang, Xingmei; Wen, Qingwei; Zhang, Shijun; Xuan, Feifei; Jian, Jie; Lin, Xing; Huang, Renbin

    2014-01-01

    We investigated the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC), which was isolated from the roots of Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (Papilionaceae) (MKL), on the progression of cardiac hypertrophy to failure in a rat model of abdominal aortic banding (AAB)-induced pressure overloading. Endothelial dysfunction is central to pressure overload-induced cardiac hypertrophy and failure. It would be useful to clarify whether MHBFC could prevent this dysfunction. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using the progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats exhibited a greater progression to heart failure and had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, and evidence of left ventricular hypertrophy (LVH). LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These symptoms could be prevented by treatment with MHBFC at daily oral doses of 6 and 12 mg/kg for 6 weeks. The progression to cardiac failure, which was demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial natriuretic peptide (ANP) mRNA, could also be prevented. Furthermore, MHBFC partialy rescued the downregulated nitric oxide signaling system, whereas inhibited the upregulated endothelin signaling system, normalizing the balance between these two systems. MHBFC protected the endothelium and prevented the pressure overload-induced progression of cardiac hypertrophy to cardiac failure. PMID:24622486

  17. The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on the Pressure Overload-Induced Progression of Cardiac Hypertrophy to Cardiac Failure

    PubMed Central

    Liang, Xingmei; Wen, Qingwei; Zhang, Shijun; Xuan, Feifei; Jian, Jie; Lin, Xing; Huang, Renbin

    2014-01-01

    We investigated the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC), which was isolated from the roots of Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (Papilionaceae) (MKL), on the progression of cardiac hypertrophy to failure in a rat model of abdominal aortic banding (AAB)-induced pressure overloading. Endothelial dysfunction is central to pressure overload-induced cardiac hypertrophy and failure. It would be useful to clarify whether MHBFC could prevent this dysfunction. The effects of pressure overload were assessed in male Sprague–Dawley rats 6 weeks after AAB using the progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats exhibited a greater progression to heart failure and had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, and evidence of left ventricular hypertrophy (LVH). LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These symptoms could be prevented by treatment with MHBFC at daily oral doses of 6 and 12 mg/kg for 6 weeks. The progression to cardiac failure, which was demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial natriuretic peptide (ANP) mRNA, could also be prevented. Furthermore, MHBFC partialy rescued the downregulated nitric oxide signaling system, whereas inhibited the upregulated endothelin signaling system, normalizing the balance between these two systems. MHBFC protected the endothelium and prevented the pressure overload-induced progression of cardiac hypertrophy to cardiac failure. PMID:24622486

  18. Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin.

    PubMed

    Paul, David S; Grevengoed, Trisha J; Pascual, Florencia; Ellis, Jessica M; Willis, Monte S; Coleman, Rosalind A

    2014-06-01

    In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1(H-/-)), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1(H-/-) hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1(H-/-) hearts exhibited an 8-fold higher uptake of 2-deoxy[1-(14)C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-(14)C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1(H-/-) mice. PMID:24631848

  19. The effects of compensated cardiac hypertrophy on dihydropyridine and ryanodine receptors in rat, ferret and guinea-pig hearts.

    PubMed

    Rannou, F; Sainte-Beuve, C; Oliviero, P; Do, E; Trouvé, P; Charlemagne, D

    1995-05-01

    The number of dihydropyridine and ryanodine receptors (DHP-R and RyR) has been measured in control and hypertrophied ventricles from rats, guinea pigs and ferrets to determine whether these two channels contribute to the alterations in excitation-contraction coupling (ECC), and in Ca2+ transient during compensated cardiac hypertrophy. We found that ventricular hypertrophy did not change the density of DHP-R. Mild hypertrophy did not alter the density of RyR in the rat but decreased it in the guinea-pig and in the ferret (30% and 36%, respectively). Severe hypertrophy decreased the density of RyR by 20% in the rat and by 34% in the guinea-pig. Therefore, the decrease is greater in ferret and guinea-pig hearts than in rat heart. We conclude that the sarcoplasmic reticulum (SR) Ca2+ release channels but not the L-type Ca2+ channels could contribute to the slowing of intracellular Ca2+ movements and to the reduced velocity of shortening of the hypertrophied hearts. We suggest that, in the guinea pig and ferret hearts which express only the beta myosin heavy chain (MHC) isoform, the reduced velocity of shortening during hypertrophy is related to the decrease in RyR density, whereas in the rat, it is regulated primarily via a shift in the MHC isoform, except in severe hypertrophy in which the moderate decrease in RyR would also be involved. PMID:7473781

  20. Integrated glycoprotein immobilization method for glycopeptide and glycan analysis of cardiac hypertrophy.

    PubMed

    Yang, Shuang; Mishra, Sumita; Chen, Lijun; Zhou, Jian-Ying; Chan, Daniel W; Chatterjee, Subroto; Zhang, Hui

    2015-10-01

    Post-translational modifications of proteins can have a major role in disease initiation and progression. Incredible efforts have recently been made to study the regulation of glycoproteins for disease prognosis and diagnosis. It is essential to elucidate glycans and intact glycoproteins to understand the role of glycosylation in diseases. Sialylated N-glycans play crucial roles in physiological and pathological processes; however, it is laborious to study sialylated glycoproteins due to the labile nature of sialic acid residues. In this study, an integrated platform is developed for the analysis of intact glycoproteins and glycans using a chemoenzymatic approach for immobilization and derivatization of sialic acids. N-Glycans, deglycosylated proteins, and intact glycoproteins from heart tissues of wild type (WT) and transverse aortic constriction (TAC) mouse models were analyzed. We identified 291 unique glycopeptides from 195 glycoproteins; the comparative studies between WT and TAC mice indicate the overexpression of extracellular proteins for heart matrix remodeling and the down-regulation of proteins associated with energy metabolism in cardiac hypertrophy. The integrated platform is a powerful tool for the analysis of glycans and glycoproteins in the discovery of potential cardiac hypertrophy biomarkers.

  1. Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia

    PubMed Central

    Ducat, Aurélien; Doridot, Ludivine; Calicchio, Rosamaria; Méhats, Celine; Vilotte, Jean-Luc; Castille, Johann; Barbaux, Sandrine; Couderc, Betty; Jacques, Sébastien; Letourneur, Franck; Buffat, Christophe; Le Grand, Fabien; Laissue, Paul; Miralles, Francisco; Vaiman, Daniel

    2016-01-01

    Preeclampsia is a disease of pregnancy involving systemic endothelial dysfunction. However, cardiovascular consequences of preeclampsia are difficult to analyze in humans. The objective of the present study is to evaluate the cardiovascular dysfunction induced by preeclampsia by examining the endothelium of mice suffering of severe preeclampsia induced by STOX1 overexpression. Using Next Generation Sequencing on endothelial cells of mice carrying either transgenic or control embryos, we discovered significant alterations of gene networks involved in inflammation, cell cycle, and cardiac hypertrophy. In addition, the heart of the preeclamptic mice revealed cardiac hypertrophy associated with histological anomalies. Bioinformatics comparison of the networks of modified genes in the endothelial cells of the preeclamptic mice and HUVECs exposed to plasma from preeclamptic women identified striking similarities. The cardiovascular alterations in the pregnant mice are comparable to those endured by the cardiovascular system of preeclamptic women. The STOX1 mice could help to better understand the endothelial dysfunction in the context of preeclampsia, and guide the search for efficient therapies able to protect the maternal endothelium during the disease and its aftermath. PMID:26758611

  2. Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload

    PubMed Central

    Zhang, Yi; Huang, Yan; Cantalupo, Anna; Azevedo, Paula S.; Siragusa, Mauro; Bielawski, Jacek; Giordano, Frank J.; Di Lorenzo, Annarita

    2016-01-01

    We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α–activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological cardiac hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B–deficient mice to WT levels, whereas SEW2871, an S1P1 receptor agonist, prevents myocardial permeability, inflammation, and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy and proposes a potential therapeutic target for the attenuation or reversal of this clinical condition. PMID:27158676

  3. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.

    PubMed

    Grabner, Alexander; Amaral, Ansel P; Schramm, Karla; Singh, Saurav; Sloan, Alexis; Yanucil, Christopher; Li, Jihe; Shehadeh, Lina A; Hare, Joshua M; David, Valentin; Martin, Aline; Fornoni, Alessia; Di Marco, Giovana Seno; Kentrup, Dominik; Reuter, Stefan; Mayer, Anna B; Pavenstädt, Hermann; Stypmann, Jörg; Kuhn, Christian; Hille, Susanne; Frey, Norbert; Leifheit-Nestler, Maren; Richter, Beatrice; Haffner, Dieter; Abraham, Reimar; Bange, Johannes; Sperl, Bianca; Ullrich, Axel; Brand, Marcus; Wolf, Myles; Faul, Christian

    2015-12-01

    Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

  4. C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle.

    PubMed

    Olson, Aaron K; Ledee, Dolena; Iwamoto, Kate; Kajimoto, Masaki; O'Kelly Priddy, Colleen; Isern, Nancy; Portman, Michael A

    2013-02-01

    The protooncogene C-Myc (Myc) regulates cardiac hypertrophy. Myc promotes compensated cardiac function, suggesting that the operative mechanisms differ from those leading to heart failure. Myc regulation of substrate metabolism is a reasonable target, as Myc alters metabolism in other tissues. We hypothesize that Myc induced shifts in substrate utilization signal and promote compensated hypertrophy. We used cardiac specific Myc-inducible C57/BL6 male mice between 4-6 months old that develop hypertrophy with tamoxifen (tam) injections. Isolated working hearts and (13)Carbon ((13)C)-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing (13)C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and insulin. Studies were performed at pre-hypertrophy (3-days tam, 3dMyc), established hypertrophy (7-days tam, 7dMyc) or vehicle control (Cont). Non-transgenic siblings (NTG) received 7-days tam or vehicle to assess drug effect. Hypertrophy was assessed by echocardiograms and heart weights. Western blots were performed on key metabolic enzymes. Hypertrophy occurred in 7dMyc only. Cardiac function did not differ between groups. Tam alone did not affect substrate contributions in NTG. Substrate utilization was not significantly altered in 3dMyc versus Cont. The free fatty acid FC was significantly greater in 7dMyc versus Cont with decreased unlabeled Fc, which is predominately exogenous glucose. Free fatty acid flux to the citric acid cycle increased while lactate flux was diminished in 7dMyc compared to Cont. Total protein levels of a panel of key metabolic enzymes were unchanged; however total protein O-GlcNAcylation was increased in 7dMyc. Substrate utilization changes for the citric acid cycle did not precede hypertrophy; therefore they are not the primary signal for cardiac growth in this model. Free fatty acid utilization and oxidation increase at established hypertrophy. Understanding the

  5. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial SIRT3

    PubMed Central

    Pillai, Vinodkumar B.; Samant, Sadhana; Sundaresan, Nagalingam R.; Raghuraman, Hariharasundaram; Kim, Gene; Bonner, Michael Y.; Arbiser, Jack L.; Walker, Douglas I.; Jones, Dean P.; Gius, David; Gupta, Mahesh P.

    2015-01-01

    Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumor and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase SIRT3. We demonstrate that HKL is present in mitochondria, enhances SIRT3 expression nearly two-fold and suggest that HKL may bind to SIRT3 to further increase its activity. Increased SIRT3 activity is associated with reduced acetylation of mitochondrial SIRT3 substrates, MnSOD and OSCP. HKL-treatment increases mitochondrial rate of oxygen consumption and reduces ROS synthesis in wild-type, but not in SIRT3-KO cells. Moreover, HKL-treatment blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in SIRT3-dependent manner. These results suggest that HKL is a pharmacological activator of SIRT3 capable of blocking, and even reversing, the cardiac hypertrophic response. PMID:25871545

  6. Integration of cardiac myofilament activity and regulation with pathways signaling hypertrophy and failure.

    PubMed

    de Tombe, P P; Solaro, R J

    2000-08-01

    The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function, which is eventually lethal. The mechanisms that underlie the decline in cardiac function are incompletely understood. A central theme in solving the mystery of heart failure is the identification of mechanisms by which the myofilament contractile machine of the myocardium is altered in CHF and how these alterations act in concert with pathways that signal cell growth and death. The cardiac myofilaments are a point of confluence of signals that promote the hypertrophic/failure process. Our hypothesis is that a prevailing hemodynamic stress leads to an increased strain on the myocardium. The increased strain in turn leads to miscues of the normal physiological pathway by which heart cells are signaled to match and adapt the intensity and dynamics of their mechanical activity to prevailing hemodynamic demands. These miscues result in a maladaptation to the stressor and failure of the heart to respond to hemodynamic loads at optimal end diastolic volumes. The result is a vicious cycle exacerbating the failure. Cardiac myofilament activity, the ultimate determinant of cellular dynamics and force, is a central player in the integration and regulation of pathways that signal hypertrophy and failure.

  7. Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice

    PubMed Central

    2014-01-01

    Background Myeloproliferative neoplasms (MPNs) are blood malignancies manifested in increased production of red blood cells, white blood cells, and/or platelets. A major molecular lesion associated with the diseases is JAK2V617F, an activation mutation form of tyrosine kinase JAK2. Cardiovascular events represent the leading cause of morbidity and mortality associated MPNs, but the underlying mechanism is not well understood. Methods Previously, we generated JAK2V617F transgenic mice which displayed MPN-like phenotypes. In the present study, we further characterized these mice by analyzing the time course of MPN phenotype development and associated cardiac abnormalities. We performed detailed histochemical staining of cardiac sections. Results JAK2V617F transgenic mice developed cardiomegaly as a subsequent event of increased blood cell production during the course of MPN phenotype development. The cardiomegaly is manifested in increased ventricular wall thickness and enlarged cardiomyocytes. Trichrome and reticulin staining revealed extensive collagen fibrosis in the heart of JAK2V617F transgenic mice. Thrombosis in the coronary artery and inflammatory cell infiltration into cardiac muscle were also observed in JAK2V617F transgenic mice, and the latter event was accompanied by fibrosis. Conclusion JAK2V617F-induced blood disorders have a major impact on heart function and lead to cardiac hypertrophy. JAK2V617F transgenic mice represent an excellent model system to study both hematological malignancies and cardiovascular diseases. PMID:24646493

  8. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure

    PubMed Central

    van Rooij, Eva; Sutherland, Lillian B.; Liu, Ning; Williams, Andrew H.; McAnally, John; Gerard, Robert D.; Richardson, James A.; Olson, Eric N.

    2006-01-01

    Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease. PMID:17108080

  9. Carboxyl terminus of Hsp70-interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise.

    PubMed

    Willis, Monte S; Min, Jin-Na; Wang, Shaobin; McDonough, Holly; Lockyer, Pamela; Wadosky, Kristine M; Patterson, Cam

    2013-12-01

    The carboxyl terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase/cochaperone critical for the maintenance of cardiac function. Mice lacking CHIP (CHIP-/-) suffer decreased survival, enhanced myocardial injury and increased arrhythmias compared with wild-type controls following challenge with cardiac ischaemia reperfusion injury. Recent evidence implicates a role for CHIP in chaperone-assisted selective autophagy, a process that is associated with exercise-induced cardioprotection. To determine whether CHIP is involved in cardiac autophagy, we challenged CHIP-/- mice with voluntary exercise. CHIP-/- mice respond to exercise with an enhanced autophagic response that is associated with an exaggerated cardiac hypertrophy phenotype. No impairment of function was identified in the CHIP-/- mice by serial echocardiography over the 5 weeks of running, indicating that the cardiac hypertrophy was physiologic not pathologic in nature. It was further determined that CHIP plays a role in inhibiting Akt signalling and autophagy determined by autophagic flux in cardiomyocytes and in the intact heart. Taken together, cardiac CHIP appears to play a role in regulating autophagy during the development of cardiac hypertrophy, possibly by its role in supporting Akt signalling, induced by voluntary running in vivo.

  10. Effects of pressure- or volume-overload hypertrophy on passive stiffness in isolated adult cardiac muscle cells

    NASA Technical Reports Server (NTRS)

    Kato, S.; Koide, M.; Cooper, G. 4th; Zile, M. R.

    1996-01-01

    It has been hypothesized that the changes in myocardial stiffness induced by chronic hemodynamic overloading are dependent on changes in the passive stiffness of the cardiac muscle cell (cardiocyte). However, no previous studies have examined the passive constitutive properties of cardiocytes isolated from animals with myocardial hypertrophy. Accordingly, changes in relative passive stiffness of cardiocytes isolated from animals with chronic pressure- or volume-overload hypertrophy were determined by examining the effects of anisosmotic stress on cardiocyte size. Anisosmotic stress was produced by altering superfusate osmolarity. Hypertrophied cardiocytes were enzymatically isolated from 16 adult cats with right ventricular (RV) pressure-overload hypertrophy induced by pulmonary artery banding (PAB) and from 6 adult cats with RV volume-overload hypertrophy induced by creating an atrial septal defect (ASD). Left ventricular (LV) cardiocytes from each cat served as nonhypertrophied, normally loaded, same-animal controls. Superfusate osmolarity was decreased from 305 +/- 3 to 135 +/- 5 mosM and increased to 645 +/- 4 mosM. During anisosmotic stress, there were no significant differences between hypertrophied RV and normal LV cardiocytes in pressure overload PAB cats with respect to percent change in cardiocyte area (47 +/- 2% in RV vs. 48 +/- 2% in LV), diameter (46 +/- 3% in RV vs. 48 +/- 2% in LV), or length (2.4 +/- 0.2% in RV vs. 2.0 +/- 0.3% in LV), or sarcomere length (1.5 +/- 0.1% in RV vs. 1.3 +/- 0.3% in LV). Likewise, there were no significant differences in cardiocyte strain between hypertrophied RV and normal LV cardiocytes from ASD cats. In conclusion, chronic pressure-overload hypertrophy and chronic volume-overload hypertrophy did not alter the cardiocyte response to anisosmotic stress. Thus chronic overload hypertrophy did not alter relative passive cardiocyte stiffness.

  11. C-Myc Induced Compensated Cardiac Hypertrophy Increases Free Fatty Acid Utilization for the Citric Acid Cycle

    SciTech Connect

    Olson, Aaron; Ledee, Dolena; Iwamoto, Kate; Kajimoto, Masaki; O'Kelly-Priddy, Colleen M.; Isern, Nancy G.; Portman, Michael A.

    2013-02-01

    The protooncogene C-Myc (Myc) regulates cardiac hypertrophy. Myc promotes compensated cardiac function, suggesting that the operative mechanisms differ from those leading to heart failure. Myc regulation of substrate metabolism is a reasonable target, as Myc alters metabolism in other tissues. We hypothesize that Myc-induced shifts in substrate utilization signal and promote compensated hypertrophy. We used cardiac specific Myc-inducible C57/BL6 male mice between 4-6 months old that develop hypertrophy with tamoxifen (tam). Isolated working hearts and 13Carbon (13C )-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing 13C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and insulin. Studies were performed at pre-hypertrophy (3-days tam, 3dMyc), established hypertrophy (7-days tam, 7dMyc) or vehicle control (cont). Non-transgenic siblings (NTG) received 7-days tam or vehicle to assess drug effect. Hypertrophy was confirmed by echocardiograms and heart weights. Western blots were performed on key metabolic enzymes. Hypertrophy occurred in 7dMyc only. Cardiac function did not differ between groups. Tam alone did not affect substrate contribution in NTG. Substrate utilization was not significantly altered in 3dMyc versus cont. The free fatty acid FC was significantly greater in 7dMyc vs cont with decreased unlabeled Fc, which is predominately exogenous glucose. Free fatty acid flux to the citric acid cycle increased while lactate flux was diminished in 7dMyc compared to cont. Total protein levels of a panel of key metabolic enzymes were unchanged; however total protein O-GlcNAcylation was increased in 7dMyc. Substrate utilization changes did not precede hypertrophy; therefore they are not the primary signal for cardiac growth in this model. Free fatty acid utilization and oxidation increase at established hypertrophy. Understanding the mechanisms whereby this change maintained

  12. Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis

    PubMed Central

    Hofmann, Nina P.; Giusca, Sorin; Klingel, Karin; Nunninger, Peter; Korosoglou, Grigorios

    2016-01-01

    Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m2), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease. PMID:27247807

  13. Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling.

    PubMed

    Bolte, Craig; Zhang, Yufang; York, Allen; Kalin, Tanya V; Schultz, Jo El J; Molkentin, Jeffery D; Kalinichenko, Vladimir V

    2012-01-01

    Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2) plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1(fl/fl) mice were generated. Surprisingly, αMHC-Cre/Foxm1(fl/fl) mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

  14. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure.

    PubMed

    Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Chapski, Douglas J; Rau, Christoph D; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M; Xiao, Xinshu; Fu, Xiang-Dong; Chen, Jau-Nian; Wang, Yibin

    2016-01-01

    RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload-induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease.

  15. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

    PubMed Central

    Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Chapski, Douglas J.; Rau, Christoph D.; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M.; Xiao, Xinshu; Fu, Xiang-Dong; Chen, Jau-Nian; Wang, Yibin

    2015-01-01

    RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload–induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease. PMID:26619120

  16. Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling.

    PubMed

    Ying, Huang; Xu, Mao-Chun; Tan, Jing-Hua; Shen, Jing-Hua; Wang, Hao; Zhang, Dai-Fu

    2014-01-01

    Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II. PMID:25380525

  17. Gestational hypertension and the developmental origins of cardiac hypertrophy and diastolic dysfunction.

    PubMed

    Armstrong, David W J; Tse, M Yat; Wong, Philip G; Ventura, Nicole M; Meens, Jalna A; Johri, Amer M; Matangi, Murray F; Pang, Stephen C

    2014-06-01

    The developmental origins of health and disease refer to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease in adulthood. We used the chronically hypertensive atrial natriuretic peptide knockout (ANP-/-) mouse as a model of gestational hypertension, and attempted to determine the effect of gestational hypertension on left ventricular (LV) structure and function in adult offspring. We crossed normotensive ANP+/+ females with ANP-/- males (yielding ANP+/-(WT) offspring) and hypertensive ANP-/- females with ANP+/+ males (yielding ANP+/-(KO) offspring). Cardiac gene expression was measured using real-time quantitative PCR. Cardiac function was assessed using echocardiography. Daily injections of isoproterenol (ISO) were used to induce cardiac stress. Collagen deposition was assessed using picrosirius red staining. All mice were 10 weeks of age. Gestational hypertension resulted in significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e') and interstitial myocardial fibrosis only in ANP+/-(KO) and not ANP+/-(WT) offspring. Gestational hypertension programs adverse LV structural and functional remodeling in offspring. These data suggest that adverse maternal environments may increase the risk of heart failure in offspring later in life.

  18. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure.

    PubMed

    Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Chapski, Douglas J; Rau, Christoph D; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M; Xiao, Xinshu; Fu, Xiang-Dong; Chen, Jau-Nian; Wang, Yibin

    2016-01-01

    RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload-induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease. PMID:26619120

  19. miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy

    PubMed Central

    Yang, Yong; Zhou, Yong; Cao, Zheng; Tong, Xin Zhu; Xie, Hua Qiang; Luo, Tao; Hua, Xian Ping; Wang, Han Qin

    2016-01-01

    Cardiac hypertrophy is characterized by maladaptive tissue remodeling that may lead to heart failure or sudden death. MicroRNAs (miRs) are negative regulators of angiotensin II and the angiotensin II receptor subtype 1 (AGTR1), which are two components involved in cardiac hypertrophy. In the present study, the interaction between angiotensin II receptor subtype 1 (AGTR1) signaling and miR-155 was investigated. Rat H9C2 (2–1) cardiomyocytes were transfected with miR-155 analogues or inhibitors, then stimulated with angiotensin II to induce cardiac hypertrophy. miR-155 expression was revealed to be altered following transfection with chemically-modified miR-155 analogues and inhibitors in rat cardiomyocytes. In cell cardiac hypertrophy models, the cell surface area, AGTR1, atrial natriuretic peptide and myosin heavy chain-β mRNA expression levels were revealed to be lower in cells stimulated with miR-155 analogue-transfected cells treated with angiotensin II compared with cells stimulated with angiotensin alone (P<0.05), as determined using reverse transcription-polymerase chain reaction (PCR), quantitative PCR and western blot analyses. Furthermore, calcineurin mRNA and protein, intracellular free calcium and nuclear factor of activated T-cells-4 proteins were downregulated in miR-155 analogue-transfected cells treated with angiotensin II, as compared with cells stimulated with angiotensin II alone (P<0.05). In conclusion, the current study indicates that miR-155 may improve cardiac hypertrophy by downregulating AGTR1 and suppressing the calcium signaling pathways activated by AGTR1. PMID:27588076

  20. Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

    PubMed Central

    La Merrill, Michele A.; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

    2016-01-01

    Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. Objective: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. Methods: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Results: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. Conclusions: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722–1727; http://dx.doi.org/10.1289/EHP164 PMID:27325568

  1. Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA

    PubMed Central

    Cui, Huanhuan; Schlesinger, Jenny; Schoenhals, Sophia; Tönjes, Martje; Dunkel, Ilona; Meierhofer, David; Cano, Elena; Schulz, Kerstin; Berger, Michael F.; Haack, Timm; Abdelilah-Seyfried, Salim; Bulyk, Martha L.; Sauer, Sascha; Sperling, Silke R.

    2016-01-01

    DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. PMID:26582913

  2. Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells.

    PubMed

    Oi, S; Haneda, T; Osaki, J; Kashiwagi, Y; Nakamura, Y; Kawabe, J; Kikuchi, K

    1999-07-01

    Angiotensin II activates p21ras, and mediates cardiac hypertrophic growth through the type 1 angiotensin II receptor in cardiac myocytes. An inhibitor of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase has been shown to block the post-translational farnesylation of p21ras and inhibit protein synthesis in several cell types. Primary cultures of neonatal cardiac myocytes were used to determine whether HMG-CoA reductase inhibitors, lovastatin, simvastatin and pravastatin inhibit the angiotensin II-induced hypertrophic growth. Angiotensin II (10(-6) M) significantly increased protein-DNA ratio, RNA-DNA ratio, ratios of protein synthesis and mitogen-activated protein (MAP) kinase activity. Lipid-soluble HMG-CoA reductase inhibitors, lovastatin (10(-6) M) and simvastatin (10(-6) M) partially and significantly inhibited the angiotensin II-induced increases in these parameters, but a water-soluble HMG-CoA reductase inhibitor, pravastatin (10(-6) M) did not. Mevalonate (10(-4) M) overcame the inhibitory effects of lovastatin and simvastatin on angiotensin II-induced increases in these parameters. A selective protein kinase C inhibitor, calphostin C (10(-6) M) partially and significantly prevented angiotensin II-induced increases in these parameters, and treatment with both lovastatin and calphostin C inhibited completely. Angiotensin II increased p21ras activity and membrane association, and lovastatin inhibited them. These studies demonstrate that a lipid-soluble HMG-CoA reductase inhibitor, lovastatin, may prevent angiotensin II-induced cardiac hypertrophy, at least in part, through p21ras/MAP kinase pathway, which is linked to mevalonate metabolism.

  3. Inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt in spontaneously hypertensive rat hearts.

    PubMed

    Lin, Pei-Pei; Hsieh, You-Miin; Kuo, Wei-Wen; Lin, Chien-Chung; Tsai, Fuu-Jen; Tsai, Chang-Hai; Huang, Chih-Yang; Tsai, Cheng-Chih

    2012-12-01

    Cardiovascular hypertrophy is a common feature of hypertension and an important risk factor for heart damage. The regression of cardiovascular hypertrophy is currently considered an important therapeutic target in reducing the omplications of hypertension. The aim of this study was to investigate the inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt (PSPY) with high γ-aminobutyric acid (GABA) content in spontaneously hypertensive rat (SHR) hearts. Six-week-old male SHRs were separated randomly and equally into 4 experimental groups: sterile water, captopril and 2 PSPY groups with different doses (10 and 100%) for 8 weeks. The changes in myocardial architecture and key molecules of the hypertrophy-related pathway in the excised left ventricle from these rats were determined by histopathological analysis, hematoxylin and eosin staining and western blot analysis. Abnormal myocardial architecture and enlarged interstitial spaces observed in the SHRs were significantly decreased in the captopril and PSPY groups compared with the sterile water group. Moreover, the increases in atrial natriuretic peptide, B-type natriuretic peptide, phosphorilated protein kinase Cα and calmodulin-dependent protein kinase II levels in the left ventricle were accompanied by hypertension and increases in phosphorylated extracellular signal-regulated kinase 5 activities with enhanced cardiac hypertrophy. However, the protein levels of the hypertrophic-related pathways were completely reversed by the administration of PSPY. PSPY may repress the activation of ANP and BNP which subsequently inhibit the dephosphorylation of the nuclear factor of activated T-cells, cytoplasmic 3 and ultimately prevent the progression of cardiac hypertrophy.

  4. Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases

    PubMed Central

    Choukroun, Gabriel; Hajjar, Roger; Fry, Stefanie; del Monte, Federica; Haq, Syed; Guerrero, J. Luis; Picard, Michael; Rosenzweig, Anthony; Force, Thomas

    1999-01-01

    Cardiac hypertrophy often presages the development of heart failure. Numerous cytosolic signaling pathways have been implicated in the hypertrophic response in cardiomyocytes in culture, but their roles in the hypertrophic response to physiologically relevant stimuli in vivo is unclear. We previously reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activated protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-1 in culture. We now report that gene transfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Furthermore, gene transfer of SEK-1(KR) inhibited pressure overload–induced cardiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV weight to body weight, cardiomyocyte diameter, and inhibition of atrial natriuretic factor expression. Our data suggest that the SAPKs are critical regulators of cardiac hypertrophy in vivo, and therefore may serve as novel drug targets in the treatment of hypertrophy and heart failure. J. Clin. Invest. 104:391–398 (1999). PMID:10449431

  5. Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo.

    PubMed

    van Berlo, Jop H; Elrod, John W; Aronow, Bruce J; Pu, William T; Molkentin, Jeffery D

    2011-07-26

    Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in Gata4 that augments activity was mutated to alanine. Homozygous Gata4-S105A mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in Gata4-S105A mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation. Gata4-S105A mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from Gata4-S105A mice did not efficiently hypertrophy following direct ERK1/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from Gata4-S105A mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes.

  6. Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate*

    PubMed Central

    Foryst-Ludwig, Anna; Kreissl, Michael C.; Benz, Verena; Brix, Sarah; Smeir, Elia; Ban, Zsofia; Januszewicz, Elżbieta; Salatzki, Janek; Grune, Jana; Schwanstecher, Anne-Kathrin; Blumrich, Annelie; Schirbel, Andreas; Klopfleisch, Robert; Rothe, Michael; Blume, Katharina; Halle, Martin; Wolfarth, Bernd; Kershaw, Erin E.; Kintscher, Ulrich

    2015-01-01

    Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure. PMID:26260790

  7. Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats

    PubMed Central

    Dalpiaz, P. L. M.; Lamas, A. Z.; Caliman, I. F.; Ribeiro, R. F.; Abreu, G. R.; Moyses, M. R.; Andrade, T. U.; Gouvea, S. A.; Alves, M. F.; Carmona, A. K.; Bissoli, N. S.

    2015-01-01

    Background There is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs). Methodology / Principal Findings Twelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV) and dP/dt minimum LV, respectively), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity (fluorimetrically). Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban) and the PLB to SERCA2a ratio in female rats, but did not change in male rats. Conclusion Ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components. PMID:26010093

  8. Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size.

    PubMed

    Zhou, Yang; Jiang, Youchun; Kang, Y James

    2008-07-01

    Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine (PE) at a final concentration of 100 microM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 microM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta-myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 microg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF-dependent. PMID:18495151

  9. Doppler estimation of reduced coronary flow reserve in mice with pressure overload cardiac hypertrophy

    PubMed Central

    Hartley, Craig J.; Reddy, Anilkumar K.; Madala, Sridhar; Michael, Lloyd H.; Entman, Mark L.; Taffet, George E.

    2008-01-01

    Aortic banding produces pressure overload cardiac hypertrophy in mice leading to decompensated heart failure in 4–8 wks, but the effects on coronary blood flow velocity and reserve are unknown. To determine whether coronary flow reserve (CFR) was reduced, we used noninvasive 20 MHz Doppler ultrasound to measure left main coronary flow velocity at baseline (B) and at hyperemia (H) induced by low (1%) and high (2.5%) concentrations of isoflurane gas anesthesia. Ten mice were studied before (Pre) and at 1d, 7d, 14d, and 21d after constricting the aortic arch to 0.4 mm diameter distal to the innominate artery. We also measured cardiac inflow and outflow velocities at the mitral and aortic valves and velocity at the jet distal to the aortic constriction. The pressure drop as estimated by 4V2 at the jet was 51 ± 5.1 (mean ± SE) mmHg at 1d increasing progressively to 74 ± 5.2 mmHg at 21d. Aortic and mitral blood velocities were not significantly different after banding (p = NS), but CFR, as estimated by H/B, dropped progressively from 3.2 ± 0.3 before banding to 2.2 ± 0.4, 1.7 ± 0.3, 1.4 ± 0.2, and 1.1 ± 0.1 at 1d, 7d, 14d, and 21d respectively (all P < 0.01 vs Pre). There was also a significant and progressive increase the systolic/diastolic velocity ratio (0.17 Pre to 0.92 at 21d, all P < 0.01 vs Pre) suggesting a redistribution of perfusion from subendocardium to subepicardium. We show for the first time that CFR, as estimated by the hyperemic response to isoflurane and measured by Doppler ultrasound, can be measured serially in mice and conclude that CFR is virtually eliminated in banded mice after 21 days of remodeling and hypertrophy. These results demonstrate that CFR is reduced in mice as in humans with cardiac disease but before the onset of decompensated heart failure. PMID:18255218

  10. Knockout of Toll-Like Receptors 2 and 4 Prevents Renal Ischemia-Reperfusion-Induced Cardiac Hypertrophy in Mice

    PubMed Central

    Trentin-Sonoda, Mayra; da Silva, Rogério Cirino; Kmit, Fernanda Vieira; Abrahão, Mariana Vieira; Monnerat Cahli, Gustavo; Brasil, Guilherme Visconde; Muzi-Filho, Humberto; Silva, Paulo André; Tovar-Moll, Fernanda Freire; Vieyra, Adalberto; Medei, Emiliano; Carneiro-Ramos, Marcela Sorelli

    2015-01-01

    We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation. PMID

  11. GATA4-mediated cardiac hypertrophy induced by D-myo-inositol 1,4,5-tris-phosphate

    SciTech Connect

    Zhu Zhiming . E-mail: zhuzming@mail.dph-fsi.com; Zhu Shanjun; Liu Daoyan; Yu Zengping; Yang Yongjian; Giet, Markus van der; Tepel, Martin . E-mail: Martin.Tepel@charite.de

    2005-12-16

    We evaluated the effects of D-myo-inositol 1,4,5-tris-phosphate on cardiac hypertrophy. D-myo-inositol 1,4,5-tris-phosphate augmented cardiac hypertrophy as evidenced by its effects on DNA synthesis, protein synthesis, and expression of immediate-early genes c-myc and c-fos, {beta}-myosin heavy chain, and {alpha}-actin. The administration of D-myo-inositol 1,4,5-tris-phosphate increased the expression of nuclear factor of activated T-cells and cardiac-restricted zinc finger transcription factor (GATA4). Real-time quantitative RT-PCR showed that D-myo-inositol 1,4,5-tris-phosphate-induced GATA4 mRNA was significantly enhanced even in the presence of the calcineurin inhibitor, cyclosporine A. The effect of D-myo-inositol 1,4,5-tris-phosphate was blocked after inhibition of inositol-trisphosphate receptors but not after inhibition of c-Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) or p38 mitogen-activated protein kinase pathways. The study shows that D-myo-inositol 1,4,5-tris-phosphate-induced cardiac hypertrophy is mediated by GATA4 but independent from the calcineurin pathway.

  12. Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure.

    PubMed

    Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi; Sun, Ke; Garrott, Kara; Kuzmiak-Glancy, Sarah; Kay, Matthew W; Mendelowitz, David

    2015-10-01

    Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases. PMID:26371169

  13. Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure.

    PubMed

    Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi; Sun, Ke; Garrott, Kara; Kuzmiak-Glancy, Sarah; Kay, Matthew W; Mendelowitz, David

    2015-10-01

    Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases.

  14. Do big athletes have big hearts? Impact of extreme anthropometry upon cardiac hypertrophy in professional male athletes

    PubMed Central

    Riding, Nathan R; Salah, Othman; Sharma, Sanjay; Carré, François; O'Hanlon, Rory; George, Keith P; Hamilton, Bruce; Chalabi, Hakim; Whyte, Gregory P; Wilson, Mathew G

    2012-01-01

    Aim Differentiating physiological cardiac hypertrophy from pathology is challenging when the athlete presents with extreme anthropometry. While upper normal limits exist for maximal left ventricular (LV) wall thickness (14 mm) and LV internal diameter in diastole (LVIDd, 65 mm), it is unknown if these limits are applicable to athletes with a body surface area (BSA) >2.3 m2. Purpose To investigate cardiac structure in professional male athletes with a BSA>2.3 m2, and to assess the validity of established upper normal limits for physiological cardiac hypertrophy. Methods 836 asymptomatic athletes without a family history of sudden death underwent ECG and echocardiographic screening. Athletes were grouped according to BSA (Group 1, BSA>2.3 m2, n=100; Group 2, 2–2.29 m2, n=244; Group 3, <1.99 m2, n=492). Results There was strong linear relationship between BSA and LV dimensions; yet no athlete with a normal ECG presented a maximal wall thickness and LVIDd greater than 13 and 65 mm, respectively. In Group 3 athletes, Black African ethnicity was associated with larger cardiac dimensions than either Caucasian or West Asian ethnicity. Three athletes were diagnosed with a cardiomyopathy (0.4% prevalence); with two athletes presenting a maximal wall thickness >13 mm, but in combination with an abnormal ECG suspicious of an inherited cardiac disease. Conclusion Regardless of extreme anthropometry, established upper limits for physiological cardiac hypertrophy of 14 mm for maximal wall thickness and 65 mm for LVIDd are clinically appropriate for all athletes. However, the abnormal ECG is key to diagnosis and guides follow-up, particularly when cardiac dimensions are within accepted limits. PMID:23097487

  15. Trpm4 Gene Invalidation Leads to Cardiac Hypertrophy and Electrophysiological Alterations

    PubMed Central

    Gueffier, Mélanie; Finan, Amanda; Khoueiry, Ziad; Cassan, Cécile; Serafini, Nicolas; Aimond, Franck; Granier, Mathieu; Pasquié, Jean-Luc; Launay, Pierre; Richard, Sylvain

    2014-01-01

    Rationale TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear. Objectives We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model. Methods and Results Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase. Conclusions TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity

  16. Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis.

    PubMed

    Radovits, Tamás; Oláh, Attila; Lux, Árpád; Németh, Balázs Tamás; Hidi, László; Birtalan, Ede; Kellermayer, Dalma; Mátyás, Csaba; Szabó, Gábor; Merkely, Béla

    2013-07-01

    Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in

  17. Cardiac Hypertrophy in Mice with Long-Chain Acyl-CoA Dehydrogenase (LCAD) or Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency

    PubMed Central

    Cox, Keith B.; Liu, Jian; Tian, Liqun; Barnes, Stephen; Yang, Qinglin; Wood, Philip A.

    2009-01-01

    Cardiac hypertrophy is a common finding in human patients with inborn errors of long-chain fatty acid oxidation. Mice with either very long-chain acyl-CoA dehydrogenase deficiency (VLCAD−/−) or long-chain acyl-CoA dehydrogenase deficiency (LCAD−/−) develop cardiac hypertrophy. Cardiac hypertrophy, initially measured using heart/body weight ratios, was manifested most severely in LCAD−/− male mice. VLCAD−/− mice, as a group, showed a mild increase in normalized cardiac mass (8.8% hypertrophy compared to all wild-type [WT] mice). In contrast, LCAD−/− mice as a group showed more severe cardiac hypertrophy (32.2% increase compared to all WT mice). Based on a clear male predilection, we investigated the role of dietary plant estrogenic compounds commonly found in mouse diets due to soy or alfalfa components providing natural phytoestrogens or isoflavones in cardioprotection of LCAD−/− mice. Male LCAD−/− mice fed an isoflavone-free test diet had more severe cardiac hypertrophy (58.1% hypertrophy compared to WT mice fed the same diet. There were no significant differences in the female groups fed any of the diets. Echocardiography measurement performed on male LCAD deficient mice fed a standard diet at ~3 months of age confirmed the substantial cardiac hypertrophy in these mice compared with WT controls. Left ventricular wall thickness of interventricular septum and posterior wall was remarkably increased in LCAD−/− mice compared with that of WT controls. Accordingly, the calculated LV mass after normalization to body weight was increased about 40% in the LCAD−/− mice compared with WT mice. In summary, we found that metabolic cardiomyopathy, expressed as hypertrophy, developed in mice due to either VLCAD deficiency or LCAD deficiency; however, LCAD deficiency was the most profound and appeared to be attenuated either by endogenous estrogen in females or phytoestrogens in the diet as isoflavones in males. PMID:19736549

  18. Carnitine Palmitoyltransferase-1b (CPT1b) Deficiency Aggravates Pressure-Overload-Induced Cardiac Hypertrophy due to Lipotoxicity

    PubMed Central

    He, Lan; Kim, Teayoun; Long, Qinqiang; Liu, Jian; Wang, Peiyong; Zhou, Yiqun; Ding, Yishu; Prasain, Jeevan; Wood, Philip A.; Yang, Qinglin

    2012-01-01

    Background Carnitine palmitoyltransferase 1(CPT1) is a rate-limiting step of mitochondrial β-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT-1 activity by specific CPT-1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 in order to evaluate it as a safe and effective therapeutic approach. Methods and Results Heterozygous CPT1b knockout mice (CPT1b+/−) were subjected to transverse aorta constriction (TAC)-induced pressure-overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), CPT1b+/− mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b+/− mice exhibited exacerbated cardiac hypertrophy and remodeling compared with that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/− than in controlled mice. Moreover, the CPT1b+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis. Conclusions We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors. PMID:22932257

  19. Angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the increase in TGF-beta1 in thyroid hormone-induced cardiac hypertrophy.

    PubMed

    Diniz, G P; Carneiro-Ramos, M S; Barreto-Chaves, M L M

    2007-04-01

    Increased thyroid hormone (TH) levels are known to induce cardiac hypertrophy. Some studies have provided evidence for a functional link between angiotensin II (ANG II) and transforming growth factor beta1 (TGF-beta1) in the heart, both being able to also induce cardiac hypertrophy. However, the contribution of this growth factor activated directly by TH or indirectly by ANG II in cardiac hypertrophy development remains unknown. To analyze the possible role of TGF-beta1 in cardiac hypertrophy induced by TH and also to evaluate if the TGF-beta1 effect is mediated by ANG II receptors, we employed Wistar rats separated into control, hypothyroid (hypo) and hyperthyroid (T4 - 10) groups combined or not with ANG II receptor blockers (losartan or PD123319). Serum levels of T3 and T4, systolic pressure and heart rate confirmed the thyroid state of the groups. The T4 - 10 group presented a significant increase in cardiac TGF-beta1 levels; however, TGF-beta1 levels in the hypo group did not change in relation to the control. Inhibition of the increase in cardiac TGF-beta1 levels was observed in the groups treated with T4 in association with losartan or PD123319 when compared to the T4 - 10 group. These results demonstrate for the first time the TH-modulated induction of cardiac TGF-beta1 in cardiac hypertrophy, and that this effect is mediated by ANG II receptors. PMID:17206447

  20. Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

    PubMed Central

    Mokni, Walid; Keravis, Thérèse; Etienne-Selloum, Nelly; Walter, Alison; Kane, Modou O.; Schini-Kerth, Valérie B.; Lugnier, Claire

    2010-01-01

    Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored. Rats developed arterial hypertension associated with a slight cardiac hypertrophy (+24%). cAMP-PDE4 activity was specifically increased while cGMP-PDE activities were broadly increased (+130% for PDE1; +76% for PDE2; +113% for PDE5) and associated with increased expressions for PDE1A, PDE1C and PDE5A. The cGMP-PDE1 activation by Ca2+/CaM was reduced. BNP expression was increased by 3.5-fold, while NOX2 expression was reduced by 66% and AMP kinase activation was increased by 64%. In early cardiac hypertrophy induced by angiotensin II, all specific PDE activities in left cardiac ventricles were increased, favoring an increase in cGMP hydrolysis by PDE1, PDE2 and PDE5. Increased cAMP hydrolysis was related to PDE4. We observed the establishment of two cardioprotective mechanisms and we suggest that these mechanisms could lead to increase intracellular cGMP: i) increased expression of BNP could increase “particulate” cGMP pool; ii) increased activation of AMPK, subsequent to increase in PDE4 activity and 5′AMP generation, could elevate “soluble” cGMP pool by enhancing NO bioavailability through NOX2 down-regulation. More studies are needed to support these assumptions. Nevertheless, our results suggest a potential link between PDE4 and AMPK/NOX2 and they point out that cGMP-PDEs, especially PDE1 and PDE2

  1. MicroRNA-26a protects against cardiac hypertrophy via inhibiting GATA4 in rat model and cultured cardiomyocytes.

    PubMed

    Liu, Yan; Wang, Zhiqian; Xiao, Wenliang

    2016-09-01

    Pathological cardiac hypertrophy is characterized by deleterious changes developed in cardiovascular diseases, whereas microRNAs (miRNAs) are involved in the mediation of cardiac hypertrophy. To investigate the role of microRNA-26a (miR-26a) in regulating cardiac hypertrophy and its functioning mechanisms, overexpression and suppression of miR‑26a via its mimic and inhibitor in a transverse abdominal aortic constriction (TAAC)-induced rat model and in angiotensin II (Ang II)-induced cardiomyocytes (CMs) was performed. In the rat model, the heart weight (HW) compared with the body weight (BW), the CM area, and expression of the hypertrophy‑associated factors, atrial natriuretic factor (ANF) and β‑myosin heavy chain (β‑MHC), were assessed. In CMs, the protein synthesis rate was determined using a leucine incorporation assay. Mutation of the GATA‑binding protein 4 (GATA4) 3'‑untranslated region (UTR) and overexpression of GATA4 were performed to confirm whether GATA4 is the target of miR‑26a. The results indicated that miR-26a was significantly downregulated in the heart tissue of the rat model, as well as in Ang II‑induced CMs (P<0.05). The TAAC-induced rat model exhibited a higher HW/BW ratio, a larger CM area, and higher expression levels of ANF and β‑MHC. CMs, upon Ang II treatment, also demonstrated a larger CM area, higher levels of ANF and β‑MHC, as well as accelerated protein synthesis. miR‑26a was not able to regulate GATA4 with mutations in the 3'‑UTR, indicating that GATA4 was the direct target of miR‑26a. Overexpression of GATA4 abrogated the inhibitory functions of miR‑26a in cardiac hypertrophy. Taken together, the present study suggested an anti‑hypertrophic role of miR‑26a in cardiac hypertrophy, possibly via inhibition of GATA4. These findings may be useful in terms of facilitating cardiac treatment, with potential therapeutic targets and strategies. PMID:27485101

  2. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy.

    PubMed

    Thattaliyath, Bijoy D; Livi, Carolina B; Steinhelper, Mark E; Toney, Glenn M; Firulli, Anthony B

    2002-10-01

    The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extraembryonic development. Although highly evolutionarily conserved genes, HAND cardiac expression patterns differ across species. Mouse expression of HAND1 and HAND2 was reported absent in the adult heart. Human HAND genes are expressed in the adult heart and HAND1 expression is downregulated in cardiomyopathies. As rodent and human expression profiles are inconsistent, we re-examined expression of HAND1 and HAND2 in adult-rodent hearts. HAND1 and HAND2 are expressed in adult-rodent hearts and HAND2 is expressed in the atria. Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy. The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing, cardiomyocytes to reinitiate the fetal gene program and initiate the adaptive physiological changes that allow the heart to compensate (hypertrophy) for the increase in afterload.

  3. Puerarin Attenuates Cardiac Hypertrophy Partly Through Increasing Mir-15b/195 Expression and Suppressing Non-Canonical Transforming Growth Factor Beta (Tgfβ) Signal Pathway

    PubMed Central

    Zhang, Xiuzhou; Liu, Yuxiang; Han, Qingliang

    2016-01-01

    Background Previous studies demonstrated that puerarin has therapeutic effects on cardiac hypertrophy. This study aimed to explore whether the effect of puerarin on attenuating cardiac hypertrophy is related to regulation of microRNAs (miRNAs) and the transforming growth factor beta (TGFβ) signal pathway. Material/Methods The therapeutic effect of puerarin was assessed using an angiotensin (Ang) II-induced heart hypertrophy model in mice. The primary cardiomyocytes were used as an in vitro model. MiR-15 family expression was quantified using qRT-PCR analysis. The expression of the genes involved in canonical and non-canonical TGFβ signal pathways was measured using qRT-PCR and Western blot analysis. In vitro cardiac hypertrophic features were assessed by quantifying cardiac hypertrophic genes and measurement of cell surface, protein synthesis, and total protein content. Results Puerarin attenuated cardiac hypertrophy and increased miR-15b and miR-195 expression in the mouse cardiac hypertrophy model and in primary cardiomyocytes. It suppressed both canonical and non-canonical TGFβ signal pathways, partially through miR-15b and miR-195. Puerarin reduced mRNA expression of cardiac hypertrophic genes, reduced cell surface area, and lowered the rate of protein synthesis and the total protein content induced by Ang II. Knockdown of endogenous miR-15b and miR-195 partly abrogated these effects. Knockdown of endogenous p38, but not Smad2/3/4, presented similar effects as miR-15b. Conclusions Puerarin administration enhances miR-15b and miR-195 expression in an Ang II-induced cardiac hypertrophy model, through which it suppresses both canonical and non-canonical TGFβ signal pathways at the same time. However, the effect of puerarin on attenuating cardiac hypertrophy is mainly through the non-canonical TGFβ pathway. PMID:27145790

  4. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure

    PubMed Central

    Seddon, Mike; Looi, Yee H; Shah, Ajay M

    2007-01-01

    Substantial evidence suggests the involvement of oxidative stress in the pathophysiology of congestive heart failure and its antecedent conditions such as cardiac hypertrophy and adverse remodelling after MI. Oxidative stress describes an imbalance between antioxidant defences and the production of reactive oxygen species (ROS), which at high levels cause cell damage but at lower levels induce subtle changes in intracellular signalling pathways (termed redox signalling). ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases. The latter enzymes are especially important in redox signalling, being implicated in the pathophysiology of hypertension and atherosclerosis, and activated by diverse pathologically relevant stimuli. We review the contribution of ROS to heart failure pathophysiology and discuss potential therapies that may specifically target detrimental redox signalling. Indeed, drugs such as ACE inhibitors and statins may act in part through such mechanisms. A better understanding of redox signalling mechanisms may enable the development of new targeted therapeutic strategies rather than the non‐specific antioxidant approaches that have to date been disappointing in clinical trials. PMID:16670100

  5. Overview of MicroRNAs in Cardiac Hypertrophy, Fibrosis, and Apoptosis

    PubMed Central

    Wang, Juan; Liew, Oi Wah; Richards, Arthur Mark; Chen, Yei-Tsung

    2016-01-01

    MicroRNAs (miRNAs) are non-coding RNAs that play essential roles in modulating the gene expression in almost all biological events. In the past decade, the involvement of miRNAs in various cardiovascular disorders has been explored in numerous in vitro and in vivo studies. In this paper, studies focused upon the discovery of miRNAs, their target genes, and functionality are reviewed. The selected miRNAs discussed herein have regulatory effects on target gene expression as demonstrated by miRNA/3′ end untranslated region (3′UTR) interaction assay and/or gain/loss-of-function approaches. The listed miRNA entities are categorized according to the biological relevance of their target genes in relation to three cardiovascular pathologies, namely cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, comparison across 86 studies identified several candidate miRNAs that might be of particular importance in the ontogenesis of cardiovascular diseases as they modulate the expression of clusters of target genes involved in the progression of multiple adverse cardiovascular events. This review illustrates the involvement of miRNAs in diverse biological signaling pathways and provides an overview of current understanding of, and progress of research into, of the roles of miRNAs in cardiovascular health and disease. PMID:27213331

  6. IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation.

    PubMed

    Yang, Qiwei; Sun, Miranda; Ramchandran, Ramaswamy; Raj, J Usha

    2015-10-01

    Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKT(S473) is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia-induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease. PMID:25921925

  7. Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression

    PubMed Central

    Morales, Cyndi R.; Li, Dan L.; Pedrozo, Zully; May, Herman I.; Jiang, Nan; Kyrychenko, Viktoriia; Cho, Geoffrey; Kim, Soo Young; Wang, Zhao V.; Rotter, David; Rothermel, Beverly A.; Schneider, Jay W.; Lavandero, Sergio; Gillette, Thomas G.; Hill, Joseph A.

    2016-01-01

    Altering chromatin structure through histone posttranslational modifications has emerged as a key driver of transcriptional responses in cells. Modulation of these transcriptional responses by pharmacological inhibition of class I histone deacetylases (HDACs), a group of chromatin remodeling enzymes, has been successful in blocking the growth of some cancer cell types. These inhibitors also attenuate the pathogenesis of pathological cardiac remodeling by blunting and even reversing pathological hypertrophy. The mechanistic target of rapamycin (mTOR) is a critical sensor and regulator of cell growth that as part of mTOR complex I (mTORC1) drives changes in protein synthesis and metabolism in both pathological and physiological hypertrophy. Here, we demonstrated through pharmacological and genetic methods that inhibition of class I HDACs suppressed pathological cardiac hypertrophy through inhibition of mTOR activity. Mice genetically silenced for HDAC1 and HDAC2 had a reduced hypertrophic response to TAC and showed reduced mTOR activity. We determined that the abundance of tuberous sclerosis complex 2 (TSC2), an mTOR inhibitor, was increased through a transcriptional mechanism in cardiomyocytes when class I HDACs were inhibited. In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC-dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine. These findings point to mTOR and TSC2-dependent control of mTOR as critical components of the mechanism by which HDAC inhibitors blunt pathological cardiac growth. These results also suggest a strategy to modulate mTOR activity and facilitate the translational exploitation of HDAC inhibitors in heart disease. PMID:27048565

  8. Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

    PubMed

    Moreira-Gonçalves, Daniel; Henriques-Coelho, Tiago; Fonseca, Hélder; Ferreira, Rita; Padrão, Ana Isabel; Santa, Cátia; Vieira, Sara; Silva, Ana Filipa; Amado, Francisco; Leite-Moreira, Adelino; Duarte, José Alberto

    2015-09-01

    The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or β-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and

  9. Analysis of hypoxia-induced metabolic reprogramming.

    PubMed

    Yang, Chendong; Jiang, Lei; Zhang, Huafeng; Shimoda, Larissa A; DeBerardinis, Ralph J; Semenza, Gregg L

    2014-01-01

    Hypoxia is a common finding in advanced human tumors and is often associated with metastatic dissemination and poor prognosis. Cancer cells adapt to hypoxia by utilizing physiological adaptation pathways that promote a switch from oxidative to glycolytic metabolism. This promotes the conversion of glucose into lactate while limiting its transformation into acetyl coenzyme A (acetyl-CoA). The uptake of glucose and the glycolytic flux are increased under hypoxic conditions, mostly owing to the upregulation of genes encoding glucose transporters and glycolytic enzymes, a process that depends on hypoxia-inducible factor 1 (HIF-1). The reduced delivery of acetyl-CoA to the tricarboxylic acid cycle leads to a switch from glucose to glutamine as the major substrate for fatty acid synthesis in hypoxic cells. In addition, hypoxia induces (1) the HIF-1-dependent expression of BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L), which trigger mitochondrial autophagy, thereby decreasing the oxidative metabolism of both fatty acids and glucose, and (2) the expression of the sodium-hydrogen exchanger NHE1, which maintains an alkaline intracellular pH. Here, we present a compendium of methods to study hypoxia-induced metabolic alterations.

  10. Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

    PubMed Central

    Seo, Kinya; Rainer, Peter P.; Shalkey Hahn, Virginia; Lee, Dong-ik; Jo, Su-Hyun; Andersen, Asger; Liu, Ting; Xu, Xiaoping; Willette, Robert N.; Lepore, John J.; Marino, Joseph P.; Birnbaumer, Lutz; Schnackenberg, Christine G.; Kass, David A.

    2014-01-01

    Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC50, 3–21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management. PMID:24453217

  11. Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy.

    PubMed

    Seo, Kinya; Rainer, Peter P; Shalkey Hahn, Virginia; Lee, Dong-Ik; Jo, Su-Hyun; Andersen, Asger; Liu, Ting; Xu, Xiaoping; Willette, Robert N; Lepore, John J; Marino, Joseph P; Birnbaumer, Lutz; Schnackenberg, Christine G; Kass, David A

    2014-01-28

    Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC50, 3-21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.

  12. CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.

    PubMed

    Wang, Bei; Zeng, Hesong; Wen, Zheng; Chen, Chen; Wang, Dao Wen

    2016-10-01

    Cytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5'-AMP-activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p-Akt1), and stimulated nuclear translocation of p-Akt1, to exert their antihypertrophic effects. AMPKα2(-/-) mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild-type mice but not AMPKα2(-/-) mice. The CYP2J2 metabolites, 11,12-EET, activated AMPKα2 to induce nuclear translocation of p-Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co-immunoprecipitation analysis, we found that AMPKα2β2γ1 and p-Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12-EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

  13. Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes*

    PubMed Central

    Markandeya, Yogananda S.; Phelan, Laura J.; Woon, Marites T.; Keefe, Alexis M.; Reynolds, Courtney R.; August, Benjamin K.; Hacker, Timothy A.; Roth, David M.; Patel, Hemal H.; Balijepalli, Ravi C.

    2015-01-01

    Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte with a reduction in the scaffolding protein caveolin-3 (Cav-3), altered Ca2+ cycling, increased protein kinase C expression, and hyperactivation of calcineurin/nuclear factor of activated T cell (NFAT) signaling. However, the precise role of Cav-3 in the regulation of local Ca2+ signaling in pathological cardiac hypertrophy is unclear. We used cardiac-specific Cav-3-overexpressing mice and in vivo and in vitro cardiac hypertrophy models to determine the essential requirement for Cav-3 expression in protection against pharmacologically and pressure overload-induced cardiac hypertrophy. Transverse aortic constriction and angiotensin-II (Ang-II) infusion in wild type (WT) mice resulted in cardiac hypertrophy characterized by significant reduction in fractional shortening, ejection fraction, and a reduced expression of Cav-3. In addition, association of PKCα and angiotensin-II receptor, type 1, with Cav-3 was disrupted in the hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated increased expression of T-type Ca2+ current (ICa, T) in hypertrophic ventricular myocytes. In contrast, the Cav-3-overexpressing mice demonstrated protection from transverse aortic constriction or Ang-II-induced pathological hypertrophy with inhibition of ICa, T and intact Cav-3-associated macromolecular signaling complexes. siRNA-mediated knockdown of Cav-3 in the neonatal cardiomyocytes resulted in enhanced Ang-II stimulation of ICa, T mediated by PKCα, which caused nuclear translocation of NFAT. Overexpression of Cav-3 in neonatal myocytes prevented a PKCα-mediated increase in ICa, T and nuclear translocation of NFAT. In conclusion, we show that stable Cav-3 expression is essential for protecting the signaling mechanisms in pharmacologically and pressure overload-induced cardiac hypertrophy. PMID:26170457

  14. Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity

    PubMed Central

    Ryu, Yuhee; Jin, Li; Kee, Hae Jin; Piao, Zhe Hao; Cho, Jae Yeong; Kim, Gwi Ran; Choi, Sin Young; Lin, Ming Quan; Jeong, Myung Ho

    2016-01-01

    Gallic acid, a type of phenolic acid, has been shown to have beneficial effects in inflammation, vascular calcification, and metabolic diseases. The present study was aimed at determining the effect and regulatory mechanism of gallic acid in cardiac hypertrophy and fibrosis. Cardiac hypertrophy was induced by isoproterenol (ISP) in mice and primary neonatal cardiomyocytes. Gallic acid pretreatment attenuated concentric cardiac hypertrophy. It downregulated the expression of atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain in vivo and in vitro. Moreover, it prevented interstitial collagen deposition and expression of fibrosis-associated genes. Upregulation of collagen type I by Smad3 overexpression was observed in cardiac myoblast H9c2 cells but not in cardiac fibroblasts. Gallic acid reduced the DNA binding activity of phosphorylated Smad3 in Smad binding sites of collagen type I promoter in rat cardiac fibroblasts. Furthermore, it decreased the ISP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) protein in mice. JNK2 overexpression reduced collagen type I and Smad3 expression as well as GATA4 expression in H9c2 cells and cardiac fibroblasts. Gallic acid might be a novel therapeutic agent for the prevention of cardiac hypertrophy and fibrosis by regulating the JNK2 and Smad3 signaling pathway. PMID:27703224

  15. Cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2) prevents metabolic remodeling during pressure-overload hypertrophy

    PubMed Central

    Kolwicz, Stephen C.; Olson, David P.; Marney, Luke C.; Garcia-Menendez, Lorena; Synovec, Robert E.; Tian, Rong

    2012-01-01

    Rationale Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics. Objectives Since malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits mitochondrial fatty acid transport, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H−/−) would maintain cardiac fatty acid oxidation (FAO) and improve function and energetics during the development of pressure-overload hypertrophy. Methods and Results ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular (LV) function and oxygen consumption were similiar in ACC2H−/− mice despite an ~60% increase in FAO compared to controls (CON). After 8 weeks of pressure-overload via transverse aortic constriction (TAC), ACC2H−/− mice exhibited a substrate utilization profile similar to sham animals while CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by 31P NMR spectroscopy, and cardiac function were maintained in ACC2H−/− after 8 weeks of TAC. Furthermore, ACC2H−/−-TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC. Conclusions These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy. PMID:22730442

  16. Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

    PubMed

    Moens, An L; Ketner, Elizabeth A; Takimoto, Eiki; Schmidt, Tim S; O'Neill, Charles A; Wolin, Michael S; Alp, Nicholas J; Channon, Keith M; Kass, David A

    2011-10-01

    The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.'' PMID:21645517

  17. Vigabatrin Therapy for Infantile Spasms in a Case of Cardiofaciocutaneous Syndrome with Cardiac Hypertrophy Developing during Adrenocorticotropic Hormone Treatment.

    PubMed

    Hatori, Takayuki; Sugiyama, Yohei; Yamashita, Shinichiro; Hirakubo, Yuka; Nonaka, Kazuhito; Ichihashi, Ko

    2016-01-01

    In a patient with cardiofaciocutaneous syndrome complicated by intractable infantile spasms (West syndrome), cardiac hypertrophy developed during adrenocorticotropic hormone treatment. Various types of antiepileptic drugs, intravenous immunoglobulin, thyrotropin releasing hormone, and a ketogenic diet were ineffective in this case. However, vigabatrin both decreased clinical seizures and improved electroencephalogram findings. Although vigabatrin has not been approved for use in Japan, the results in the present case suggest that this drug should be considered as an alternative therapy for cases of infantile spasms associated with syndromes involving cardiomyopathy or its potential risk factors, such as cardiofaciocutaneous syndrome. PMID:27680485

  18. Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

    SciTech Connect

    Busk, Peter K. . E-mail: pkbu@novonordisk.com; Hinrichsen, Rebecca; Bartkova, Jirina; Hansen, Ane H.; Christoffersen, Tue E.H.; Bartek, Jiri; Haunso, Stig

    2005-03-10

    The myocytes of the adult mammalian heart are considered unable to divide. Instead, mitogens induce cardiomyocyte hypertrophy. We have investigated the effect of adenoviral overexpression of cyclin D2 on myocyte proliferation and morphology. Cardiomyocytes in culture were identified by established markers. Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum. At the molecular level, cyclin D2 activated CDK4/6 and lead to pRB phosphorylation and downregulation of the cell cycle inhibitors p21{sup Waf1/Cip1} and p27{sup Kip1}. Expression of the CDK4/6 inhibitor p16 inhibited proliferation and cyclin D2 overexpressing myocytes became hypertrophic under such conditions. Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27{sup Kip1}. These data show that hypertrophy and proliferation are highly related processes and suggest that cardiomyocyte hypertrophy is due to low amounts of cell cycle activators unable to overcome the block imposed by cell cycle inhibitors. Cell cycle entry upon hypertrophy may be converted to cell division by increased expression of activators such as cyclin D2.

  19. Role of α-crystallin B as a regulatory switch in modulating cardiomyocyte apoptosis by mitochondria or endoplasmic reticulum during cardiac hypertrophy and myocardial infarction.

    PubMed

    Mitra, A; Basak, T; Datta, K; Naskar, S; Sengupta, S; Sarkar, S

    2013-04-04

    Cardiac hypertrophy and myocardial infarction (MI) are two major causes of heart failure with different etiologies. However, the molecular mechanisms associated with these two diseases are not yet fully understood. So, this study was designed to decipher the process of cardiomyocyte apoptosis during cardiac hypertrophy and MI in vivo. Our study revealed that mitochondrial outer membrane channel protein voltage-dependent anion channel-1 (VDAC1) was upregulated exclusively during cardiac hypertrophy, whereas 78 kDa glucose-regulated protein (GRP78) was exclusively upregulated during MI, which is an important upstream regulator of the endoplasmic reticulum (ER) stress pathway. Further downstream analysis revealed that mitochondrial pathway of apoptosis is instrumental in case of hypertrophy, whereas ER stress-induced apoptosis is predominant during MI, which was confirmed by treatment with either siRNA against VDAC1 or ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Very interestingly, our data also showed that the expression and interaction of small heat-shock protein α-crystallin B (CRYAB) with VDAC1 was much more pronounced during MI compared with either hypertrophy or control. The study demonstrated for the first time that two different organelles--mitochondria and ER have predominant roles in mediating cardiomyocyte death signaling during hypertrophy and MI, respectively, and activation of CRYAB acts as a molecular switch in bypassing mitochondrial pathway of apoptosis during MI.

  20. Insulin over expression induces heart abnormalities via reactive oxygen species regulation, might be step towards cardiac hypertrophy.

    PubMed

    Mushtaq, S; Ali, T; Gul, M; Javed, Q; Emanueli, C; Murtaza, I

    2015-01-01

    Insulin is known to regulate blood—glucose level and promote its utilization as an energy source in cardiac tissues under normal physiological conditions as well as stimulates signaling pathways that involved cell growth and proliferation. Although recently insulin generated free radicals via NAD(P)H has been documented but the molecular mechanism is still under investigation. The aim of present study is to elucidate the reactive oxygen species (ROS) dependent possible role of insulin in cardiac abnormalities, including hypertrophy by regulation of antioxidants enzyme (SOD) activity. In the current study, 60 cardiac patients and 50 healthy individuals as well as the rat model with insulin administration were under investigation. Oxidant, anti—oxidant biochemical assays, hypertrophic marker expression via immunobloting and histopathology were performed. We observed statistically significant elevation of the reactive oxygen species level in the serum of patients as well as in the insulin administrated rat model, a mild expression of cardiac marker in experimental models along with abnormal histopathology of hearts. However, super oxide dismutase free radical scavenger activity was down regulated upon insulin treatment compared to control rats. Conclusively, the present study showed that over expression of insulin might stimulate cardiac hypertrophic signal via up regulation of free radicals and down regulation of antioxidants enzymes including SOD activity.

  1. Genetic background influences adaptation to cardiac hypertrophy and Ca(2+) handling gene expression.

    PubMed

    Waters, Steve B; Diak, Douglass M; Zuckermann, Matthew; Goldspink, Paul H; Leoni, Lara; Roman, Brian B

    2013-01-01

    Genetic variability has a profound effect on the development of cardiac hypertrophy in response to stress. Consequently, using a variety of inbred mouse strains with known genetic profiles may be powerful models for studying the response to cardiovascular stress. To explore this approach we looked at male C57BL/6J and 129/SvJ mice. Hemodynamic analyses of left ventricular pressures (LVPs) indicated significant differences in 129/SvJ and C57BL/6J mice that implied altered Ca(2+) handling. Specifically, 129/SvJ mice demonstrated reduced rates of relaxation and insensitivity to dobutamine (Db). We hypothesized that altered expression of genes controlling the influx and efflux of Ca(2+) from the sarcoplasmic reticulum (SR) was responsible and investigated the expression of several genes involved in maintaining the intracellular and sarcoluminal Ca(2+) concentration using quantitative real-time PCR analyses (qRT-PCR). We observed significant differences in baseline gene expression as well as different responses in expression to isoproterenol (ISO) challenge. In untreated control animals, 129/SvJ mice expressed 1.68× more ryanodine receptor 2(Ryr2) mRNA than C57BL/6J mice but only 0.37× as much calsequestrin 2 (Casq2). After treatment with ISO, sarco(endo)plasmic reticulum Ca(2+)-ATPase(Serca2) expression was reduced nearly two-fold in 129/SvJ while expression in C57BL/6J was stable. Interestingly, β (1) adrenergic receptor(Adrb1) expression was lower in 129/SvJ compared to C57BL/6J at baseline and lower in both strains after treatment. Metabolically, the brain isoform of creatine kinase (Ckb) was up-regulated in response to ISO in C57BL/6J but not in 129/SvJ. These data suggest that the two strains of mice regulate Ca(2+) homeostasis via different mechanisms and may be useful in developing personalized therapies in human patients.

  2. New Approaches to Prevent LEOPARD Syndrome-associated Cardiac Hypertrophy by Specifically Targeting Shp2-dependent Signaling*

    PubMed Central

    Schramm, Christine; Edwards, Michelle A.; Krenz, Maike

    2013-01-01

    In LEOPARD syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy. The prohypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin. Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets. Using cultured neonatal rat cardiomyocytes with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase as well as mammalian target of rapamycin. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective because this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2. PMID:23673659

  3. VCP746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model.

    PubMed

    Chuo, Chung H; Devine, Shane M; Scammells, Peter J; Krum, Henry; Christopoulos, Arthur; May, Lauren T; White, Paul J; Wang, Bing H

    2016-10-01

    VCP746 is a novel A1 adenosine receptor (A1 AR) biased agonist previously shown to be cytoprotective with no effect on heart rate. The aim of this study was to investigate the potential anti-hypertrophic effect of VCP746 in neonatal rat cardiac myocytes (NCM). NCM hypertrophy was stimulated with interleukin (IL)-1β (10 ng/mL), tumour necrosis factor (TNF)-α (10 ng/mL) or Ang II (100 nmol/L) and was assessed by (3) H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by (3) H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1 AR agonist, N(6) -cyclopentyladenosine (CPA). Further investigation with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay showed that neither CPA nor VCP746 had any effect on cell viability, confirming that the reduction in (3) H-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1β, TNF-α and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, β-MHC and α-SKA in NCM. Treatment with VCP746 at concentrations as low as 1 nmol/L suppressed mRNA expression of ANP, β-MHC and α-SKA stimulated by IL-1β, TNF-α or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A1 AR agonist, VCP746, is able to attenuate cardiac myocyte hypertrophy. As such, VCP746 is potentially useful as a pharmacological agent in attenuating cardiac remodelling, especially in the post-myocardial infarction setting, given its previously established cytoprotective properties.

  4. Cardiomyocyte-Specific Deletion of Endothelin Receptor A Rescues Ageing-Associated Cardiac Hypertrophy and Contractile Dysfunction: Role of Autophagy

    PubMed Central

    Ceylan-Isik, Asli F.; Dong, Maolong; Zhang, Yingmei; Dong, Feng; Turdi, Subat; Nair, Sreejayan; Yanagisawa, Masashi; Ren, Jun

    2013-01-01

    Cardiac ageing is manifested as cardiac remodeling and contractile dysfunction although precise mechanisms remain elusive. This study was designed to examine the role of endothelin-1 (ET-1) in ageing-associated myocardial morphological and contractile defects. Echocardiographic and cardiomyocyte contractile properties were evaluated in young (5–6 mo) and old (26–28 mo) C57BL/6 wild-type and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. Cardiac ROS production and histology were examined. Our data revealed that ETAKO mice displayed an improved survival. Ageing increased plasma levels of ET-1 and Ang II, compromised cardiac function (fractional shortening, cardiomyocyte peak shortening, maximal velocity of shortening/ relengthening and prolonged relengthening) and intracellular Ca2+ handling (reduced intracellular Ca2+ release and decay), the effects of which with the exception of ET-1 and Ang II levels was improved by ETAKO. Histological examination displayed cardiomyocyte hypertrophy and interstitial fibrosis associated with cardiac remodeling in aged C57 mice, which were alleviated in ETAKO mice. Ageing promoted ROS generation, protein damage, ER stress, upregulated GATA4, ANP, NFATc3, and the autophagosome cargo protein p62, downregulated intracellular Ca2+ regulatory proteins SERCA2a and phospholamban as well as the autophagic markers Beclin-1, Atg7, Atg5 and LC3BII, which were ablated by ETAKO. ET-1 triggered a decrease in autophagy and increased hypertrophic markers in vitrothe effect of which were reversed by the ETA receptor antagonist BQ123 and the autophagy inducer rapamycin. Antagonism of ETA but not ETB receptor rescued cardiac ageing, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ETA receptor ablation protects against ageing-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation. PMID:23381122

  5. Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy

    PubMed Central

    Johnson, Keven R.; Nicodemus-Johnson, Jessie; Spindler, Mathew J.

    2015-01-01

    In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo. PMID:26192751

  6. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

    SciTech Connect

    Lund, Amie K.; Goens, M. Beth; Nunez, Bethany A.; Walker, Mary K. . E-mail: mkwalker@unm.edu

    2006-04-15

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ET{sub A} receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, {beta}-myosin heavy chain ({beta}-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ET{sub A} receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and {beta}-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ET{sub A} receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.

  7. Low carbohydrate/high-fat diet attenuates cardiac hypertrophy, remodeling, and altered gene expression in hypertension

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hype...

  8. Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure: Its Beneficial Effects on ACE2/Ang(1-7)/Mas Axis and NADPH Oxidase Expression.

    PubMed

    Tanno, Tomohiro; Tomita, Hirofumi; Narita, Ikuyo; Kinjo, Takahiko; Nishizaki, Kimitaka; Ichikawa, Hiroaki; Kimura, Yoshihiro; Tanaka, Makoto; Osanai, Tomohiro; Okumura, Ken

    2016-06-01

    Enhanced renin-angiotensin activity causes hypertension and cardiac hypertrophy. The angiotensin (Ang)-converting enzyme (ACE)2/Ang(1-7)/Mas axis pathway functions against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits cardiac hypertrophy independently of blood pressure, and evaluated the potential mechanisms. The 3- to 4-month-old male mice overexpressing renin in the liver (Ren-Tg) were given Olm (5 mg/kg/d) and hydralazine (Hyd) (3.5 mg/kg/d) orally for 2 months. Systolic blood pressure was higher in the Ren-Tg mice than in wild-type littermates. Olm and Hyd treatments lowered systolic blood pressure to the same degree. However, cardiac hypertrophy, evaluated by echocardiography, heart weight, cross-sectional area of cardiomyocytes, and gene expression, was inhibited by only Olm treatment, but not by Hyd. Olm treatment reversed decreased gene expressions of ACE2 and Mas receptor of Ren-Tg mice and inhibited enhanced NADPH oxidase (Nox)4 expression and reactive oxygen species, whereas Hyd treatment had no influence on them. These findings indicate that Olm treatment inhibits cardiac hypertrophy independently of blood pressure, not only through its original AT1R blockade but partly through enhancement of ACE2/Ang(1-7)/Mas axis and suppression of Nox4 expression. PMID:26886190

  9. A peptide of the RGS domain of GRK2 binds and inhibits Gαq to suppress pathological cardiac hypertrophy and dysfunction

    PubMed Central

    Schumacher, Sarah M.; Gao, Erhe; Cohen, Maya; Lieu, Melissa; Chuprun, J. Kurt; Koch, Walter J.

    2016-01-01

    G protein–coupled receptor (GPCR) kinases (GRKs) play a critical role in cardiac function by regulating GPCR activity. GRK2 suppresses GPCR signaling by phosphorylating and desensitizing active GPCRs, and through protein-protein interactions that uncouple GPCRs from their downstream effectors. Several GRK2 interacting partners, including Gαq, promote maladaptive cardiac hypertrophy, which leads to heart failure, a leading cause of mortality worldwide. The regulator of G protein signaling (RGS) domain of GRK2 interacts with and inhibits Gαq in vitro. We generated TgβARKrgs mice with cardiac-specific expression of the RGS domain of GRK2 and subjected these mice to pressure overload to trigger adaptive changes that lead to heart failure. Unlike their nontransgenic littermate controls, the TgβARKrgs mice exhibited less hypertrophy as indicated by reduced left ventricular wall thickness, decreased expression of genes linked to cardiac hypertrophy, and less adverse structural remodeling. The βARKrgs peptide, but not endogenous GRK2, interacted with Gαq and interfered with signaling through this G protein. These data support the development of GRK2-based therapeutic approaches to prevent hypertrophy and heart failure. PMID:27016525

  10. Molecular changes in the early phase of renin-dependent cardiac hypertrophy in hypertensive cyp1a1ren-2 transgenic rats.

    PubMed

    Kunert-Keil, Christiane; Landsberger, Martin; Jantzen, Franziska; Niessner, Felix; Kroemer, Heyo K; Felix, Stephan B; Brinkmeier, Heinrich; Peters, Jörg

    2013-03-01

    An early response to high arterial pressure is the development of cardiac hypertrophy. Functional and transcriptional regulation of ion channels and Ca(2+) handling proteins are involved in this process but the relative contribution of each is unclear. In this study, we investigated the expression of genes involved in action potential generation and Ca(2+) homeostasis of cardiomyocytes in hypertensive cyp1a1ren-2 transgenic rats. In this model, the transgene prorenin was induced by indole-3-carbinol for 2 weeks allowing the induction of hypertension. Electrophysiological recordings from cardiomyocytes of hypertensive rats revealed a slight increase in membrane capacitance consistent with cellular hypertrophy. L-type calcium current density was reduced by 30%. Left ventricles of hypertensive rats showed a significant increase in transcript and protein levels of the cation channel TRPC6 and FK506-binding protein, whereas levels of SERCA2 and voltage-dependent potassium channels K(v)4.2 and K(v)4.3 were found to be decreased. Further, a marked nuclear localization of the transcription factors GATA4 and NFATC4 was observed in cardiac tissue of hypertensive rats. The cyp1a1ren-2 transgenic rat thus appears to be a valid model to investigate early changes in cardiac hypertrophy. This study points to roles for TRPC6, FK506BP, SERCA2, K(v)4.2, and K(v)4.3 in the development of cardiac hypertrophy. PMID:23060473

  11. Hypertrophy, gene expression, and beating of neonatal cardiac myocytes are affected by microdomain heterogeneity in 3D

    PubMed Central

    Curtis, Matthew W.; Sharma, Sadhana; Desai, Tejal A.

    2011-01-01

    Cardiac myocytes are known to be influenced by the rigidity and topography of their physical microenvironment. It was hypothesized that 3D heterogeneity introduced by purely physical microdomains regulates cardiac myocyte size and contraction. This was tested in vitro using polymeric microstructures (G′=1.66 GPa) suspended with random orientation in 3D by a soft Matrigel matrix (G′=22.9 Pa). After 10 days of culture, the presence of 100 μm-long microstructures in 3D gels induced fold increases in neonatal rat ventricular myocyte size (1.61±0.06, p<0.01) and total protein/cell ratios (1.43± 0.08, p<0.05) that were comparable to those induced chemically by 50 μM phenylephrine treatment. Upon attachment to microstructures, individual myocytes also had larger cross-sectional areas (1.57±0.05, p<0.01) and higher average rates of spontaneous contraction (2.01±0.08, p<0.01) than unattached myocytes. Furthermore, the inclusion of microstructures in myocyte-seeded gels caused significant increases in the expression of beta-1 adrenergic receptor (β1-AR, 1.19±0.01), cardiac ankyrin repeat protein (CARP, 1.26±0.02), and sarcoplasmic reticulum calcium-ATPase (SERCA2, 1.59±0.12, p<0.05), genes implicated in hypertrophy and contractile activity. Together, the results demonstrate that cardiac myocyte behavior can be controlled through local 3D microdomains alone. This approach of defining physical cues as independent features may help to advance the elemental design considerations for scaffolds in cardiac tissue engineering and therapeutic microdevices. PMID:20668947

  12. Pressure overload stimulated cardiac hypertrophy leads to a rapid decrease in the mRNA for creatine kinase

    SciTech Connect

    Boheler, K.; Popovich, B.; Dillmann, W.H.

    1987-05-01

    Cardiac hypertrophy (CH) leads to a decrease in creatine kinase (CK) enzymatic activity. To determine if the mRNA for CK also decreases with CH, they performed the following studies. Cardiac RNA was isolated from rats subjected to either abdominal aortic stenosis (AS) or sham surgery. Through Northern blot analysis, total cardiac RNA was quantitated with a CK specific /sup 32/P-labelled cDNA clone. At 3 and 8 days post-constriction, the mRNA for CK decreases by 54.6 +/- 7% and 65.3 +/- 18% respectively, whereas the heart weight increases by 19% and 37% relative to controls. Further studies indicate that CK mRNA also decreases by 41.8% in hypothyroid rats (Tx) but decreases by a total of 68.1% in Tx rats subjected to 8 days of AS. Pressure overload stimulated CH leads to a rapid decrease in CK mRNA in normal and Tx rats. This CK mRNA decrease may account for the decreased efficiency of contraction seen in CH.

  13. Mitogen-activated protein kinases (p38 and c-Jun NH2-terminal kinase) are differentially regulated during cardiac volume and pressure overload hypertrophy.

    PubMed

    Sopontammarak, Somkiat; Aliharoob, Assad; Ocampo, Catherina; Arcilla, Rene A; Gupta, Mahesh P; Gupta, Madhu

    2005-01-01

    -MHC expression was downregulated in PO but remained unchanged in VO hypertrophy hearts. Thus, these results demonstrate differential activation of MAPKs in two types of cardiac hypertrophy and this, in part, may contribute to differential expression of cardiac muscle gene expression, giving rise to unique cardiac phenotype associated with different hemodynamic overloads.

  14. Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts

    PubMed Central

    Tur, Jared; Chapalamadugu, Kalyan C.; Padawer, Timothy; Badole, Sachin L.; Kilfoil, Peter J.; Bhatnagar, Aruni; Tipparaju, Srinivas M.

    2016-01-01

    Cardiovascular disease is the leading cause of death and debility in women in the USA, and cardiac arrhythmias are a major concern. Voltage-gated potassium (Kv) channels along with the binding partners; Kvβ subunits are major regulators of the action potential (AP) shape and duration (APD). The regulation of Kv channels by the Kvβ1 subunit is unknown in female hearts. In the present study, we hypothesized that the Kvβ1 subunit is an important regulator of female cardiac physiology. To test this hypothesis, we ablated (knocked out; KO) the KCNAB1 isoform 1 (Kvβ1.1) subunit in mice and evaluated cardiac function and electrical activity by using ECG, monophasic action potential recordings and echocardiography. Our results showed that the female Kvβ1.1 KO mice developed cardiac hypertrophy, and the hearts were structurally different, with enlargement and increased area. The electrical derangements caused by Kvβ1.1 KO in female mice included long QTc and QRS intervals along with increased APD (APD20–90% repolarization). The male Kvβ1.1 KO mice did not develop cardiac hypertrophy, but they showed long QTc and prolonged APD. Molecular analysis showed that several genes that support cardiac hypertrophy were significantly altered in Kvβ1.1 KO female hearts. In particular, myosin heavy chain αexpression was significantly elevated in Kvβ1.1 KO mouse heart. Using a small interfering RNA strategy, we identified that knockdown of Kvβ1 increases myosin heavy chain αexpression in H9C2 cells. Collectively, changes in molecular and cell signalling pathways clearly point towards a distinct electrical and structural remodelling consistent with cardiac hypertrophy in the Kvβ1.1 KO female mice. PMID:27038296

  15. Immediate effects of a single exercise bout on protein O-GlcNAcylation and chromatin regulation of cardiac hypertrophy

    PubMed Central

    Medford, Heidi M.; Porter, Karen

    2013-01-01

    Cardiac hypertrophy induced by pathological stimuli is regulated by a complex formed by the repressor element 1-silencing transcription factor (REST) and its corepressor mSin3A. We previously reported that hypertrophic signaling is blunted by O-linked attachment of β-N-acetylglucosamine (O-GlcNAc) to proteins. Regular exercise induces a physiological hypertrophic phenotype in the heart that is associated with decreased O-GlcNAc levels, but a link between O-GlcNAc, the REST complex, and initiation of exercise-induced cardiac hypertrophy is not known. Therefore, mice underwent a single 15- or 30-min bout of moderate- to high-intensity treadmill running, and hearts were harvested immediately and compared with sedentary controls. Cytosolic O-GlcNAc was lower (P < 0.05) following 15 min exercise with no differences in nuclear levels (P > 0.05). There were no differences in cytosolic or nuclear O-GlcNAc levels in hearts after 30 min exercise (P > 0.05). Cellular compartment levels of O-GlcNAc transferase (OGT, the enzyme that removes the O-GlcNAc moiety from proteins), REST, mSin3A, and histone deacetylases (HDACs) 1, 2, 3, 4, and 5 were not changed with exercise. Immunoprecipitation revealed O-GlcNAcylation of OGT and HDACs 1, 2, 4, and 5 that was not changed with acute exercise; however, exercised hearts did exhibit lower interactions between OGT and REST (P < 0.05) but not between OGT and mSin3A. These data suggest that hypertrophic signaling in the heart may be initiated by as little as 15 min of exercise via intracellular changes in protein O-GlcNAcylation distribution and reduced interactions between OGT and the REST chromatin repressor. PMID:23624624

  16. Establishment of a prediction model of changing trends in cardiac hypertrophy disease based on microarray data screening

    PubMed Central

    MA, CAIYAN; YING, YONGJUN; ZHANG, TIANJIE; ZHANG, WEI; PENG, HUI; CHENG, XUFENG; XU, LIN; TONG, HONG

    2016-01-01

    The aim of the present study was to construct a mathematical model to predict the changing trends of cardiac hypertrophy at gene level. Microarray data were downloaded from Gene Expression Omnibus database (accession, GSE21600), which included 35 samples harvested from the heart of Wistar rats on postoperative days 1 (D1 group), 6 (D6 group) and 42 (D42 group) following aorta ligation and sham operated Wistar rats, respectively. Each group contained six samples, with the exception of the samples harvested from the aorta ligated group after 6 days, where n=5. Differentially expressed genes (DEGs) were identified using a Limma package in R. Hierarchical clustering analysis was performed on common DEGs in order to construct a linear equation between the D1 and D42 groups, using linear discriminant analysis. Subsequent verification was performed using receiver operating characteristic (ROC) curve and the measurement data at day 42. A total of 319, 44 and 57 DEGs were detected in D1, D6 and D42 sample groups, respectively. AKIP1, ANKRD23, LTBP2, TGF-β2 and TNFRSF12A were identified as common DEGs in all groups. The predicted linear equation between D1 and D42 group was calculated to be y=1.526×-186.671. Assessment of the ROC curve demonstrated that the area under the curve was 0.831, with a specificity and sensitivity of 0.8. As compared with the predictive and measurement data at day 42, the consistency of the two sets of data was 76.5%. In conclusion, the present model may contribute to the early prediction of changing trends in cardiac hypertrophy disease at gene level. PMID:27168795

  17. Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1.

    PubMed

    Li, Haobo; Yao, Weifeng; Irwin, Michael G; Wang, Tingting; Wang, Shuang; Zhang, Liangqing; Xia, Zhengyuan

    2015-07-01

    Hyperglycemia-induced oxidative stress is implicated in the development of cardiomyopathy in diabetes that is associated with reduced adiponectin (APN) and heme oxygenase-1 (HO-1). Brahma-related gene 1 (Brg1) assists nuclear factor-erythroid-2-related factor-2 (Nrf2) to activate HO-1 to increase myocardial antioxidant capacity in response to oxidative stress. We hypothesized that reduced adiponectin (APN) impairs HO-1 induction which contributes to the development of diabetic cardiomyopathy, and that supplementation of APN may ameliorate diabetic cardiomyopathy by activating HO-1 through Nrf2 and Brg1 in diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were untreated or treated with APN adenovirus (1×10(9) pfu) 3 weeks after diabetes induction and examined and terminated 1 week afterward. Rat left ventricular functions were assessed by a pressure-volume conductance system, before the rat hearts were removed to perform histological and biochemical assays. Four weeks after diabetes induction, D rats developed cardiac hypertrophy evidenced as increased ratio of heart weight to body weight, elevated myocardial collagen I content, and larger cardiomyocyte cross-sectional area (all P<0.05 vs C). Diabetes elevated cardiac oxidative stress (increased 15-F2t-isoprostane, 4-hydroxynonenal generation, 8-hydroxy-2'-deoxyguanosine, and superoxide anion generation), increased myocardial apoptosis, and impaired cardiac function (all P<0.05 vs C). In D rats, myocardial HO-1 mRNA and protein expression were reduced which was associated with reduced Brg1 and nuclear Nrf2 protein expression. All these changes were either attenuated or prevented by APN. In primarily cultured cardiomyocytes (CMs) isolated from D rats or in the embryonic rat cardiomyocytes cell line H9C2 cells incubated with high glucose (HG, 25 mM), supplementation of recombined globular APN (gAd, 2μg/mL) reversed HG-induced reductions of HO-1, Brg1, and nuclear Nrf2 protein expression and

  18. NFIL3 suppresses hypoxia-induced apoptotic cell death by targeting the insulin-like growth factor 2 receptor.

    PubMed

    Lin, Kuan-Ho; Kuo, Chia-Hua; Kuo, Wei-Wen; Ho, Tsung-Jung; Pai, Peiying; Chen, Wei-Kung; Pan, Lung-Fa; Wang, Chien-Cheng; Padma, V Vijaya; Huang, Chih-Yang

    2015-06-01

    The insulin-like growth factor-II/mannose 6-phosphate receptor (IGF2R) over-expression correlates with heart disease progression. The IGF2R is not only an IGF2 clearance receptor, but it also triggers signal transduction, resulting in cardiac hypertrophy, apoptosis and fibrosis. The present study investigated the nuclear factor IL-3 (NFIL3), a transcription factor of the basic leucine zipper superfamily, and its potential pro-survival effects in cardiomyocytes. NFIL3 might play a key role in heart development and act as a survival factor in the heart, but the regulatory mechanisms are still unclear. IGF2 and IGF2R protein expression were highly increased in rat hearts subjected to hemorrhagic shock. IGF2R protein expression was also up-regulated in H9c2 cells exposed to hypoxia. Over-expression of NFIL3 in H9c2 cardiomyoblast cells inhibited the induction of hypoxia-induced apoptosis and down-regulated IGF2R expression levels. Gel shift assay, double-stranded DNA pull-down assay and chromatin immune-precipitation analyses indicated that NFIL3 binds directly to the IGF2R promoter region. Using a luciferase assay, we further observed NFIL3 repress IGF2R gene promoter activity. Our results demonstrate that NFIL3 is an important negative transcription factor, which through binding to the promoter of IGF2R, suppresses the apoptosis induced by IGF2R signaling in H9c2 cardiomyoblast cells under hypoxic conditions. PMID:25536374

  19. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.

    PubMed Central

    Schunkert, H; Dzau, V J; Tang, S S; Hirsch, A T; Apstein, C S; Lorell, B H

    1990-01-01

    We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls. Images PMID:2174912

  20. PULMONARY ARTERIAL DISEASE ASSOCIATED WITH RIGHT-SIDED CARDIAC HYPERTROPHY AND CONGESTIVE HEART FAILURE IN ZOO MAMMALS HOUSED AT 2,100 M ABOVE SEA LEVEL.

    PubMed

    Juan-Sallés, Carles; Martínez, Liliana Sofía; Rosas-Rosas, Arely G; Parás, Alberto; Martínez, Osvaldo; Hernández, Alejandra; Garner, Michael M

    2015-12-01

    Subacute and chronic mountain sickness of humans and the related brisket disease of cattle are characterized by right-sided congestive heart failure in individuals living at high altitudes as a result of sustained hypoxic pulmonary hypertension. Adaptations to high altitude and disease resistance vary among species, breeds, and individuals. The authors conducted a retrospective survey of right-sided cardiac hypertrophy associated with pulmonary arterial hypertrophy or arteriosclerosis in zoo mammals housed at Africam Safari (Puebla, México), which is located at 2,100 m above sea level. Seventeen animals with detailed pathology records matched the study criterion. Included were 10 maras (Dolichotis patagonum), 2 cotton-top tamarins (Saguinus oedipus oedipus), 2 capybaras (Hydrochaeris hydrochaeris), and 1 case each of Bennet's wallaby (Macropus rufogriseus), nilgai antelope (Boselaphus tragocamelus), and scimitar-horned oryx (Oryx dammah). All had right-sided cardiac hypertrophy and a variety of arterial lesions restricted to the pulmonary circulation and causing arterial thickening with narrowing of the arterial lumen. Arterial lesions most often consisted of medial hypertrophy or hyperplasia of small and medium-sized pulmonary arteries. All maras also had single or multiple elevated plaques in the pulmonary arterial trunk consisting of fibrosis, accompanied by chondroid metaplasia in some cases. Both antelopes were juvenile and died with right-sided congestive heart failure associated with severe pulmonary arterial lesions. To the authors' knowledge, this is the first description of cardiac and pulmonary arterial disease in zoo mammals housed at high altitudes.

  1. PULMONARY ARTERIAL DISEASE ASSOCIATED WITH RIGHT-SIDED CARDIAC HYPERTROPHY AND CONGESTIVE HEART FAILURE IN ZOO MAMMALS HOUSED AT 2,100 M ABOVE SEA LEVEL.

    PubMed

    Juan-Sallés, Carles; Martínez, Liliana Sofía; Rosas-Rosas, Arely G; Parás, Alberto; Martínez, Osvaldo; Hernández, Alejandra; Garner, Michael M

    2015-12-01

    Subacute and chronic mountain sickness of humans and the related brisket disease of cattle are characterized by right-sided congestive heart failure in individuals living at high altitudes as a result of sustained hypoxic pulmonary hypertension. Adaptations to high altitude and disease resistance vary among species, breeds, and individuals. The authors conducted a retrospective survey of right-sided cardiac hypertrophy associated with pulmonary arterial hypertrophy or arteriosclerosis in zoo mammals housed at Africam Safari (Puebla, México), which is located at 2,100 m above sea level. Seventeen animals with detailed pathology records matched the study criterion. Included were 10 maras (Dolichotis patagonum), 2 cotton-top tamarins (Saguinus oedipus oedipus), 2 capybaras (Hydrochaeris hydrochaeris), and 1 case each of Bennet's wallaby (Macropus rufogriseus), nilgai antelope (Boselaphus tragocamelus), and scimitar-horned oryx (Oryx dammah). All had right-sided cardiac hypertrophy and a variety of arterial lesions restricted to the pulmonary circulation and causing arterial thickening with narrowing of the arterial lumen. Arterial lesions most often consisted of medial hypertrophy or hyperplasia of small and medium-sized pulmonary arteries. All maras also had single or multiple elevated plaques in the pulmonary arterial trunk consisting of fibrosis, accompanied by chondroid metaplasia in some cases. Both antelopes were juvenile and died with right-sided congestive heart failure associated with severe pulmonary arterial lesions. To the authors' knowledge, this is the first description of cardiac and pulmonary arterial disease in zoo mammals housed at high altitudes. PMID:26667539

  2. p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling.

    PubMed

    Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2016-09-01

    The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart. PMID:27486069

  3. p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling.

    PubMed

    Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2016-09-01

    The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart.

  4. Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

    PubMed Central

    Brusselmans, Koen; Compernolle, Veerle; Tjwa, Marc; Wiesener, Michael S.; Maxwell, Patrick H.; Collen, Désiré; Carmeliet, Peter

    2003-01-01

    Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor–1α (HIF-1α), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2α is a homologue of HIF-1α and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2α–deficient (Hif2α+/–) mice after exposure to 10% O2 for 4 weeks. In contrast to WT mice, Hif2α+/– mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2α in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2α+/– mice after hypoxia, suggesting that HIF-2α–mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling. PMID:12750401

  5. Global Transcriptomic Profiling of Cardiac Hypertrophy and Fatty Heart Induced by Long-Term High-Energy Diet in Bama Miniature Pigs

    PubMed Central

    Xia, Jihan; Zhang, Yuanyuan; Xin, Leilei; Kong, Siyuan; Chen, Yaoxing; Yang, Shulin; Li, Kui

    2015-01-01

    A long-term high-energy diet affects human health and leads to obesity and metabolic syndrome in addition to cardiac steatosis and hypertrophy. Ectopic fat accumulation in the heart has been demonstrated to be a risk factor for heart disorders, but the molecular mechanism of heart disease remains largely unknown. Bama miniature pigs were fed a high-fat, high-sucrose diet (HFHSD) for 23 months. These pigs developed symptoms of metabolic syndrome and showed cardiac steatosis and hypertrophy with a greatly increased body weight (2.73-fold, P<0.01), insulin level (4.60-fold, P<0.01), heart weight (1.82-fold, P<0.05) and heart volume (1.60-fold, P<0.05) compared with the control pigs. To understand the molecular mechanisms of cardiac steatosis and hypertrophy, nine pig heart cRNA samples were hybridized to porcine GeneChips. Microarray analyses revealed that 1,022 genes were significantly differentially expressed (P<0.05, ≥1.5-fold change), including 591 up-regulated and 431 down-regulated genes in the HFHSD group relative to the control group. KEGG analysis indicated that the observed heart disorder involved the signal transduction-related MAPK, cytokine, and PPAR signaling pathways, energy metabolism-related fatty acid and oxidative phosphorylation signaling pathways, heart function signaling-related focal adhesion, axon guidance, hypertrophic cardiomyopathy and actin cytoskeleton signaling pathways, inflammation and apoptosis pathways, and others. Quantitative RT-PCR assays identified several important differentially expressed heart-related genes, including STAT3, ACSL4, ATF4, FADD, PPP3CA, CD74, SLA-8, VCL, ACTN2 and FGFR1, which may be targets of further research. This study shows that a long-term, high-energy diet induces obesity, cardiac steatosis, and hypertrophy and provides insights into the molecular mechanisms of hypertrophy and fatty heart to facilitate further research. PMID:26161779

  6. Structural integration in hypoxia-inducible factors

    SciTech Connect

    Wu, Dalei; Potluri, Nalini; Lu, Jingping; Kim, Youngchang; Rastinejad, Fraydoon

    2015-08-20

    The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

  7. Hypoxia-Inducible Factor in Thyroid Carcinoma

    PubMed Central

    Burrows, Natalie; Babur, Muhammad; Resch, Julia; Williams, Kaye J.; Brabant, Georg

    2011-01-01

    Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden. PMID:21765994

  8. Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

    PubMed Central

    Cai, Yin; Tang, Eva Hoi Ching; Ma, Haichun

    2016-01-01

    Prostaglandin E2 (PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2 are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects. PMID:27190998

  9. Chronic high fat diet induces cardiac hypertrophy and fibrosis in mice

    PubMed Central

    Wang, Zhi; Li, Liaoliao; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2015-01-01

    Background Obesity can cause pathological changes in organs. We determined the effects of chronic high fat diet (HFD) and intermittent fasting, a paradigm providing organ protection, on mouse heart. Methods Seven-week old CD1 male mice were randomly assigned to control, HFD and intermittent fasting groups. Control mice had free access to regular diet (RD). RD was provided every other day to mice in the intermittent fasting group. Mice in HFD group had free access to HFD. Their left ventricles were harvested 11 months after they had been on these diet regimens. Results HFD increased cardiomyocyte cross-section area and fibrosis. HFD decreased active caspase 3, an apoptosis marker, and the ratio of microtubule-associated protein 1A/1B-light chain 3 (LC3) II/LC3 I, an autophagy marker. HFD increased the phospho-glycogen synthase kinase-3β (GSK-3β) at Ser9, a sign of GSK-3β inhibition. Nuclear GATA binding protein 4 and yes-associated protein, two GSK-3β targeting transcription factors that can induce hypertrophy-related gene expression, were increased in HFD-fed mice. Mice on intermittent fasting did not have these changes except for the increased active caspase 3 and decreased ratio of LC3II/LC3I. Conclusions These results suggest that chronic HFD induces myocardial hypertrophy and fibrosis, which may be mediated by GSK-3β inhibition. PMID:25982698

  10. Cell contact as an independent factor modulating cardiac myocyte hypertrophy and survival in long-term primary culture

    NASA Technical Reports Server (NTRS)

    Clark, W. A.; Decker, M. L.; Behnke-Barclay, M.; Janes, D. M.; Decker, R. S.

    1998-01-01

    Cardiac myocytes maintained in cell culture develop hypertrophy both in response to mechanical loading as well as to receptor-mediated signaling mechanisms. However, it has been shown that the hypertrophic response to these stimuli may be modulated through effects of intercellular contact achieved by maintaining cells at different plating densities. In this study, we show that the myocyte plating density affects not only the hypertrophic response and features of the differentiated phenotype of isolated adult myocytes, but also plays a significant role influencing myocyte survival in vitro. The native rod-shaped phenotype of freshly isolated adult myocytes persists in an environment which minimizes myocyte attachment and spreading on the substratum. However, these conditions are not optimal for long-term maintenance of cultured adult cardiac myocytes. Conditions which promote myocyte attachment and spreading on the substratum, on the other hand, also promote the re-establishment of new intercellular contacts between myocytes. These contacts appear to play a significant role in the development of spontaneous activity, which enhances the redevelopment of highly differentiated contractile, junctional, and sarcoplasmic reticulum structures in the cultured adult cardiomyocyte. Although it has previously been shown that adult cardiac myocytes are typically quiescent in culture, the addition of beta-adrenergic agonists stimulates beating and myocyte hypertrophy, and thereby serves to increase the level of intercellular contact as well. However, in densely-plated cultures with intrinsically high levels of intercellular contact, spontaneous contractile activity develops without the addition of beta-adrenergic agonists. In this study, we compare the function, morphology, and natural history of adult feline cardiomyocytes which have been maintained in cultures with different levels of intercellular contact, with and without the addition of beta-adrenergic agonists

  11. Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis.

    PubMed Central

    Ching, G. W.; Franklyn, J. A.; Stallard, T. J.; Daykin, J.; Sheppard, M. C.; Gammage, M. D.

    1996-01-01

    OBJECTIVES: To define the effects of long-term thyroxine treatment upon heart rate, blood pressure, left ventricular systolic function, and left ventricular size, as well as indices of autonomic function, and to compare findings with those in patients with thyrotoxicosis before and during treatment. DESIGN: Cross sectional study of patients prescribed thyroxine long term (n = 11), patients with thyrotoxicosis studied at presentation (n = 23), compared with controls (n = 25); longitudinal study of patients with thyrotoxicosis studied at presentation and serially after beginning antithyroid drug treatment (n = 23). METHODS: 24 h ambulatory monitoring of pulse and blood pressure, echocardiography, forearm plethysmography, and autonomic function tests. RESULTS: Long-term thyroxine treatment in doses that reduced serum thyrotrophin to below normal had no effect on blood pressure, heart rate, left ventricular systolic function or stroke volume index, but was associated with an 18.4% increase in left ventricular mass index (mean (SEM) 101.9 (3.09) g/m2 v controls 86.1 (4.61), P < 0.01). Thryoxine treatment, like thyrotoxicosis, had no effect on tests of autonomic function. Untreated thyrotoxicosis resulted in pronounced changes in systolic and diastolic blood pressure and an increase in heart rate during waking and sleep. Patients with thyrotoxicosis at presentation had an increase in left ventricular systolic function (ejection fraction 70.5 (1.66)% v 65.4 (1.79), P < 0.01; fractional shortening 40.4 (1.54)% v 35.6 (1.46), P < 0.01), increased stroke volume index (45.9 (2.4) ml/m2 v 36.6 (1.7), P < 0.001), and an increase in forearm blood flow, and decrease in vascular resistance. They had a similar degree of left ventricular hypertrophy to that associated with thyroxine treatment (99.3 (4.03) g/m2); all changes were corrected within 2 months by antithyroid drugs. CONCLUSIONS: The development of left ventricular hypertrophy in patients receiving thyroxine in the absence

  12. New gender-specific partition values for ECG criteria of left ventricular hypertrophy: recalibration against cardiac MRI.

    PubMed

    Alfakih, Khaled; Walters, Kevin; Jones, Tim; Ridgway, John; Hall, Alistair S; Sivananthan, Mohan

    2004-08-01

    ECG criteria for left ventricular hypertrophy (LVH) were mostly validated using left ventricular mass (LVM) as measured by M-mode echocardiography. LVM as measured by cardiac MRI has been demonstrated to be much more accurate and reproducible. We reevaluated the sensitivity and specificity of 4 ECG criteria of LVH against LVM as measured by cardiac MRI. Patients with systemic hypertension (n=288) and 60 normal volunteers had their LVM measured using a 1.5-Tesla MRI system. A 12-lead ECG was recorded, and 4 ECG criteria were evaluated: Sokolow-Lyon voltage, Cornell voltage, Cornell product, and Sokolow-Lyon product. Based on a cardiac MRI normal range, 39.9% of the hypertensive males and 36.7% of the hypertensive females had elevated LVM index. At a specificity of 95%, the Sokolow-Lyon product criterion had the highest sensitivity in females (26.2%), the Cornell criterion had the highest sensitivity in males (26.2%), and the Cornell product criteria had a relatively high sensitivity in both males and females (25.0% and 23.8%). Receiver operating characteristic curves showed the Cornell and Cornell product criteria to be superior for males whereas the Sokolow-Lyon product criterion was superior for females. Comparing the mean LVM index values of the subjects who were ECG LVH positive to the normal volunteers indicated that the ECG LVH criteria detect individuals with an LVM index substantially above the normal range. We have redefined the partition values for 4 different ECG LVH criteria, according to gender, and found that they detect subjects with markedly elevated LVM index.

  13. Astragalus polysaccharide inhibits isoprenaline-induced cardiac hypertrophy via suppressing Ca²⁺-mediated calcineurin/NFATc3 and CaMKII signaling cascades.

    PubMed

    Dai, Hongliang; Jia, Guizhi; Liu, Xin; Liu, Zhining; Wang, Hongxin

    2014-07-01

    Pathological cardiac hypertrophy induced by increased sympathetic drive can subsequently lead to congestive heart failure, which represents the major cause of morbidity and mortality worldwide. Astragalus polysaccharide (APS) is an active compound extracted from Chinese herb Astragalus membranaceus (AM), a frequently used "Qi-invigorating" herbal medicine in traditional medicine broadly used for the treatment of cardiovascular and other diseases. Currently, little is known about the effect of APS on cardiac hypertrophy. In the present study, we aimed to investigate its effect on cardiac hypertrophy and to clarify its possible mechanisms. In vitro cardiac hypertrophic model induced by isoprenaline (ISO) was employed to explore the anti-hypertrophic action of APS. We found that 10 μM ISO treatment for 48 h caused cultured cardiomyocytes to undergo significant increases in cell surface area, total protein content, protein synthesis as well as the expression of hypertrophic markers, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which were effectively inhibited by APS in a dose dependent manner. Moreover, we found that APS pretreatment alleviated the augment of intracellular free calcium during cardiac hypertrophy induced by ISO. Our further study revealed that the upregulated expression of calcineurin, translocation of nuclear factor of activated T cells, cytoplasmic 3 (NFATc3) into nucleus and activation of calmodulin kinase II (reflected by p-CaMKII) were dose dependently suppressed by the application of APS. According to this research, APS exerted its anti-hypertrophic action via inhibiting Ca(2+)-mediated calcineurin/NFATc3 and CaMKII signaling cascades, which provided new insights into the application of APS to the therapy of heart diseases.

  14. Dipyridamole-thallium tests are predictive of severe cardiac arrhythmias in patients with left ventricular hypertrophy

    SciTech Connect

    Saragoca, M.A.; Canziani, M.E.; Gil, M.A.; Castiglioni, M.L.; Cassiolato, J.L.; Barbieri, A.; Lima, V.C.; Draibe, S.A.; Martinez, E.E. )

    1991-01-01

    In a population of patients with chronic renal failure (CRF) and a high prevalence of left ventricular hypertrophy (LVH) undergoing chronic hemodialysis, the authors investigated the association between the results of dipyridamole-thallium tests (DTTs) and the occurrence of ventricular arrhythmias. They observed a positive significant association between positive DTTs and the occurrence of severe forms of ventricular arrhythmias. A significant association was also observed between the presence of severe LVH and the occurrence of severe ventricular arrhythmias. However, no association was found between the presence of LVH and the positivity of the DTT. As most of their patients with positive DTTs had unimpaired coronary circulations, they conclude that positive DTTs, although falsely indicative of impaired myocardial blood supply, does have an important clinical relevance, indicating increased risk of morbidity (and, possibly, mortality) due to ventricular arrhythmias in a population of CRF patients submitted to chronic renal function replacement program.

  15. Assessment of cardiac function and rheumatic heart disease in children with adenotonsillar hypertrophy.

    PubMed Central

    Odemis, Ender; Catal, Ferhat; Karadag, Ahmet; Kurtaran, Hanifi; Ark, Nebil; Mete, Emin

    2006-01-01

    Our aim was to evaluate whether adenotonsillar hypertrophy (ATH) is associated with rheumatic heart disease (RHD) in children. Fifty-three patients with ATH and 50 healthy children as a control group were enrolled in the study. Medical history and clinical findings were investigated, and echocardiographies were done by researchers who were unaware of the diagnosis. The two groups were compared. Valvular findings suggesting RHD were encountered in four patients (7.5%) in the ATH group and in two children (4%) in the control group. This difference was not statistically significant (p = 0.098); however, we found physiological mitral regurgitation to be significantly more frequent in the ATH group than in the control group (p = 0.023). ATH did not increase the risk of valvulitis related to RHD regardless of adenoid size and frequency of the infection. To preclude the misdiagnosis of mitral regurgitation that results from RHD, diagnostic criteria for pathological mitral regurgitation should be carefully applied. PMID:17225844

  16. Cardiac energetics in short and long term hypertrophy induced by aortic coarctation.

    PubMed

    Coughlin, P; Gibbs, C L

    1981-11-01

    Hypertrophy was induced in rats by constriction of the abdominal aorta proximal to the coeliac trunk. The effects of both short-term, STH. (2 to 4 days) and long term, LTH (40 to 55 days) hypertrophy were studied by mechanical and myothermic measurements on papillary muscles from the left ventricle. In agreement with other studies aortic coarctation increased the left ventricle to body weight ratio. In isometric experiments it was shown that peak stress development was enhanced in the STH group compared with the control and LTH groups. Active heat production was related to active stress development by linear regression in the control and pressure overload groups. There was no significant difference between the mean slopes of the groups but there was a significant increase in the intercept in the STH group and a decrease in the LTH group. This intercept corresponds to the tension-independent heat component. In isotonic experiments load enthalpy relationships were determined for the different groups and the data for each group were pooled. In the LTH group there was a 19% fall in work output per contraction and a 20% fall in total enthalpy. In the STH group there was a 31% increase in work output and a 39% rise in total enthalpy. Because of the parallel changes in work and enthalpy there was no significant change in the mechanical efficiency of the two groups as compared to the controls. The simplest interpretation of the results is that in STH the intracellular free calcium level is raised whereas in LTH it is lowered.

  17. microRNA-340-5p Functions Downstream of Cardiotrophin-1 to Regulate Cardiac Eccentric Hypertrophy and Heart Failure via Target Gene Dystrophin.

    PubMed

    Zhou, Jian; Gao, Jie; Zhang, Xiaoya; Liu, Yan; Gu, Song; Zhang, Xitao; An, Xiangguang; Yan, Jun; Xin, Yue; Su, Pixiong

    2015-01-01

    Pathological cardiac hypertrophy inevitably leads to the unfavorable outcomes of heart failure (HF) or even sudden death. microRNAs are key regulation factors participating in many pathophysiological processes. Recently, we observed upregulation of microRNA-340-5p (miR-340) in failing human hearts because of dilated cardiomyopathy, but the functional consequence of miR-340 remains to be clarified.We transfected neonatal cardiomyocytes with miR-340 and found fetal gene expression including Nppa, Nppb and Myh7. We also observed eccentric hypertrophy development upon treatment which was analogous to the phenotype after cardiotrophin-1 (CT-1) stimulation. As a potent inducer of cardiac eccentric hypertrophy, treatment by IL-6 family members CT-1 and leukemia inhibitory factor (LIF) led to the elevation of miR-340. Knockdown of miR-340 using antagomir attenuated fetal gene expression and hypertrophy formation, which means miR-340 could convey the hypertrophic signal of CT-1. To demonstrate the initial factor of miR-340 activation, we constructed a volume overloaded abdominal aorta-inferior vena cava fistula rat HF model. miR-340 and CT-1 were found to be up-regulated in the left ventricle. Dystrophin (DMD), a putative target gene of miR-340 which is eccentric hypertrophy-susceptible, was decreased in this HF model upon Western blotting and immunohistochemistry tests. Luciferase assay constructed in two seed sequence of DMD gene 3'UTR showed decreased luciferase activities, and miR-340 transfected cells resulted in the degradation of DMD.miR-340 is a pro-eccentric hypertrophy miRNA, and its expression is dependent on volume overload and cytokine CT-1 activation. Cardiomyocyte structure protein DMD is a target of miR-340.

  18. Elevated Transglutaminase 2 Activity is Associated with Hypoxia-Induced Experimental Pulmonary Hypertension in Mice

    PubMed Central

    DiRaimondo, Thomas R.; Klock, Cornelius; Warburton, Rod; Herrera, Zachary; Penumatsa, Krishna; Toksoz, Deniz; Hill, Nicholas; Khosla, Chaitan; Fanburg, Barry

    2013-01-01

    Previous studies in human patients and animal models have suggested that transglutaminase 2 (TG2) is upregulated in pulmonary hypertension (PH), a phenomenon that appears to be associated with the effects of serotonin (5-hydroxytryptamine; 5-HT) in this disease. Using chemical tools to interrogate and inhibit TG2 activity in vivo, we have shown that pulmonary TG2 undergoes marked post-translational activation in a mouse model of hypoxia-induced PH. We have also identified irreversible fluorinated TG2 inhibitors that may find use as non-invasive positron emission tomography probes for diagnosis and management of this debilitating, lifelong disorder. Pharmacological inhibition of TG2 attenuated the elevated right ventricular pressure but had no effect on hypertrophy of the right ventricle of the heart. A longitudinal study of pulmonary TG2 activity in PH patients is warranted. PMID:24152195

  19. Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling.

    PubMed

    Wang, Shudong; Luo, Manyu; Zhang, Zhiguo; Gu, Junlian; Chen, Jing; Payne, Kristen McClung; Tan, Yi; Wang, Yuehui; Yin, Xia; Zhang, Xiang; Liu, Gilbert C; Wintergerst, Kupper; Liu, Quan; Zheng, Yang; Cai, Lu

    2016-09-01

    Childhood obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), in adulthood, due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors; however, its role in ORCH and underlying mechanism(s) remain unclear and were explored here in mice with obesity induced with high-fat diet (HFD). Four week old mice were fed on either HFD (60%kcal fat) or normal diet (ND, 10% kcal fat) for 3 or 6 months, respectively. Either diet contained one of three different zinc quantities: deficiency (ZD, 10mg zinc per 4057kcal), normal (ZN, 30mg zinc per 4057kcal) or supplement (ZS, 90mg zinc per 4057kcal). HFD induced a time-dependent obesity and ORCH, which was accompanied by increased cardiac inflammation and p38 MAPK activation. These effects were worsened by ZD in HFD/ZD mice and attenuated by ZS in HFD/ZS group, respectively. Also, administration of a p38 MAPK specific inhibitor in HFD mice for 3 months did not affect HFD-induced obesity, but completely abolished HFD-induced, and zinc deficiency-worsened, ORCH and cardiac inflammation. In vitro exposure of adult cardiomyocytes to palmitate induced cell hypertrophy accompanied by increased p38 MAPK activation, which was heightened by zinc depletion with its chelator TPEN. Inhibition of p38 MAPK with its specific siRNA also prevented the effects of palmitate on cardiomyocytes. These findings demonstrate that ZS alleviates but ZD heightens cardiac hypertrophy in HFD-induced obese mice through suppressing p38 MAPK-dependent cardiac inflammatory and hypertrophic pathways.

  20. Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling.

    PubMed

    Wang, Shudong; Luo, Manyu; Zhang, Zhiguo; Gu, Junlian; Chen, Jing; Payne, Kristen McClung; Tan, Yi; Wang, Yuehui; Yin, Xia; Zhang, Xiang; Liu, Gilbert C; Wintergerst, Kupper; Liu, Quan; Zheng, Yang; Cai, Lu

    2016-09-01

    Childhood obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), in adulthood, due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors; however, its role in ORCH and underlying mechanism(s) remain unclear and were explored here in mice with obesity induced with high-fat diet (HFD). Four week old mice were fed on either HFD (60%kcal fat) or normal diet (ND, 10% kcal fat) for 3 or 6 months, respectively. Either diet contained one of three different zinc quantities: deficiency (ZD, 10mg zinc per 4057kcal), normal (ZN, 30mg zinc per 4057kcal) or supplement (ZS, 90mg zinc per 4057kcal). HFD induced a time-dependent obesity and ORCH, which was accompanied by increased cardiac inflammation and p38 MAPK activation. These effects were worsened by ZD in HFD/ZD mice and attenuated by ZS in HFD/ZS group, respectively. Also, administration of a p38 MAPK specific inhibitor in HFD mice for 3 months did not affect HFD-induced obesity, but completely abolished HFD-induced, and zinc deficiency-worsened, ORCH and cardiac inflammation. In vitro exposure of adult cardiomyocytes to palmitate induced cell hypertrophy accompanied by increased p38 MAPK activation, which was heightened by zinc depletion with its chelator TPEN. Inhibition of p38 MAPK with its specific siRNA also prevented the effects of palmitate on cardiomyocytes. These findings demonstrate that ZS alleviates but ZD heightens cardiac hypertrophy in HFD-induced obese mice through suppressing p38 MAPK-dependent cardiac inflammatory and hypertrophic pathways. PMID:27346292

  1. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    PubMed Central

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  2. Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy and Inflammatory Gene Expression

    PubMed Central

    Singh, Madhu V.; Cicha, Michael Z.; Meyerholz, David K.; Chapleau, Mark W.; Abboud, François M.

    2015-01-01

    Hypertension is recognized as an immune disorder whereby immune cells play a defining role in the genesis and progression of the disease. The innate immune system and its component toll-like receptors (TLRs) are key determinants of the immunological outcome through their pro-inflammatory response. TLR activated signaling pathways utilize several adaptor proteins of which adaptor proteins MyD88 and TRIF define two major inflammatory pathways. In this study, we compared the contributions of MyD88 and TRIF adaptor proteins to angiotensin II (Ang II)-induced hypertension and cardiac hypertrophy in mice. Deletion of MyD88 did not prevent cardiac hypertrophy and the pressor response to Ang II tended to increase. Moreover, the increase in inflammatory gene expression (Tnfa, Nox4 and Agtr1a) was significantly greater in the heart and kidney of MyD88-deficient mice compared with wild type mice. Thus, pathways involving MyD88 may actually restrain the inflammatory responses. On the other hand, in mice with non-functional TRIF (Trifmut mice), Ang II induced hypertension and cardiac hypertrophy were abrogated, and pro-inflammatory gene expression in heart and kidneys was unchanged or decreased. Our results indicate that Ang II induces activation of a pro-inflammatory innate immune response, causing hypertension, and cardiac hypertrophy. These effects require functional adaptor protein TRIF-mediated pathways. However, the common MyD88 dependent signaling pathway, which is also activated simultaneously by Ang II, paradoxically exerts a negative regulatory influence on these responses. PMID:26195481

  3. 3,3'-Diindolylmethane attenuates cardiac H9c2 cell hypertrophy through 5'-adenosine monophosphate-activated protein kinase-α.

    PubMed

    Zong, Jing; Wu, Qing-Qing; Zhou, Heng; Zhang, Jie-Yu; Yuan, Yuan; Bian, Zhou-Yan; Deng, Wei; Dai, Jia; Li, Fang-Fang; Xu, Man; Fang, Yi; Tang, Qi-Zhu

    2015-07-01

    3,3'-Diindolylmethane (DIM) is the major product of the acid-catalyzed condensation of indole-3-carbinol (I3C), a component of extracts of Brassica food plants. Numerous studies have suggested that DIM has several beneficial biological activities, including elimination of free radicals, antioxidant and anti-angiogenic effects and activation of apoptosis of various tumor cells. In the present study, an in vitro model was established, using 1 µM angiotensin II (Ang II) in cultured rat cardiac H9c2 cells, to observe the effects of DIM on cardiac hypertrophy. Following 24 h stimulation with DIM (1, 5, and 10 µM) with or without Ang II, cells were characterized by immunofluorescence to analyze cardiac α-actinin expression. Cardiomyocyte hypertrophy and molecular markers of cardiac hypertrophy were assessed by quantitative polymerase chain reaction. Atrial natriuretic peptide, brain natriuretic peptide and myosin heavy chain β mRNA expression were induced by Ang II in H9c2 cells treated with the optimal concentration of DIM for 6, 12, and 24 h. The levels of phosphorylated and total proteins of the 5' AMP-activated protein kinase α (AMPKα)/mitogen-activated protein kinase (MAPK)/mechanistic target of rapamycin (mTOR) signaling pathways in H9c2 cells treated with DIM for 0, 15, 30, and 60 min induced by Ang II were determined by western blot analysis. The results showed that DIM attenuated cellular hypertrophy in vitro, enhanced the phosphorylation of AMPKα and inhibited the MAPK‑mTOR signaling pathway in response to hypertrophic stimuli. PMID:25816057

  4. Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy.

    PubMed

    Vasconcellos, Vivian; Lacchini, Riccardo; Jacob-Ferreira, Anna L B; Sales, Maria L; Ferreira-Sae, Maria C; Schreiber, Roberto; Nadruz, Wilson; Tanus-Santos, Jose E

    2010-04-01

    Left ventricular hypertrophy (LVH) is a complication that may result from chronic hypertension. While nitric oxide (NO) deficiency has been associated with LVH, inconsistent results have been reported with regards to the association of endothelial NO synthase (eNOS) polymorphisms and LVH in hypertensive patients. This study aims to assess whether eNOS haplotypes are associated with LVH in hypertensive patients. This study included 101 healthy controls and 173 hypertensive patients submitted to echocardiography examination. Genotypes for three eNOS polymorphisms were determined: a single-nucleotide polymorphism in the promoter region (T-786C) and in exon 7 (Glu298Asp), and variable number of tandem repeats in intron 4. We found no significant association between eNOS genotypes and hypertension or with LVH (all p > 0.05). However, while we found two eNOS haplotypes associated with variable risk of hypertension (all p < 0.05), we found no significant associations between eNOS haplotypes and LVH (all p > 0.05), even after adjustment in multiple linear regression analysis. These findings suggest that eNOS haplotypes that have been associated with variable susceptibility to hypertension were not associated with LVH in hypertensive patients. Further studies are necessary to examine whether other genes downstream may interact with eNOS polymorphisms and predispose to LVH in hypertensive patients. PMID:20070154

  5. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

    PubMed

    Zhang, Qun; Yuan, Lin; Zhang, Qingrui; Gao, Yan; Liu, Guangheng; Xiu, Meng; Wei, Xiang; Wang, Zhen; Liu, Dexiang

    2015-09-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia-induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IκB-alpha and phosphorylation of p65 NF-κB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia-stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-ĸB, ERK and JNK MAPK signaling pathways. PMID:26225925

  6. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    PubMed Central

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  7. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

    PubMed Central

    Shawl, Asif Iqbal; Im, Soo-Yeul; Nam, Tae-Sik; Lee, Sun-Hwa; Ko, Jae-Ki; Jang, Kyu Yoon; Kim, Donghee; Kim, Uh-Hyun

    2016-01-01

    Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively. PMID:26959359

  8. Achievement of a target dose of bisoprolol may not be a preferred option for attenuating pressure overload-induced cardiac hypertrophy and fibrosis

    PubMed Central

    Xiang, Shizhao; Zhang, Ning; Yang, Zheng; Bian, Zhouyan; Yuan, Yuan; Tang, Qizhu

    2016-01-01

    Bisoprolol is a drug that acts via the mechanism of specifically and selectively inhibiting the β1-adrenoreceptor in cardiac myocytes, and provides a pure reduction of heart rate without changing other cardiac parameters. It has long been clinically used to treat cerebrovascular and cardiovascular illnesses. However, there is little information available on whether the role of bisoprolol in the attenuation of ventricular remodeling is dependent upon the achievement of a target dose, and whether it must be used as a preferred option. The aim of the present study was to clarify the underlying benefits of bisoprolol in the attenuation of pressure overload-induced cardiac hypertrophy and fibrosis at different doses. C57BL/6J male mice, aged 6–8 weeks, were treated with saline or one of three different doses of bisoprolol (Biso: 2.5, 5 or 10 mg/kg/day) for 8 weeks from day 1 after aortic banding (AB). A number of mice underwent sham surgery and were treated with saline or bisoprolol. The mice were randomly assigned into the sham (n=24) and AB (n=62) groups. The results revealed that bisoprolol had a protective role against the cardiac hypertrophy, fibrosis and dysfunction caused by AB. This was determined on the basis of heart/body and lung/body weight ratios and heart weight/tibia length ratios, as well as echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The present study revealed that administration of bisoprolol for a long time period may enhance its role in the prevention of cardiac hypertrophy and fibrosis induced by AB, whereas no statistically significant difference was observed between the middle- and high-doses. These observations indicated that the function of bisoprolol in protecting against cardiac hypertrophy, fibrosis and dysfunction is time-dependent. Furthermore, it is proposed that a middle dose of bisoprolol may be a better option for patients with

  9. Achievement of a target dose of bisoprolol may not be a preferred option for attenuating pressure overload-induced cardiac hypertrophy and fibrosis

    PubMed Central

    Xiang, Shizhao; Zhang, Ning; Yang, Zheng; Bian, Zhouyan; Yuan, Yuan; Tang, Qizhu

    2016-01-01

    Bisoprolol is a drug that acts via the mechanism of specifically and selectively inhibiting the β1-adrenoreceptor in cardiac myocytes, and provides a pure reduction of heart rate without changing other cardiac parameters. It has long been clinically used to treat cerebrovascular and cardiovascular illnesses. However, there is little information available on whether the role of bisoprolol in the attenuation of ventricular remodeling is dependent upon the achievement of a target dose, and whether it must be used as a preferred option. The aim of the present study was to clarify the underlying benefits of bisoprolol in the attenuation of pressure overload-induced cardiac hypertrophy and fibrosis at different doses. C57BL/6J male mice, aged 6–8 weeks, were treated with saline or one of three different doses of bisoprolol (Biso: 2.5, 5 or 10 mg/kg/day) for 8 weeks from day 1 after aortic banding (AB). A number of mice underwent sham surgery and were treated with saline or bisoprolol. The mice were randomly assigned into the sham (n=24) and AB (n=62) groups. The results revealed that bisoprolol had a protective role against the cardiac hypertrophy, fibrosis and dysfunction caused by AB. This was determined on the basis of heart/body and lung/body weight ratios and heart weight/tibia length ratios, as well as echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The present study revealed that administration of bisoprolol for a long time period may enhance its role in the prevention of cardiac hypertrophy and fibrosis induced by AB, whereas no statistically significant difference was observed between the middle- and high-doses. These observations indicated that the function of bisoprolol in protecting against cardiac hypertrophy, fibrosis and dysfunction is time-dependent. Furthermore, it is proposed that a middle dose of bisoprolol may be a better option for patients with

  10. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline.

    PubMed

    Kumar, Sandeep; Wei, Chuanyu; Thomas, Candice M; Kim, Il-Kwon; Seqqat, Rachid; Kumar, Rajesh; Baker, Kenneth M; Jones, W Keith; Gupta, Sudhiranjan

    2012-04-15

    Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been

  11. Hypoxia inducible factor-1 alpha and multiple myeloma

    PubMed Central

    Tiwary, Bhupendra Nath

    2016-01-01

    Rapid tumor growth creates a state of hypoxia in the tumor microenvironment and results in release of hypoxia inducible factor-1 alpha (HiF-1α) in the local milieu. Hypoxia inducible factor activity is deregulated in many human cancers, especially those that are highly hypoxic. In multiple myeloma (MM) in initial stages of disease establishment, the hypoxic bone marrow microenvironment supports the initial survival and growth of the myeloma cells. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Therefore, HIF is an attractive, although challenging, therapeutic target in MM directly or indirectly in recent years. PMID:26900575

  12. Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.

    PubMed

    Wende, Adam R; O'Neill, Brian T; Bugger, Heiko; Riehle, Christian; Tuinei, Joseph; Buchanan, Jonathan; Tsushima, Kensuke; Wang, Li; Caro, Pilar; Guo, Aili; Sloan, Crystal; Kim, Bum Jun; Wang, Xiaohui; Pereira, Renata O; McCrory, Mark A; Nye, Brenna G; Benavides, Gloria A; Darley-Usmar, Victor M; Shioi, Tetsuo; Weimer, Bart C; Abel, E Dale

    2015-03-01

    Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.

  13. Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

    PubMed Central

    Wende, Adam R.; O'Neill, Brian T.; Bugger, Heiko; Riehle, Christian; Tuinei, Joseph; Buchanan, Jonathan; Tsushima, Kensuke; Wang, Li; Caro, Pilar; Guo, Aili; Sloan, Crystal; Kim, Bum Jun; Wang, Xiaohui; Pereira, Renata O.; McCrory, Mark A.; Nye, Brenna G.; Benavides, Gloria A.; Darley-Usmar, Victor M.; Shioi, Tetsuo; Weimer, Bart C.

    2014-01-01

    Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. PMID:25535334

  14. CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia.

    PubMed

    Lin, Chih-Yuan; Hsu, Yu-Juei; Hsu, Shih-Che; Chen, Ying; Lee, Herng-Sheng; Lin, Shih-Hua; Huang, Shih-Ming; Tsai, Chien-Sung; Shih, Chun-Che

    2015-08-01

    Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis-2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy. Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling. The heart size and myocardial fibrosis were evaluated by echocardiography and immunohistochemical staining, respectively, in 5/6 nephrectomy chronic kidney disease (CKD) mice treated with a CB1R antagonist. CB1R and fibrosis marker expression levels were determined by immunoblotting in H9c2 cells exposed to the uremic toxin indoxyl sulfate (IS), with an organic anion transporter 1 inhibitor or a CB1R antagonist or agonist. Akt phosphorylation was also assessed to examine the signaling pathways downstream of CB1R activation induced by IS in H9c2 cells. CKD mice exhibited marked left ventricular hypertrophy and myocardial fibrosis, which were reversed by treatment with the CB1R antagonist. CB1R, collagen I, transforming growth factor (TGF)-β, and α-smooth muscle actin (SMA) expression showed time- and dose-dependent upregulation in H9c2 cells treated with IS. The inhibition of CB1R by either CB1R antagonist or small interfering RNA-mediated knockdown attenuated the expression of collagen I, TGF-β, and α-SMA in IS-treated H9c2 cells, while Akt phosphorylation was enhanced by CB1R agonist and abrogated by CB1R antagonist in these cells. In summary, we conclude that CB1R blockade attenuates LVH and Akt-mediated cardiac fibrosis in a CKD mouse model. Uremic toxin IS stimulates the expression of CB1R and fibrotic markers and CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts. Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy. PMID:26093151

  15. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

    SciTech Connect

    Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong; Cui, Wei; Chen, Wensheng; Zhu, Guo-Qing; Qin, Da-Nian; Kang, Yu-Ming

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  16. miR-30c and miR-181a synergistically modulate p53-p21 pathway in diabetes induced cardiac hypertrophy.

    PubMed

    Raut, Satish K; Singh, Gurinder B; Rastogi, Bhawna; Saikia, Uma Nahar; Mittal, Anupam; Dogra, Nilambra; Singh, Sandeep; Prasad, Rishikesh; Khullar, Madhu

    2016-06-01

    p53-p21 pathway mediates cardiomyocyte hypertrophy and apoptosis and is upregulated in diabetic cardiomyopathy (DbCM). We investigated role of microRNAs in regulating p53-p21 pathway in high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis. miR-30c and miR-181a were identified to target p53. Cardiac expression of microRNAs was measured in diabetic patients, diabetic rats, and in HG-treated cardiomyocytes. Effect of microRNAs over-expression and inhibition on HG-induced cardiomyocyte hypertrophy and apoptosis was examined. Myocardial expression of p53 and p21 genes was increased and expression of miR-30c and miR-181a was significantly decreased in diabetic patients, DbCM rats, and in HG-treated cardiomyocytes. Luciferase assay confirmed p53 as target of miR-30c and miR-181a. Over-expression of miR-30c or miR-181a decreased expression of p53, p21, ANP, cardiomyocyte cell size, and apoptosis in HG-treated cardiomyocytes. Concurrent over-expression of these microRNAs resulted in greater decrease in cardiomyocyte hypertrophy and apoptosis, suggesting a synergistic effect of these microRNAs. Our results suggest that dysregulation of miR-30c and miR-181a may be involved in upregulation of p53-p21 pathway in DbCM. PMID:27221738

  17. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

    PubMed Central

    Yu, Aimee Y.; Shimoda, Larissa A.; Iyer, Narayan V.; Huso, David L.; Sun, Xing; McWilliams, Rita; Beaty, Terri; Sham, James S.K.; Wiener, Charles M.; Sylvester, J.T.; Semenza, Gregg L.

    1999-01-01

    Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O2 concentration is decreased. Hif1a–/– mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a+/– heterozygotes develop normally and are indistinguishable from Hif1a+/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a+/– and Hif1a+/+ mice exposed to 10% O2 for one to six weeks were analyzed. Hif1a+/– mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia. J. Clin. Invest. 103:691–696 (1999) PMID:10074486

  18. High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy

    PubMed Central

    2014-01-01

    Background Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-β) contributes to the pathogenesis of the fibrotic interstitium observed in diabetic cardiomyopathy. We hypothesized that high glucose enhances the activity of the transcriptional co-activator p300, leading to the activation of TGF-β via acetylation of Smad2; and that by inhibiting p300, TGF-β activity will be reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy. Methods p300 activity was assessed in H9c2 cardiomyoblasts under normal glucose (5.6 mmol/L—NG) and high glucose (25 mmol/L—HG) conditions. 3H-proline incorporation in cardiac fibroblasts was also assessed as a marker of collagen synthesis. The role of p300 activity in modifying TGF-β activity was investigated with a known p300 inhibitor, curcumin or p300 siRNA in vitro, and the functional effects of p300 inhibition were assessed using curcumin in a hemodynamically validated model of diabetic cardiomyopathy – the diabetic TG m(Ren-2)27 rat. Results In vitro, H9c2 cells exposed to HG demonstrated increased p300 activity, Smad2 acetylation and increased TGF-β activity as assessed by Smad7 induction (all p < 0.05 c/w NG). Furthermore, HG induced 3H-proline incorporation as a marker of collagen synthesis (p < 0.05 c/w NG). p300 inhibition, using either siRNA or curcumin reduced p300 activity, Smad acetylation and TGF-β activity (all p < 0.05 c/w vehicle or scrambled siRNA). Furthermore, curcumin therapy reduced 3H-proline incorporation in HG and TGF-β stimulated fibroblasts (p < 0.05 c/w NG). To determine the functional significance of p300 inhibition, diabetic Ren-2 rats were randomized to receive curcumin or vehicle for 6 weeks. Curcumin treatment reduced cardiac hypertrophy, improved diastolic function and reduced extracellular matrix production, without

  19. Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function.

    PubMed

    Erkens, Ralf; Kramer, Christian M; Lückstädt, Wiebke; Panknin, Christina; Krause, Lisann; Weidenbach, Mathias; Dirzka, Jennifer; Krenz, Thomas; Mergia, Evanthia; Suvorava, Tatsiana; Kelm, Malte; Cortese-Krott, Miriam M

    2015-12-01

    Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to β-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system.

  20. Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

    SciTech Connect

    Song, Xin-Ai; Jia, Lin-Lin; Cui, Wei; Zhang, Meng; Chen, Wensheng; Yuan, Zu-Yi; Guo, Jing; Li, Hui-Hua; Zhu, Guo-Qing; Liu, Hao; Kang, Yu-Ming

    2014-11-15

    We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of

  1. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    SciTech Connect

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  2. Idiopathic left ventricular hypertrophy in an infant.

    PubMed

    Bhardwaj, Rajeev; Bhardwaj, Praveen

    2011-01-01

    Cardiac hypertrophy in infancy has been a subject of considerable interest. We present a case of significant left ventricular hypertrophy without any associated cause, presenting in infancy. PMID:23550435

  3. Reduced expression of adherens and gap junction proteins can have a fundamental role in the development of heart failure following cardiac hypertrophy in rats.

    PubMed

    dos Santos, Daniele O; Blefari, Valdecir; Prado, Fernanda P; Silva, Carlos A; Fazan, Rubens; Salgado, Helio C; Ramos, Simone G; Prado, Cibele M

    2016-02-01

    Hypertension causes cardiac hypertrophy, cardiac dysfunction and heart failure (HF). The mechanisms implicated in the transition from compensated to decompensated cardiac hypertrophy are not fully understood. This study was aimed to investigate whether alterations in the expression of intercalated disk proteins could contribute to the transition of compensated cardiac hypertrophy to dilated heart development that culminates in HF. Male rats were submitted to abdominal aortic constriction and at 90 days post surgery (dps), three groups were observed: sham-operated animals (controls), animals with hypertrophic hearts (HH) and animals with hypertrophic + dilated hearts (HD). Blood pressure was evaluated. The hearts were collected and Western blot and immunofluorescence were performed to desmoglein-2, desmocollin-2, N-cadherin, plakoglobin, Bcatenin, and connexin-43. Cardiac systolic function was evaluated using the Vevo 2100 ultrasound system. Data were considered significant when p b 0.05. Seventy percent of the animals presented with HH and 30% were HD at 90 dps. The blood pressure increased in both groups. The amount of desmoglein-2 and desmocollin-2 expression was increased in both groups and no difference was observed in either group. The expression of N-cadherin, plakoglobin and B-catenin increased in the HHgroup and decreased in the HDgroup; and connexin-43 decreased only in theHDgroup. Therewas no difference between the ejection fraction and fractional shortening at 30 and 60 dps; however, they were decreased in the HD group at 90 dps. We found that while some proteins have increased expression accompanied by the increase in the cell volume associated with preserved systolic cardiac function in theHHgroup, these same proteins had decreased expression evenwithout significant reduction in the cell volume associated with decreased systolic cardiac function in HD group. The increased expression of desmoglein-2 and desmocollin-2 in both the HH and HD groups could

  4. Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR-1 expression via up-regulation of the homeobox gene Nkx2.5.

    PubMed

    Wu, Meifang; Wu, Di; Wang, Chonggang; Guo, Zhizhun; Li, Bowen; Zuo, Zhenghong

    2016-01-25

    Hexabromocyclododecane (HBCD) is one of the most widely used brominated flame retardants. Although studies have reported that HBCD can cause a wide range of toxic effects on animals including humans, limited information can be found about its cardiac toxicity. In the present study, zebrafish embryos were exposed to HBCD at low concentrations of 0, 2, 20 and 200 nM. The results showed that HBCD exposure could induce cardiac hypertrophy and increased deposition of collagen. In addition, disordered calcium (Ca(2+)) handling was observed in H9C2 rat cardiomyocyte cells exposed to HBCD. Using small RNA sequencing and real-time quantitative PCR, HBCD exposure was shown to induce significant changes in the miRNA expression profile associated with the cardiovascular system. Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells. PMID:26476318

  5. Lack of Salt-Inducible Kinase 2 (SIK2) Prevents the Development of Cardiac Hypertrophy in Response to Chronic High-Salt Intake

    PubMed Central

    Tokudome, Takeshi; Mao, Yuanjie; Otani, Kentaro; Mochizuki, Naoki; Pires, Nuno; Pinho, Maria João; Franco-Cereceda, Anders; Torielli, Lucia; Ferrandi, Mara; Hamsten, Anders; Soares-da-Silva, Patricio; Eriksson, Per; Brion, Laura

    2014-01-01

    Cardiac left ventricle hypertrophy (LVH) constitutes a major risk factor for heart failure. Although LVH is most commonly caused by chronic elevation in arterial blood pressure, reduction of blood pressure to normal levels does not always result in regression of LVH, suggesting that additional factors contribute to the development of this pathology. We tested whether genetic preconditions associated with the imbalance in sodium homeostasis could trigger the development of LVH without concomitant increases in blood pressure. The results showed that the presence of a hypertensive variant of α-adducin gene in Milan rats (before they become hypertensive) resulted in elevated expression of genes associated with LVH, and of salt-inducible kinase 2 (SIK2) in the left ventricle (LV). Moreover, the mRNA expression levels of SIK2, α-adducin, and several markers of cardiac hypertrophy were positively correlated in tissue biopsies obtained from human hearts. In addition, we found in cardiac myocytes that α-adducin regulates the expression of SIK2, which in turn mediates the effects of adducin on hypertrophy markers gene activation. Furthermore, evidence that SIK2 is critical for the development of LVH in response to chronic high salt diet (HS) was obtained in mice with ablation of the sik2 gene. Increases in the expression of genes associated with LVH, as well as increases in LV wall thickness upon HS, occurred only in sik2+/+ but not in sik2−/− mice. Thus LVH triggered by HS or the presence of a genetic variant of α-adducin requires SIK2 and is independent of elevated blood pressure. Inhibitors of SIK2 may constitute part of a novel therapeutic regimen aimed at prevention/regression of LVH. PMID:24752134

  6. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy

    SciTech Connect

    Xu, Tongyi; Zhang, Ben; Yang, Fan; Cai, Chengliang; Wang, Guokun; Han, Qingqi; Zou, Liangjian

    2015-05-08

    Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague–Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation. - Highlights: • EP could effectively reduce the cardiac hypertrophic responses induced by TAC. • EP may play a protective role by upregulating the expressions of HSF1 and HSP70 and then activating HSF1. • EP may play a protective role by inhibiting the expression

  7. Apolipoprotein A-I Mimetic Peptide D-4F Reduces Cardiac Hypertrophy and Improves Apolipoprotein A-I-Mediated Reverse Cholesterol Transport From Cardiac Tissue in LDL Receptor-null Mice Fed a Western Diet.

    PubMed

    Han, Jie; Zhang, Song; Ye, Ping; Liu, Yong-Xue; Qin, Yan-Wen; Miao, Dong-Mei

    2016-05-01

    Epidemiological studies have suggested that hypercholesterolemia is an independent determinant of increased left ventricular (LV) mass. Because high-density lipoprotein and its major protein apolipoprotein A-I (apoA-I) mediate reverse cholesterol transport (RCT) and have cardiac protective effects, we hypothesized that the apoA-I mimetic peptide D-4F could promote RCT in cardiac tissue and decrease cardiac hypertrophy induced by hypercholesterolemia. Low-density lipoprotein receptor-null mice were fed by a Western diet for 18 weeks and then randomized to receive water, or D-4F 0.3 mg/mL, or D-4F 0.5 mg/mL added to drinking water for 6 weeks. After D-4F administration, an increase in high-density lipoprotein cholesterol and a decrease in low-density lipoprotein cholesterol, total cholesterol, and triglyceride in a trend toward dose-responsivity were found in cardiac tissue. Ultrasound biomicroscopy revealed a reduction in LV posterior wall end-diastolic dimension, and an increase in mitral valve E/A ratio and LV ejection fraction. Hematoxylin-eosin staining showed reduced LV wall thickness and myocardial cell diameter. The protein levels of ABCA1 and LXRα were elevated in cardiac tissue of D-4F treated mice compared with the controls (P < 0.05). These results demonstrated that D-4F treatment reduced cardiac hypertrophy, and improved cardiac performance in low-density lipoprotein receptor-null mice fed a Western diet, presumably through the LXRα-ABCA1 pathway associated with enhanced myocardial RCT.

  8. Hypoxia and Hypoxia Inducible Factors: Diverse Roles in Liver Diseases

    PubMed Central

    Nath, Bharath; Szabo, Gyongyi

    2011-01-01

    Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The Hypoxia Inducible Factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review, we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the hypoxia inducible factors and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models. PMID:22120903

  9. Intermittent hypoxia induces functional recovery following cervical spinal injury

    PubMed Central

    Vinit, Stéphane; Lovett-Barr, Mary Rachael; Mitchell, Gordon S.

    2009-01-01

    Respiratory-related complications are the leading cause of death in spinal cord injury (SCI) patients. Few effective SCI treatments are available after therapeutic interventions are performed in the period shortly after injury (e.g. spine stabilization and prevention of further spinal damage). In this review we explore the capacity to harness endogenous spinal plasticity induced by intermittent hypoxia to optimize function of surviving (spared) neural pathways associated with breathing. Two primary questions are addressed: 1) does intermittent hypoxia induce plasticity in spinal synaptic pathways to respiratory motor neurons following experimental SCI? and 2) can this plasticity improve respiratory function? In normal rats, intermittent hypoxia induces serotonin-dependent plasticity in spinal pathways to respiratory motor neurons. Early experiments suggest that intermittent hypoxia also enhances respiratory motor output in experimental models of cervical SCI, (cervical hemisection) and that the capacity to induce functional recovery is greater with longer durations post-injury. Available evidence suggests that intermittent hypoxia-induced spinal plasticity has considerable therapeutic potential to treat respiratory insufficiency following chronic cervical spinal injury. PMID:19651247

  10. Changes in Cx43 and NaV1.5 expression precede the occurrence of substantial fibrosis in calcineurin-induced murine cardiac hypertrophy.

    PubMed

    Fontes, Magda S C; Raaijmakers, Antonia J A; van Doorn, Tessa; Kok, Bart; Nieuwenhuis, Sylvia; van der Nagel, Roel; Vos, Marc A; de Boer, Teun P; van Rijen, Harold V M; Bierhuizen, Marti F A

    2014-01-01

    In mice, the calcium-dependent phosphatase calcineurin A (CnA) induces a transcriptional pathway leading to pathological cardiac hypertrophy. Interestingly, induction of CnA has been frequently noticed in human hypertrophic and failing hearts. Independently, the arrhythmia vulnerability of such hearts has been regularly associated with remodeling of parameters determining electrical conduction (expression level of connexin43 (Cx43) and NaV1.5, connective tissue architecture), for which the precise molecular basis and sequence of events is still unknown. Recently, we observed reduced Cx43 and NaV1.5 expression in 4-week old mouse hearts, overexpressing a constitutively active form of CnA (MHC-CnA model), but the order of events is still unknown. Therefore, three key parameters of conduction (Cx43, NaV1.5 and connective tissue expression) were characterized in MHC-CnA ventricles versus wild-type (WT) during postnatal development on a weekly basis. At postnatal week 1, CnA overexpression induced cardiac hypertrophy in MHC-CnA. Moreover, protein and RNA levels of both Cx43 and NaV1.5 were reduced by at least 50% as compared to WT. Cx43 immunoreactive signal was reduced at week 2 in MHC-CnA. At postnatal week 3, Cx43 was less phosphorylated and RNA level of Cx43 normalized to WT values, although the protein level was still reduced. Additionally, MHC-CnA hearts displayed substantial fibrosis relative to WT, which was accompanied by increased RNA levels for genes previously associated with fibrosis such as Col1a1, Col1a2, Col3a1, Tgfb1, Ctgf, Timp1 and microRNA miR-21. In MHC-CnA, reduction in Cx43 and NaV1.5 expression thus coincided with overexpression of CnA and hypertrophy development and preceded significant presence of fibrosis. At postnatal week 4 the alterations in conductional parameters observed in the MHC-CnA model lead to abnormal conduction and arrhythmias, similar to those observed in cardiac remodeling in heart failure patients. The MHC-CnA model, therefore

  11. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  12. Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.

    PubMed

    Duan, Quanlu; Ni, Li; Wang, Peihua; Chen, Chen; Yang, Lei; Ma, Ben; Gong, Wei; Cai, Zhejun; Zou, Ming-Hui; Wang, Dao Wen

    2016-08-01

    Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure. XBP1 is a key ER stress signal transducer and an important pro-survival factor of the unfolded protein response (UPR) in mammalian cells. The aim of this study was to establish a role for XBP1 in the deregulation of pro-angiogenic factor VEGF expression and potential regulatory mechanisms in hypertrophic and failing heart. Western blots showed that myocardial XBP1s protein was significantly increased in both isoproterenol (ISO)-induced and pressure-overload-induced hypertrophic and failing heart compared to normal control. Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo. Consistently, experiments in cultured cardiomyocytes H9c2 (2-1) cells showed that UPR-induced VEGF-A upregulation was determined by XBP1 expression level. Importantly, VEGF-A expression was increased in failing human heart tissue and blood samples and was correlated with the levels of XBP1. These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure. PMID:27133203

  13. Hypoxia inducible factor pathway inhibitors as anticancer therapeutics

    PubMed Central

    Burroughs, Sarah K; Kaluz, Stefan; Wang, Danzhu; Wang, Ke

    2013-01-01

    Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein–protein interactions. PMID:23573973

  14. Hypertension, Cardiac Hypertrophy, and Impaired Vascular Relaxation Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin are Associated with Increased Superoxide

    PubMed Central

    Kopf, Phillip G.; Huwe, Janice K.

    2009-01-01

    The mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the incidence of human cardiovascular disease are not known. We investigated the degree to which cardiovascular disease develops in mice following subchronic TCDD exposure. Adult male C57BL/6 mice were dosed with vehicle or 300 ng TCDD/kg by oral gavage three times per week for 60 days. Blood pressure was recorded by radiotelemetry and aortic endothelial function was assessed by acetylcholine-induced vasorelaxation. Mean arterial pressure of TCDD-exposed mice was increased significantly by day 4 and between days 7–10, 25–35, and 45–60 with two periods of normalization on days 11–24 and days 36–39. Consistent with a prolonged period of systemic hypertension, heart weight was increased and was associated with concentric left ventricular hypertrophy. Significant increases in superoxide production also were observed in the kidney, heart, and aorta of TCDD-exposed mice. Furthermore, increased aortic superoxide resulted in endothelial dysfunction as demonstrated by significant impairment of acetylcholine-induced vasorelaxation in TCDD-exposed mice, which was restored by tempol, a superoxide dismutase (SOD) mimetic. Our model is the first to definitely demonstrate that sustained AhR activation by TCDD increases blood pressure and induces cardiac hypertrophy, which may be mediated, in part, by increased superoxide. PMID:18850075

  15. Aberrant Splicing Promotes Proteasomal Degradation of L-type CaV1.2 Calcium Channels by Competitive Binding for CaVβ Subunits in Cardiac Hypertrophy

    PubMed Central

    Hu, Zhenyu; Wang, Jiong-Wei; Yu, Dejie; Soon, Jia Lin; de Kleijn, Dominique P. V.; Foo, Roger; Liao, Ping; Colecraft, Henry M.; Soong, Tuck Wah

    2016-01-01

    Decreased expression and activity of CaV1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of CaV1.2 channel, named CaV1.2e21+22, that contained the pair of mutually exclusive exons 21 and 22. This variant was highly expressed in neonatal hearts. The abundance of this variant was gradually increased by 12.5-folds within 14 days of transverse aortic banding that induced cardiac hypertrophy in adult mouse hearts and was also elevated in left ventricles from patients with dilated cardiomyopathy. Although this variant did not conduct Ca2+ ions, it reduced the cell-surface expression of wild-type CaV1.2 channels and consequently decreased the whole-cell Ca2+ influx via the CaV1.2 channels. In addition, the CaV1.2e21+22 variant interacted with CaVβ subunits significantly more than wild-type CaV1.2 channels, and competition of CaVβ subunits by CaV1.2e21+22 consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type CaV1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of CaV1.2 channels in adult heart under stress may contribute to heart failure. PMID:27731386

  16. Dexamethasone impairs hypoxia-inducible factor-1 function

    SciTech Connect

    Wagner, A.E.; Huck, G.; Stiehl, D.P.; Jelkmann, W.; Hellwig-Buergel, T.

    2008-07-25

    Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription-factor composed of {alpha}- and {beta}-subunits. HIF-1 is not only necessary for the cellular adaptation to hypoxia, but it is also involved in inflammatory processes and wound healing. Glucocorticoids (GC) are therapeutically used to suppress inflammatory responses. Herein, we investigated whether GC modulate HIF-1 function using GC receptor (GR) possessing (HepG2) and GR deficient (Hep3B) human hepatoma cell cultures as model systems. Dexamethasone (DEX) treatment increased HIF-1{alpha} levels in the cytosol of HepG2 cells, while nuclear HIF-1{alpha} levels and HIF-1 DNA-binding was reduced. In addition, DEX dose-dependently lowered the hypoxia-induced luciferase activity in a reporter gene system. DEX suppressed the hypoxic stimulation of the expression of the HIF-1 target gene VEGF (vascular endothelial growth factor) in HepG2 cultures. DEX did not reduce hypoxically induced luciferase activity in HRB5 cells, a Hep3B derivative lacking GR. Transient expression of the GR in HRB5 cells restored the susceptibility to DEX. Our study discloses the inhibitory action of GC on HIF-1 dependent gene expression, which may be important with respect to the impaired wound healing in DEX-treated patients.

  17. EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy.

    PubMed

    Esposito, Giovanni; Perrino, Cinzia; Cannavo, Alessandro; Schiattarella, Gabriele G; Borgia, Francesco; Sannino, Anna; Pironti, Gianluigi; Gargiulo, Giuseppe; Di Serafino, Luigi; Franzone, Anna; Scudiero, Laura; Grieco, Paolo; Indolfi, Ciro; Chiariello, Massimo

    2011-06-01

    Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of β-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of β-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by β-arrestin 1/2, promoting cell survival and cardioprotection.

  18. c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription

    PubMed Central

    Alfranca, Arántzazu; Gutiérrez, M. Dolores; Vara, Alicia; Aragonés, Julián; Vidal, Felipe; Landázuri, Manuel O.

    2002-01-01

    Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1α subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1α are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser63 in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser63 and Ser73 impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis. PMID:11739718

  19. Up-regulation of miR-138 inhibits hypoxia-induced cardiomyocyte apoptosis via down-regulating lipocalin-2 expression

    PubMed Central

    Xiong, Haowei; Luo, Tiantian; He, Wenshuai; Xi, Dan; Lu, Hao; Li, Menghao; Liu, Jichen

    2015-01-01

    Hypoxia-induced cardiomyocyte apoptosis contributes significantly to the development of numerous cardiac diseases, such as ischemic heart disease, heart failure, etc. Promoting cell survival by inhibiting apoptosis is one of the available strategies to attenuate cardiac dysfunction caused by cardiomyocyte loss. Previous studies have been demonstrated that miR-138 and lipocalin-2 (Lcn2) play important roles in cardiomyocyte apoptosis and survival. We presently determined whether Lcn2 is a target gene of miR-138 involved in hypoxia-induced cardiomyocyte apoptosis. Firstly, mimics of miR-138 were transfected into HL-1 cells to investigate its effect on cell apoptosis. Using 3-(4,5-dimethyl-thiazol-2-y1) 2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-FITC/PI flow cytometer assays, over-expression of miR-138 significantly enhanced the cell growth and significantly attenuated the cell apoptosis in hypoxic conditions. Dual-luciferase reporter gene and western blot results confirmed Lcn2 was a direct target of miR-138. Then, the recombinant plasmid, pcDNA3.1/Lcn2 was transfected into the HL-1 cells that over-expressed miR-138. We further observed that the over-expression of Lcn2 diminished the protection of miR-138 over-expression from hypoxia-induced cell survival and apoptosis. In conclusion, our study demonstrated that up-regulation of miR-138 inhibits the hypoxia-induced cardiomyocyte apoptosis via down-regulating the pro-apoptotic gene expression of Lcn2. PMID:26129883

  20. Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy

    PubMed Central

    Wagner, Kay-Dietrich; Vukolic, Ana; Baudouy, Delphine; Michiels, Jean-François

    2016-01-01

    Peroxisome proliferator-activated receptors are nuclear receptors which function as ligand-activated transcription factors. Among them, peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in the heart and thought to have cardioprotective functions due to its beneficial effects in metabolic syndrome. As we already showed that PPARβ/δ activation resulted in an enhanced cardiac angiogenesis and growth without impairment of heart function, we were interested to determine the effects of a specific activation of PPARβ/δ in the vasculature on cardiac performance under normal and in chronic ischemic heart disease conditions. We analyzed the effects of a specific PPARβ/δ overexpression in endothelial cells on the heart using an inducible conditional vascular-specific mouse model. We demonstrate that vessel-specific overexpression of PPARβ/δ induces rapid cardiac angiogenesis and growth with an increase in cardiomyocyte size. Upon myocardial infarction, vascular overexpression of PPARβ/δ, despite the enhanced cardiac vessel formation, does not protect against chronic ischemic injury. Our results suggest that the proper balance of PPARβ/δ activation in the different cardiac cell types is required to obtain beneficial effects on the outcome in chronic ischemic heart disease. PMID:27057154

  1. Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

    PubMed

    Corda, S; Mebazaa, A; Gandolfini, M P; Fitting, C; Marotte, F; Peynet, J; Charlemagne, D; Cavaillon, J M; Payen, D; Rappaport, L; Samuel, J L

    1997-11-01

    Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy. PMID:9351441

  2. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction.

    PubMed

    Zentilin, Lorena; Puligadda, Uday; Lionetti, Vincenzo; Zacchigna, Serena; Collesi, Chiara; Pattarini, Lucia; Ruozi, Giulia; Camporesi, Silvia; Sinagra, Gianfranco; Pepe, Martino; Recchia, Fabio A; Giacca, Mauro

    2010-05-01

    Mounting evidence indicates that the function of members of the vascular endothelial growth factor (VEGF) family extends beyond blood vessel formation. Here, we show that the prolonged intramyocardial expression of VEGF-A(165) and VEGF-B(167) on adeno-associated virus-mediated gene delivery determined a marked improvement in cardiac function after myocardial infarction in rats, by promoting cardiac contractility, preserving viable cardiac tissue, and preventing remodeling of the left ventricle (LV) over time. Consistent with this functional outcome, animals treated with both factors showed diminished fibrosis and increased contractile myocardium, which were more pronounced after expression of the selective VEGF receptor-1 (VEGFR-1) ligand VEGF-B, in the absence of significant induction of angiogenesis. We found that cardiomyocytes expressed VEGFR-1, VEGFR-2, and neuropilin-1 and that, in particular, VEGFR-1 was specifically up-regulated in hypoxia and on exposure to oxidative stress. VEGF-B exerted powerful antiapoptotic effect in both cultured cardiomyocytes and after myocardial infarction in vivo. Finally, VEGFR-1 activation by VEGF-B was found to elicit a peculiar gene expression profile proper of the compensatory, hypertrophic response, consisting in activation of alphaMHC and repression of betaMHC and skeletal alpha-actin, and an increase in SERCA2a, RYR, PGC1alpha, and cardiac natriuretic peptide transcripts, both in cultured cardiomyocytes and in infarcted hearts. The finding that VEGFR-1 activation by VEGF-B prevents loss of cardiac mass and promotes maintenance of cardiac contractility over time has obvious therapeutic implications.

  3. Hypoxia-Inducible Factor-1α and Autoimmune Lupus, Arthritis.

    PubMed

    Yang, Zu-Cheng; Liu, Yi

    2016-06-01

    Hypoxia elicits an orchestrated response in cells, tissues, and entire organisms to survive a hypoxic challenge. On a molecular level, this response can be controlled by oxygen-dependent stabilization of the transcription factor hypoxia-inducible factor (HIF)-1α. Recently, studies have shown that HIF-1α plays an important role in the development and function of T helper (Th) cells, regulatory T (Treg) cells, and dendritic cells (DCs). Because these cells are critical in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, the roles of HIF-1α in these autoimmune disorders cannot be neglected. In this review, we discuss recent findings on the important roles of HIF-1α in immune cells and the possible pathologic roles of HIF-1α in autoimmune diseases. The obtained information may lead to deeper insights into the roles of HIF-1α in these disorders. PMID:27032396

  4. Hypoxia Inducible Factors and Hypertension: Lessons from Sleep Apnea Syndrome

    PubMed Central

    Nanduri, Jayasri; Peng, Ying-Jie; Yuan, Guoxiang; Kumar, Ganesh K.; Prabhakar, Nanduri R.

    2015-01-01

    Systemic hypertension is one of the most prevalent cardiovascular diseases. Sleep disordered breathing (SDB) with recurrent apnea is a major risk factor for developing essential hypertension. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of recurrent apnea. Rodent models patterned after the O2 profiles seen with SDB patients showed that CIH is the major stimulus for causing systemic hypertension. This article reviews the physiological and molecular basis of CIH-induced hypertension. Physiological studies have identified that augmented carotid body chemosensory reflex and the resulting increase in sympathetic nerve activity is a major contributor to CIH-induced hypertension. Analysis of molecular mechanisms revealed that CIH activates hypoxia-inducible factor (HIF)-1 and suppresses HIF-2- mediated transcription. Dysregulation of HIF-1- and HIF-2- mediated transcription leads to imbalance of pro-oxidant and anti-oxidant enzyme gene expression resulting in increased reactive species (ROS) generation in the chemosensory reflex which is central for developing hypertension. PMID:25772710

  5. Hypoxia inducible factors and the response to hypoxic stress

    PubMed Central

    Majmundar, Amar J.; Wong, Waihay J.; Simon, M. Celeste

    2011-01-01

    Oxygen (O2) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O2 availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the Hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFα subunits are intricately responsive to numerous other factors including Factor Inhibiting HIF-1α (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway. PMID:20965423

  6. Combined lipid emulsion and ACLS resuscitation following bupivacaine- and hypoxia-induced cardiovascular collapse in unanesthetized swine.

    PubMed

    Bushey, Brent A; Auld, Victor H; Volk, John E; Vacchiano, Charles A

    2011-04-01

    This study examined whether combining lipid emulsion and advanced cardiac life support (ACLS) improves survival in an unanesthetized swine model of bupivacaine- and hypoxia-induced cardiovascular collapse. Arterial and venous catheters and a tracheostomy were surgically placed in 26 swine receiving inhalation anesthesia. After a 1-hour recovery period, bupivacaine (5 mg/kg) was administered intravenously over 15 seconds. Following 1 minute of observation and 3 minutes of mechanical airway obstruction, during which all animals exhibited complete cardiovascular collapse, ACLS was initiated. Animals were randomized to receive either intravenous saline or 20% lipid emulsion commencing with the initiation ofACLS. Survival was defined as a return of spontaneous circulation (ROSC) with unsupported blood pressure greater than 60 mm Hg for 10 minutes after 25 minutes of resuscitation effort. Data collection included electrocardiogram, arterial blood pressure, and arterial and mixed venous oxygen saturations. There was no significant difference in survival between the saline group (4/12, 33%) and lipid emulsion group (6/12, 50%; P > .05). Additionally, there was no significant difference between groups of surviving animals in the time to ROSC (P > .05). The combination of lipid emulsion and ACLS did not improve survival from bupivacaine- and hypoxia-induced cardiovascular collapse in unanesthetized swine.

  7. Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress.

    PubMed

    Gálvez, Anita S; Brunskill, Eric W; Marreez, Yehia; Benner, Bonnie J; Regula, Kelly M; Kirschenbaum, Lorrie A; Dorn, Gerald W

    2006-01-20

    Up-regulation of myocardial Nix and BNip3 is associated with apoptosis in cardiac hypertrophy and ischemia, respectively. To identify mechanisms of gene regulation for these critical cardiac apoptosis effectors, the determinants of Nix and BNip3 promoter activation were elucidated by luciferase reporter gene expression in neonatal rat cardiac myocytes. BNip3 transcription was increased by hypoxia but not by phenylephrine (10 microM), angiotensin II (100 nM), or isoproterenol (10 microM). In contrast, Nix transcription was increased by phenylephrine but not by isoproterenol, angiotensin II, or hypoxia. Since phenylephrine stimulates cardiomyocyte hypertrophy via protein kinase C (PKC), the effects of phorbol myristate acetate (PMA, 10 nM for 24 h) and adenoviral PKC expression were assessed. PMA and PKC alpha, but not PKC epsilon or dominant negative PKC alpha, increased Nix transcription. Multiple Nix promoter GC boxes bound transcription factor Sp-1, and basal and PMA- or PKC alpha-stimulated Nix promoter activity was suppressed by mithramycin inhibition of Sp1-DNA interactions. In vivo determinants of Nix expression were evaluated in Nix promoter-luciferase (NixP) transgenic mice that underwent ischemia-reperfusion (1 h/24 h), transverse aortic coarctation (TAC), or cross-breeding with the G(q) overexpression model of hypertrophy. Luciferase activity increased in G alpha(q)-NixP hearts 3.2 +/- 0.4-fold and in TAC hearts 2.8 +/- 0.4-fold but did not increase with infarction-reperfusion. NixP activity was proportional to the extent of TAC hypertrophy and was inhibited by mithramycin. These studies revealed distinct mechanisms of transcriptional regulation for cardiac Nix and BNip3. BNip3 is hypoxia-inducible, whereas Nix expression was induced by G alpha(q)-mediated hypertrophic stimuli. PKC alpha, a G(q) effector, transduced Nix transcriptional induction via Sp1. PMID:16291751

  8. Ventricular hypertrophy--physiological mechanisms.

    PubMed

    Vaughan Williams, E M

    1986-01-01

    Adult cardiac myocytes are incapable of mitosis. Dead cells are replaced by connective tissue so that after myocardial infarction (MI), function can only be restored by compensatory hypertrophy of the surviving myocardium. In physiological hypertrophy in response to exercise, high altitude, or mild hypertension, additional myoplasm expands cell diameter in an orderly fashion; Z-lines are in register and the normal ratio of volume densities of contractile elements, mitochondria, and capillaries is conserved. In hypertrophy induced by aortic or pulmonary artery banding or by experimental or congenital hypertension, the borderline between physiological and pathological hypertrophy may be crossed, causing disorganization of fibers and an unfavourable contractile element to capillary ratio. There was, therefore, a need for a graded model of hypertrophy, which involves simulating an altitude of 6,000 m at sea level by supplying rabbits with appropriate nitrogen/oxygen mixtures. In this environment, 50% right ventricular hypertrophy can be achieved without alteration of left ventricular weight or hematocrit. Longer exposures produced 100% right ventricular hypertrophy, with only moderate increases in hematocrit and left ventricular weight. It is well known that adrenergic stimulation causes cardiac hypertrophy, and it has been suggested that release of a trophic factor from sympathetic nerves, either noradrenaline or a protein, might be a necessary stimulus for growth. If so, long-term treatment of post-MI patients with beta-adrenergic blocking agents could inhibit a desirable compensatory hypertrophy of the surviving myocardium. In the above model it has been found, however, that neither beta-blockade nor chemical sympathectomy with guanethidine or 6-hydroxydopamine had any effect on the hypertrophy, nor did treatment with verapamil or nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    SciTech Connect

    Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-ichi; Emoto, Noriaki

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in

  10. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

    PubMed Central

    Chai, S.D.; Liu, T.; Dong, M.F.; Li, Z.K.; Tang, P.Z.; Wang, J.T.; Ma, S.J.

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  11. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling.

    PubMed

    Chai, S D; Liu, T; Dong, M F; Li, Z K; Tang, P Z; Wang, J T; Ma, S J

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  12. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3.

    PubMed

    Wang, Wang; Liu, Jie; Ma, Aiping; Miao, Ran; Jin, Yuling; Zhang, Hongbing; Xu, Kaifeng; Wang, Chen; Wang, Jun

    2014-12-01

    Hypoxia-induced pulmonary hypertension (HPH) is a clinical syndrome associated with high morbidity and mortality. However, the underlying mechanisms remain unclear. Both the mammalian target of rapamycin (mTOR) and the Notch3 signaling pathways have been reported to be involved in HPH; however, it is unknown whether there is a connection between these two signaling pathways in HPH. This study was designed to investigate the relationship between mTOR and Notch3 in HPH. After treatment with 10% O2 for 4 weeks, male C57BL/6 mice developed HPH with gradually increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and pulmonary arteriolar remodeling accompanied by the activation of mTOR complex 1 (mTORC1) and Notch3 in the lung tissue and pulmonary arterioles. Pretreatment with the mTORC1 inhibitor rapamycin not only alleviated pulmonary arterial pressure and pulmonary arteriolar remodeling but also suppressed hypoxia-induced mTORC1 and Notch3 activation. Prophylactic N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) administration, a Notch signaling inhibitor, protected against the effects of hypoxia. These in vivo data were confirmed by in vitro experiments on human pulmonary arterial smooth muscle cell (PASMC) exposed to 3% O2 . Furthermore, overexpression of Notch3 intracellular domain partially abrogated the inhibitory effects of rapamycin on human PASMC proliferation. These data indicate that both mTORC1 and Notch3 signaling are involved in HPH and the downstream effects of mTORC1 activation in HPH are partially dependent on the activation of Notch3 signaling. PMID:24825564

  13. Chronic cardiac reactions. I. Assessment of ventricular and myocardial work capacity in the hypertrophied and dilated ventricle.

    PubMed

    Jacob, R; Vogt, M; Noma, K

    1987-01-01

    The end-systolic and end-diastolic pressure-volume or stress-length curves define the margins of the various conceivable courses of pressure-volume or stress-length loops. Although the end-systolic pressure-volume and stress-length relations of isovolumetric and afterloaded contractions are not entirely identical, the area between isovolumetric maxima- and end-diastolic minima curves in the pressure-volume or stress-length diagram can be taken as a measure of potential ventricular and myocardial work under different yet defined mechanical conditions. The normalized stress-length area, as derived from the left ventricular pressure-volume diagram and myocardial mass, renders a rational basis for global quantitative evaluation of myocardial work capacity. The area obtained is independent of ventricular mass and size and as such is invaluable for assessing hypertrophied and/or dilated hearts, and thus interindividual comparison of myocardial contractile capability based on physical principles. However, this measure should be supplemented by considering time dependent parameters (e.g. maximum rate of stress development as a function of end-diastolic stress). The principle set here for evaluating ventricular and myocardial performance should always be borne in mind, especially when referring to more empirical parameters.

  14. The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium.

    PubMed

    Monasky, Michelle M; Taglieri, Domenico M; Henze, Marcus; Warren, Chad M; Utter, Megan S; Soergel, David G; Violin, Jonathan D; Solaro, R John

    2013-09-15

    In the present study, we compared the cardioprotective effects of TRV120023, a novel angiotensin II (ANG II) type 1 receptor (AT1R) ligand, which blocks G protein coupling but stimulates β-arrestin signaling, against treatment with losartan, a conventional AT1R blocker in the treatment of cardiac hypertrophy and regulation of myofilament activity and phosphorylation. Rats were subjected to 3 wk of treatment with saline, ANG II, ANG II + losartan, ANG II + TRV120023, or TRV120023 alone. ANG II induced increased left ventricular mass compared with rats that received ANG II + losartan or ANG II + TRV120023. Compared with saline controls, ANG II induced a significant increase in pCa50 and maximum Ca(2+)-activated myofilament tension but reduced the Hill coefficient (nH). TRV120023 increased maximum tension and pCa50, although to lesser extent than ANG II. In contrast to ANG II, TRV120023 increased nH. Losartan blocked the effects of ANG II on pCa50 and nH and reduced maximum tension below that of saline controls. ANG II + TRV120023 showed responses similar to those of TRV120023 alone; compared with ANG II + losartan, ANG II + TRV120023 preserved maximum tension and increased both pCa50 and cooperativity. Tropomyosin phosphorylation was lower in myofilaments from saline-treated hearts compared with the other groups. Phosphorylation of cardiac troponin I was significantly reduced in ANG II + TRV120023 and TRV120023 groups versus saline controls, and myosin-binding protein C phosphorylation at Ser(282) was unaffected by ANG II or losartan but significantly reduced with TRV120023 treatment compared with all other groups. Our data indicate that TRV120023-related promotion of β-arrestin signaling and enhanced contractility involves a mechanism promoting the myofilament response to Ca(2+) via altered protein phosphorylation. Selective activation of β-arrestin-dependent pathways may provide advantages over conventional AT1R blockers.

  15. Evaluation of aspirin metabolites as inhibitors of hypoxia-inducible factor hydroxylases.

    PubMed

    Lienard, Benoit M; Conejo-García, Ana; Stolze, Ineke; Loenarz, Christoph; Oldham, Neil J; Ratcliffe, Peter J; Schofield, Christopher J

    2008-12-21

    Known and potential aspirin metabolites were evaluated as inhibitors of oxygen-sensing hypoxia-inducible transcription factor (HIF) hydroxylases; some of the metabolites were found to stabilise HIF-alpha in cells. PMID:19048166

  16. Musashi mediates translational repression of the Drosophila hypoxia inducible factor.

    PubMed

    Bertolin, Agustina P; Katz, Maximiliano J; Yano, Masato; Pozzi, Berta; Acevedo, Julieta M; Blanco-Obregón, Dalmiro; Gándara, Lautaro; Sorianello, Eleonora; Kanda, Hiroshi; Okano, Hideyuki; Srebrow, Anabella; Wappner, Pablo

    2016-09-19

    Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3' UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.

  17. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.

    PubMed

    Kauser, H; Sahu, S; Kumar, S; Panjwani, U

    2014-01-17

    Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH. PMID:24184415

  18. The neurohormone orexin stimulates hypoxia-inducible factor-1 activity.

    PubMed

    Sikder, Devanjan; Kodadek, Thomas

    2007-11-15

    Orexin A and Orexin B (also known as hypocretins) are neuropeptides that bind two related G-coupled protein receptors (OXR1 and OXR2) and thus induce wakefulness, food consumption, and locomotion. Conversely, deletion of the orexin gene in mice produces a condition similar to canine and human narcolepsy. Despite the central importance of the orexin system in regulating wakefulness and feeding behavior, little is known about the downstream signaling mechanisms that achieve these effects. In this study, genomics techniques are used to probe this question and reveal that orexin activates the hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor whose pathogenic role in stimulating angiogenesis in hypoxic tumors has been the focus of intense investigation. Orexin-stimulated HIF-1 activity is due to both increased HIF-1alpha gene transcription and a down-regulation of von Hippel-Lindau (VHL), the E3 ubiquitin ligase that mediates the turnover of HIF-1 via the ubiquitin-proteasome pathway. Orexin-mediated activation of HIF-1 results in increased glucose uptake and higher glycolytic activity, as expected from studies of hypoxic cells. However, orexin receptor-expressing cells somehow override the HIF-1-mediated preference for funneling pyruvate into anaerobic glycolysis and instead favor ATP production through the tricarboxylic acid cycle and oxidative phosphorylation. These findings implicate HIF-1 as an important transcription factor in the hormone-mediated regulation of hunger and wakefulness.

  19. Hypoxia-induced phrenic long-term facilitation: emergent properties

    PubMed Central

    Devinney, Michael J.; Huxtable, Adrianne G.; Nichols, Nicole L.; Mitchell, Gordon S.

    2013-01-01

    Just as in other neural systems, plasticity is a hallmark of the neural system controlling breathing. One spinal mechanism of respiratory plasticity is phrenic long-term facilitation (pLTF) following acute intermittent hypoxia. Although cellular mechanisms giving rise to pLTF occur within the phrenic motor nucleus, different signaling cascades elicit pLTF in different conditions. These cascades, referred to as “Q” and “S" pathways to phrenic motor facilitation (pMF), interact via cross-talk inhibition. Whereas the Q pathway dominates pLTF after mild to moderate hypoxic episodes, the S pathway dominates after severe hypoxic episodes. The biological significance of multiple pathways to pMF is not known. We discuss the possibility that interactions between pathways confer emergent properties to pLTF, including: 1) pattern sensitivity and 2) metaplasticity. Understanding these mechanisms and their interactions may enable us to optimize intermittent hypoxia induced plasticity as a treatment for patients that suffer from ventilatory impairment or other motor deficits. PMID:23531012

  20. Musashi mediates translational repression of the Drosophila hypoxia inducible factor

    PubMed Central

    Bertolin, Agustina P.; Katz, Maximiliano J.; Yano, Masato; Pozzi, Berta; Acevedo, Julieta M.; Blanco-Obregón, Dalmiro; Gándara, Lautaro; Sorianello, Eleonora; Kanda, Hiroshi; Okano, Hideyuki; Srebrow, Anabella; Wappner, Pablo

    2016-01-01

    Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3′ UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available. PMID:27141964

  1. Vitamin C supplementation does not improve hypoxia-induced erythropoiesis.

    PubMed

    Martinez-Bello, Vladimir E; Sanchis-Gomar, Fabian; Martinez-Bello, Daniel; Olaso-Gonzalez, Gloria; Gomez-Cabrera, Mari Carmen; Viña, Jose

    2012-12-01

    Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to determine whether supplementation with vitamin C is implicated in the regulation of erythropoiesis and in the oxygen-carrying capacity of the blood, and also whether antioxidant supplementation prevents the oxidative stress associated to intermittent hypoxia. Twenty-four male Wistar rats were randomly divided into four experimental groups: normoxia control (n=6), normoxia + vitamin C (n=6), hypoxia control (12 h pO(2) 12%/12 h pO(2) 21%) (n=6), and hypoxia + vitamin C (n=6). Animals were supplemented with vitamin C at a dose of 250 mg·kg(-1)·day(-1) for 21 days. Red blood cell count, hemoglobin, hematocrit, reticulocytes, erythropoietin, and oxidative stress parameters such as malondialdehyde and protein oxidation in plasma were analyzed at two different time points: basal sample (day zero) and final sample (day 21). Similar RBC, Hb, Hct, and Epo increments were observed in both hypoxic groups regardless of the vitamin C supplementation. There was no change on MDA levels after intermittent hypoxic exposure in any experimental group. However, we found an increase in plasma protein oxidation in both hypoxic groups. Vitamin C does not affect erythropoiesis and protein oxidation in rats submitted to intermittent hypoxic exposure. PMID:23270444

  2. Regulation of erythropoiesis by hypoxia-inducible factors.

    PubMed

    Haase, Volker H

    2013-01-01

    A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Hypoxia-inducible factors (HIFs) orchestrate this response by inducing cell-type specific gene expression changes that result in increased erythropoietin (EPO) production in kidney and liver, in enhanced iron uptake and utilization and in adjustments of the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. In particular HIF-2 has emerged as the transcription factor that regulates EPO synthesis in the kidney and liver and plays a critical role in the regulation of intestinal iron uptake. Its key function in the hypoxic regulation of erythropoiesis is underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis. This review provides a perspective on recent insights into HIF-controlled erythropoiesis and iron metabolism, and examines cell types that have EPO-producing capability. Furthermore, the review summarizes clinical syndromes associated with mutations in the O(2)-sensing pathway and the genetic changes that occur in high altitude natives. The therapeutic potential of pharmacologic HIF activation for the treatment of anemia is discussed. PMID:23291219

  3. Modulation of Hypoxia-Induced Pulmonary Vascular Leakage in Rats by Seabuckthorn (Hippophae rhamnoides L.)

    PubMed Central

    Purushothaman, Jayamurthy; Suryakumar, Geetha; Shukla, Dhananjay; Jayamurthy, Himani; Kasiganesan, Harinath; Kumar, Rajesh; Sawhney, Ramesh Chand

    2011-01-01

    Cerebral and pulmonary syndromes may develop in unacclimatized individuals shortly after ascent to high altitude resulting in high altitude illness, which may occur due to extravasation of fluid from intra to extravascular space in the brain, lungs and peripheral tissues. The objective of the present study was to evaluate the potential of seabuckthorn (SBT) (Hippophae rhamnoides L.) leaf extract (LE) in curtailing hypoxia-induced transvascular permeability in the lungs by measuring lung water content, leakage of fluorescein dye into the lungs and further confirmation by quantitation of albumin and protein in the bronchoalveolar lavage fluid (BALF). Exposure of rats to hypoxia caused a significant increase in the transvascular leakage in the lungs. The SBT LE treated animals showed a significant decrease in hypoxia-induced vascular permeability evidenced by decreased water content and fluorescein leakage in the lungs and decreased albumin and protein content in the BALF. The SBT extract was also able to significantly attenuate hypoxia-induced increase in the levels of proinflammatory cytokines and decrease hypoxia-induced oxidative stress by stabilizing the levels of reduced glutathione and antioxidant enzymes. Pretreatment of the extract also resulted in a significant decrease in the circulatory catecholamines and significant increase in the vasorelaxation of the pulmonary arterial rings as compared with the controls. Further, the extract significantly attenuated hypoxia-induced increase in the VEGF levels in the plasma, BALF (ELISA) and lungs (immunohistochemistry). These observations suggest that SBT LE is able to provide significant protection against hypoxia-induced pulmonary vascular leakage. PMID:19996155

  4. Central Anticholinergic Syndrome due to Hypoxia-Induced Bradycardia in a Child with Difficult Intubation Undergoing Complete Dental Restoration: A Case Report.

    PubMed

    Gharavifard, Mohamad; Razavi, Majid; Ghandehari Motlagh, Mehdi; Ziyaeifard, Mohsen

    2014-09-01

    Central anticholinergic syndrome (CAS) following general anesthesia (GA) is a well known syndrome in children and adults. Many cases of CAS have been previously reported in the literature. However, there are only two reports of post resuscitation CAS after administration of small doses of atropine. Hereby, we report a case of CAS in a child undergoing complete dental restoration under GA after receiving a small dose of atropine to reverse hypoxia induced bradycardia. Intraoperative events such as hypoxia or cardiac arrest may play a role as triggers for CAS. However, we cannot establish a causal relationship between the occurrence of CAS and such critical events.

  5. Hypoxia induces voltage-gated K+ (Kv) channel expression in pulmonary arterial smooth muscle cells through hypoxia-inducible factor-1 (HIF-1)

    PubMed Central

    Dong, Qian; Zhao, Ning; Xia, Cheng-kun; Du, Li-li; Fu, Xiao-xing; Du, Yi-mei

    2012-01-01

    Hypoxia-inducible factor-1 (HIF-1) regulates the expression of hypoxia-inducible genes by binding erythropoietin (EPO) enhancer fragments. Of these genes, HIF-1 upregulates voltage-gated K+1.2 channels (Kv1.2) in rat PC12 cells. Whether HIF-1 regulates hypoxia-induced Kv channel expression in cultured pulmonary artery smooth muscle cells (PASMCs), however, has not been determined. In this study, we investigated the effects of hypoxia on the expression of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in PASMCs and examined the direct role of HIF-1 by transfecting either wild type or mutant EPO enhancer fragments. Our results showed that 18 h exposure to hypoxia significantly increased the expression of Kv1.2, Kv1.5, Kv2.1, and Kv9.3; and this hypoxia-induced upregulation was completely inhibited after transfection with the wild type but not mutant EPO enhancer fragment. These results indicate that HIF-1 regulates hypoxia-stimulated induction of Kv1.2, Kv1.5, Kv2.1, and Kv9.3 channels in cultured PASMCs. PMID:22938542

  6. Hypoxia-Inducible Factor as an Angiogenic Master Switch

    PubMed Central

    Hashimoto, Takuya; Shibasaki, Futoshi

    2015-01-01

    Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications

  7. Hypoxia and Hypoxia-Inducible Factors in Leukemias

    PubMed Central

    Deynoux, Margaux; Sunter, Nicola; Hérault, Olivier; Mazurier, Frédéric

    2016-01-01

    Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic stem cells with the niche itself being composed of a variety of cell types, including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells, and vascular cells. A hallmark of the hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, it has been well established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukemia is not considered a “solid” tumor, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias. PMID:26955619

  8. Hypoxia inducible factor in hepatocellular carcinoma: A therapeutic target

    PubMed Central

    Lin, Daniel; Wu, Jennifer

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxia-inducible factor alpha (HIF-1α) in cancer development, specifically in HCC. We will discuss the biology of HIF-1α, the pathways with which it interacts, and the function of HIF-1α in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1α in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1α mRNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF-1α is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC. PMID:26576101

  9. Exendin-4 therapy still offered an additional benefit on reducing transverse aortic constriction-induced cardiac hypertrophy-caused myocardial damage in DPP-4 deficient rats.

    PubMed

    Lu, Hung-I; Chung, Sheng-Ying; Chen, Yi-Ling; Huang, Tein-Hung; Zhen, Yen-Yi; Liu, Chu-Feng; Chang, Meng-Wei; Chen, Yung-Lung; Sheu, Jiunn-Jye; Chua, Sarah; Yip, Hon-Kan; Lee, Fan-Yen

    2016-01-01

    Inhibition of dipeptidyl peptidase-IV (DPP-4) enzyme activity has been revealed to protect myocardium from ischemia-reperfusion through enhancing the endogenous glucagon-like peptide-1 (GLP-1) level. However, whether exogenous supply of exendin-4, an analogue of GLP-1, would still offer benefit for protecting myocardial damage from trans-aortic constriction (TAC)-induced hypertrophic cardiomyopathy in preexistence of DPP-4 deficiency (DPP-4(D)) remained unclear. Male-adult (DPP-4(D)) rats (n = 32) were randomized into group 1 [sham control (SC)], group 2 (DPP-4(D) + TAC), group 3 [DPP-4(D) + TAC + exendin-4 10 µg/day], and group 4 [DPP-4(D) + TAC + exendin-4 10 µg + exendin-9-39 10 µg/day]. The rats were sacrificed by day 60 after last echocardiographic examination. By day 60 after TAC, left ventricular ejection fraction (LVEF) (%) was highest in group 1 and lowest in group 2, and significantly lower in group 4 than that in group 3 (all p < 0.001). The protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), inflammatory (MMP-9, TNF-α, NF-κB), apoptotic (Bax, cleaved caspase 3 and PARP), fibrotic (TGF-β, Smad3), heart failure (BNP, β-MHC), DNA damaged (γ-H2AX) and ischemic stress (p-P38, p-Akt, p53, ATM) biomarkers showed an opposite pattern of LVEF among the four groups (all p < 0.03). Fibrotic area (by Masson's trichrome, Sirius red), and cellular expressions of DNA-damaged markers (Ki-67+, γ-H2AX+, CD90+/53BP1+) displayed an identical pattern, whereas cellular expressions of angiogenesis (CD31+, α-SMA+) and sarcomere length exhibited an opposite pattern compared to that of oxidative stress among the four groups (all p < 0.001). Take altogether, Exendin-4 effectively suppressed TAC-induced pathological cardiac hypertrophy in DPP-4(D) rat.

  10. Effects of taurine on myocardial cGMP/cAMP ratio, antioxidant ability, and ultrastructure in cardiac hypertrophy rats induced by isoproterenol.

    PubMed

    Yang, Qunhui; Yang, Jiancheng; Wu, Gaofeng; Feng, Ying; Lv, Qiufeng; Lin, Shumei; Hu, Jianmin

    2013-01-01

    Taurine is the most abundant free amino acid in the human body and accounts for more than 50% of the total amino acid pool in the mammalian heart. To investigate the preventive effects of taurine on cardiac hypertrophy in rats, myocardial injury was established by hypodermic injection of isoprenaline (ISO) (10 mg/kg d) for 7 days. The preventive effects of taurine (100 mg/kg d, 200 mg/kg d, and 300 mg/kg d, i.p) on heart coefficient; ultrastructure of cardiac muscle; the levels of creatine kinase heart isoenzyme (CK-MB), cAMP, and cGMP; and antioxidant ability were investigated. The results showed that taurine could significantly prevent the increase of heart coefficient induced by ISO. Compared with the model group, 100 mg/kg and 200 mg/kg taurine significantly decrease the levels of cAMP and cGMP, while 300 mg/kg taurine could significantly decrease the levels of cAMP in myocardium, and all the three concentrations of taurine could significantly increase the ratio of cGMP/cAMP. The level of serum CK-MB was significantly increased by ISO; 200 mg/kg taurine could significantly decrease it, but 100 mg/kg and 300 mg/kg taurine had no significant effect. As for the antioxidant ability, ISO administration could significantly increase the myocardial level of MDA but had no significant effects on the myocardial levels of SOD, GSH, GSH-Px, and T-AOC. However, taurine administration could significantly decrease the myocardial level of MDA and increase the levels of GSH and T-AOC compared with the model group. The serum levels of SOD, GSH-Px, GSH, and T-AOC were significantly reduced by ISO administration, but the level of MDA showed no significant changes compared with the control group. Taurine administration could significantly increase the serum levels of SOD, GSH-Px, GSH, and T-AOC and decrease the level of MDA compared with the model group. All the results indicated that 200 mg/kg taurine had better effects. The ultrastructure of cardiomyocytes showed that taurine

  11. Distinctive expression patterns of hypoxia-inducible factor-1α and endothelial nitric oxide synthase following hypergravity exposure

    PubMed Central

    Yoon, Gun; Oh, Choong Sik; Kim, Hyun-Soo

    2016-01-01

    This study was designed to examine the expression of hypoxia-inducible factor-1α (HIF-1α) and the level and activity of endothelial nitric oxide synthase (eNOS) in the hearts and livers of mice exposed to hypergravity. Hypergravity-induced hypoxia and the subsequent post-exposure reoxygenation significantly increased cardiac HIF-1α levels. Furthermore, the levels and activity of cardiac eNOS also showed significant increase immediately following hypergravity exposure and during the reoxygenation period. In contrast, the expression of phosphorylated Akt (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-ERK) showed significant elevation only during the reoxygenation period. These data raise the possibility that the increase in cardiac HIF-1α expression induced by reoxygenation involves a cascade of signaling events, including activation of the Akt and ERK pathways. In the liver, HIF-1α expression was significantly increased immediately after hypergravity exposure, indicating that hypergravity exposure to causes hepatocellular hypoxia. The hypergravity-exposed livers showed significantly higher eNOS immunoreactivity than did those of control mice. Consistent with these results, significant increases in eNOS activity and nitrate/nitrite levels were also observed. These findings suggest that hypergravity-induced hypoxia plays a significant role in the upregulation of hepatic eNOS. PMID:27191892

  12. Paeoniflorin prevents hypoxia-induced epithelial-mesenchymal transition in human breast cancer cells.

    PubMed

    Zhou, Zhenyu; Wang, Shunchang; Song, Caijuan; Hu, Zhuang

    2016-01-01

    Paeoniflorin (PF) is a monoterpene glycoside extracted from the root of Paeonia lactiflora Pall. Previous studies have demonstrated that PF inhibits the growth, invasion, and metastasis of tumors in vivo and in vitro. However, the effect of PF on hypoxia-induced epithelial-mesenchymal transition (EMT) in breast cancer cells remains unknown. Therefore, the objective of this study was to investigate the effect of PF on hypoxia-induced EMT in breast cancer cells, as well as characterize the underlying mechanism. The results presented in this study demonstrate that PF blocks the migration and invasion of breast cancer cells by repressing EMT under hypoxic conditions. PF also significantly attenuated the hypoxia-induced increase in HIF-1α level. Furthermore, PF prevented hypoxia-induced expression of phosphorylated PI3K and Akt in MDA-MB-231 cells. In conclusion, PF prevented hypoxia-induced EMT in breast cancer cells by inhibiting HIF-1α expression via modulation of PI3K/Akt signaling pathway. This finding provides evidence that PF can serve as a therapeutic agent for the treatment of breast cancer. PMID:27175085

  13. Paeoniflorin prevents hypoxia-induced epithelial–mesenchymal transition in human breast cancer cells

    PubMed Central

    Zhou, Zhenyu; Wang, Shunchang; Song, Caijuan; Hu, Zhuang

    2016-01-01

    Paeoniflorin (PF) is a monoterpene glycoside extracted from the root of Paeonia lactiflora Pall. Previous studies have demonstrated that PF inhibits the growth, invasion, and metastasis of tumors in vivo and in vitro. However, the effect of PF on hypoxia-induced epithelial–mesenchymal transition (EMT) in breast cancer cells remains unknown. Therefore, the objective of this study was to investigate the effect of PF on hypoxia-induced EMT in breast cancer cells, as well as characterize the underlying mechanism. The results presented in this study demonstrate that PF blocks the migration and invasion of breast cancer cells by repressing EMT under hypoxic conditions. PF also significantly attenuated the hypoxia-induced increase in HIF-1α level. Furthermore, PF prevented hypoxia-induced expression of phosphorylated PI3K and Akt in MDA-MB-231 cells. In conclusion, PF prevented hypoxia-induced EMT in breast cancer cells by inhibiting HIF-1α expression via modulation of PI3K/Akt signaling pathway. This finding provides evidence that PF can serve as a therapeutic agent for the treatment of breast cancer. PMID:27175085

  14. NOX2 Antisense Attenuates Hypoxia-Induced Oxidative Stress and Apoptosis in Cardiomyocyte

    PubMed Central

    Yu, Bo; Meng, Fanbo; Yang, Yushuang; Liu, Dongna; Shi, Kaiyao

    2016-01-01

    Heart ischemia is a hypoxia related disease. NOX2 and HIF-1α proteins were increased in cardiomyocytes after acute myocardial infarction. However, the relationship of the hypoxia-induced HIF-1α. NOX2-derived oxidative stress and apoptosis in cardiomyocyte remains unclear. In the current study, we use NOX2 antisense strategy to investigate the role of NOX2 in hypoxia-induced oxidative stress and apoptosis in rat cardiomyocytes. Here, we show that transduction of ADV-NOX2-AS induces potent silencing of NOX2 in cardiomyocytes, and resulting in attenuation of hypoxia-induced oxidative stress and apoptosis. This study indicates the potential of antisense-based therapies and validates NOX2 as a potent therapeutic candidate for heart ischemia. PMID:27499697

  15. Expression of hypoxia-inducible factor 3α in hepatocellular carcinoma and its association with other hypoxia-inducible factors

    PubMed Central

    LIU, PING; FANG, XIEFAN; SONG, YANG; JIANG, JIAN-XIN; HE, QIAN-JIN; LIU, XIANG-JIE

    2016-01-01

    The functional role of hypoxia-inducible factor (HIF)-3α in the development of hepatocellular carcinoma (HCC) is not yet fully understood. The aim of the present study was to elucidate the association between HIF-3α expression and the clinicopathological features as well as prognosis of HCC patients. In addition, we investigated the association between HIF-3α expression and the expression of HIF-1α and HIF-2α in tumor tissues. The protein levels of HIF-3α were determined using immunohistochemical analysis of paraffin sections of 126 paired HCC and peritumoral tissues. PLC/PRF/5 cells, a human HCC cell line, were transfected with HIF-1α and HIF-2α vectors and HIF-3α mRNA and protein expression was detected using quantitative polymerase chain reaction and western blot analysis, respectively. The expression of HIF-3α was upregulated in 46.0% (58/126) and downregulated in 42.9% (54/126) of tumor tissues, respectively, when compared to peritumoral tissues. HIF-3α protein expression was not associated with peripheral blood vessel invasion, overall survival, or disease-free survival in HCC patients (P>0.05). In HCC tissues, the levels of HIF-3α protein were positively correlated with HIF-2α, but not with HIF-1α expression in HCC tissues. HIF-3α was upregulated in PLC/PRF/5 and Hep3B cells overexpressed with HIF-1α or HIF-2α. The hypoxic microenvironment of liver cancer did not lead to elevated HIF-3α protein expression, indicating that HIF-3α is regulated differently from HIF-1α in vivo. The correlation between HIF-3α and HIF-2α expression at the cellular and tissue levels indicated that HIF-3α may be a target gene of HIF-2α. The hypoxic microenvironment did not lead to elevation of HIF-3α protein expression in liver cancer; thus, HIF-3α may be a target gene of HIF-2α. PMID:27284334

  16. Determinants of discrepancies in detection and comparison of the prognostic significance of left ventricular hypertrophy by electrocardiogram and cardiac magnetic resonance imaging.

    PubMed

    Bacharova, Ljuba; Chen, Haiying; Estes, E Harvey; Mateasik, Anton; Bluemke, David A; Lima, Joao A C; Burke, Gregory L; Soliman, Elsayed Z

    2015-02-15

    Despite the low sensitivity of the electrocardiogram (ECG) in detecting left ventricular hypertrophy (LVH), ECG-LVH is known to be a strong predictor of cardiovascular risk. Understanding reasons for the discrepancies in detection of LVH by ECG versus imaging could help improve the diagnostic ability of ECG. We examined factors associated with false-positive and false-negative ECG-LVH, using cardiac magnetic resonance imaging (MRI) as the gold standard. We also compared the prognostic significance of ECG-LVH and MRI-LVH as predictors of cardiovascular events. This analysis included 4,748 participants (mean age 61.9 years, 53.5% females, 61.7% nonwhites). Logistic regression with stepwise selection was used to identify factors associated with false-positive (n = 208) and false-negative (n = 387), compared with true-positive (n = 208) and true-negative (n = 4,041) ECG-LVH, respectively. A false-negative ECG-LVH status was associated with increased odds of Hispanic race/ethnicity, current smoking, hypertension, increased systolic blood pressure, prolongation of QRS duration, and higher body mass index and with lower odds of increased ejection fraction (model-generalized R(2) = 0.20). A false-positive ECG-LVH status was associated with lower odds of black race, Hispanic race/ethnicity, minor ST-T abnormalities, increased systolic blood pressure, and presence of any major electrocardiographic abnormalities (model-generalized R(2) = 0.29). Both ECG-LVH and MRI-LVH were associated with an increased risk of cardiovascular disease events (hazard ratio 1.51, 95% confidence interval 1.03 to 2.20 and hazard ratio 1.81, 95% confidence interval 1.33 to 2.46, respectively). In conclusion, discrepancy in LVH detection by ECG and MRI can be relatively improved by considering certain participant characteristics. Discrepancy in diagnostic performance, yet agreement on predictive ability, suggests that LVH by ECG and LVH by imaging are likely to be two distinct but somehow related

  17. Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

    PubMed Central

    Karakashev, Sergey V; Reginato, Mauricio J

    2015-01-01

    Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance. PMID:26316817

  18. Hypoxia Induces Epithelial-Mesenchymal Transition in Follicular Thyroid Cancer: Involvement of Regulation of Twist by Hypoxia Inducible Factor-1α

    PubMed Central

    Yang, Yeon Ju; Na, Hwi Jung; Suh, Michelle J.; Ban, Myung Jin; Byeon, Hyung Kwon; Kim, Won Shik; Kim, Jae Wook; Choi, Eun Chang; Kwon, Hyeong Ju; Chang, Jae Won

    2015-01-01

    Purpose Although follicular thyroid cancer (FTC) has a relatively fair prognosis, distant metastasis sometimes results in poor prognosis and survival. There is little understanding of the mechanisms contributing to the aggressiveness potential of thyroid cancer. We showed that hypoxia inducible factor-1α (HIF-1α) induced aggressiveness in FTC cells and identified the underlying mechanism of the HIF-1α-induced invasive characteristics. Materials and Methods Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on HIF-1α, and epithelial-to-mesenchymal transition (EMT) related markers were evaluated by quantitative real-time PCR, Western blot analysis and immunocytochemistry. Invasion and wound healing assay were conducted to identify functional character of EMT. The involvement of HIF-1α and Twist in EMT were studied using gene overexpression or silencing. After orthotopic nude mouse model was established using the cells transfected with lentiviral shHIF-1α, tissue analysis was done. Results Hypoxia induces HIF-1α expression and EMT, including typical morphologic changes, cadherin shift, and increased vimentin expression. We showed that overexpression of HIF-1α via transfection resulted in the aforementioned changes without hypoxia, and repression of HIF-1α with RNA interference suppressed hypoxia-induced HIF-1α and EMT. Furthermore, we also observed that Twist expression was regulated by HIF-1α. These were confirmed in the orthotopic FTC model. Conclusion Hypoxia induced HIF-1α, which in turn induced EMT, resulting in the increased capacity for invasion and migration of cells via regulation of the Twist signal pathway in FTC cells. These findings provide insight into a possible therapeutic strategy to prevent invasive and metastatic FTC. PMID:26446630

  19. Hypoxia-induced cell death and changes in hypoxia-inducible factor-1 activity in PC12 cells upon exposure to nerve growth factor.

    PubMed

    Charlier, Nico; Leclere, Norbert; Felderhoff, Ursula; Heldt, Julia; Kietzmann, Thomas; Obladen, Michael; Gross, Johann

    2002-07-15

    The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (Annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes responsible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierarchically organized signaling molecule.

  20. Potential Markers in Cardiac Hypertrophy?

    PubMed Central

    Fulgheri, Gabriele; Wicinski, Michal; Grzesk, Elzbieta; Odrowaz-Sypniewska, Grazyna; Grześk, Grzegorz; Darwish, Nasser

    2012-01-01

    Cardiomyopathies are diagnosed based on medical history of patient (symptoms and family history), physical examination, results of echocardiogram and in some situations additionally ECG or chest-X-ray results. Currently used non-invasive diagnostic methods, could be complemented by biochemical tests. In this review some emerging potential biomarkers such as: osteopontin, ST-2 receptor, osteoprotegerin, neopterin, urocortins, growth differentiation factor 15 and urotensin II are described. In current article human and non human investigations have been reviewed, since rat is most commonly used model in experimental cardiology and gives important foundations to clinical knowledge.

  1. Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells.

    PubMed

    Peng, Wan-Xin; Xiong, Er-Meng; Ge, Lu; Wan, Yan-Ya; Zhang, Chun-Li; Du, Feng-Yi; Xu, Min; Bhat, Reyaz Ahmed; Jin, Jie; Gong, Ai-Hua

    2016-01-01

    Previous studies suggest that early growth response gene-1 (Egr-1) plays an important role in hypoxia-induced drug-resistance. However, the mechanism still remains to be clarified. Herein, we investigated the role of Egr-1 in hypoxia-induced autophagy and its resulted hypoxia-driven chemo-resistance in Hepatocellular Carcinoma (HCC) cells. Our data demonstrated that Egr-1 was overexpressed in HCC tissues and cells and conferred them drug resistance under hypoxia. Mechanistically, Egr-1 transcriptionally regulated hypoxia-induced autophagy by binding to LC3 promoter in HCC cells, which resulted in resistance of HCC cells to chemotherapeutic agents; while dominant negative Egr-1 could inhibit autophagy level, and thus enhanced the sensitivity of HCC cells to chemotherapeutic agents, indicating that hypoxia-induced Egr-1 expression enhanced drug resistance of HCC cells likely through autophagy. Accordingly, it is suggested that a mechanism of hypoxia/Egr-1/autophagy axis might be involved in drug resistance in HCC. PMID:26708617

  2. Cytoskeletal Role in the Contractile Dysfunction of Hypertrophied Myocardium

    NASA Astrophysics Data System (ADS)

    Tsutsui, Hiroyuki; Ishihara, Kazuaki; Cooper, George

    1993-04-01

    Cardiac hypertrophy in response to systolic pressure loading frequently results in contractile dysfunction of unknown cause. In the present study, pressure loading increased the microtubule component of the cardiac muscle cell cytoskeleton, which was responsible for the cellular contractile dysfunction observed. The linked microtubule and contractile abnormalities were persistent and thus may have significance for the deterioration of initially compensatory cardiac hypertrophy into congestive heart failure.

  3. Intracrine prostaglandin E(2) signalling regulates hypoxia-inducible factor-1α expression through retinoic acid receptor-β.

    PubMed

    Fernández-Martínez, Ana B; Jiménez, María I Arenas; Manzano, Victoria Moreno; Lucio-Cazaña, Francisco J

    2012-12-01

    We have previously found in human renal proximal tubular HK-2 cells that hypoxia- and all-trans retinoic acid-induced hypoxia-inducible factor-1α up-regulation is accompanied by retinoic acid receptor-β up-regulation. Here we first investigated whether hypoxia-inducible factor-1α expression is dependent on retinoic acid receptor-β and our results confirmed it since (i) hypoxia-inducible factor-1α-inducing agents hypoxia, hypoxia-mimetic agent desferrioxamine, all-trans retinoic acid and interleukin-1β increased retinoic acid receptor-β expression, (ii) hypoxia-inducible factor-1α up-regulation was prevented by retinoic acid receptor-β antagonist LE-135 or siRNA retinoic acid receptor-β and (iii) there was direct binding of retinoic acid receptor-β to the retinoic acid response element in hypoxia-inducible factor-1α promoter upon treatment with all-trans retinoic acid and 16,16-dimethyl-prostaglandin E(2). Since intracellular prostaglandin E(2) mediates hypoxia-inducible factor-1α up-regulation in normoxia in HK-2 cells, we next investigated and confirmed, its role in the up-regulation of retinoic acid receptor-β in normoxia by hypoxia-inducible factor-1α-inducing agents all-trans retinoic acid, interleukin-1β and 16,16-dimethyl-prostaglandin E(2) by inhibiting cyclooxygenases, prostaglandin influx transporter or EP receptors. Interestingly, the hypoxia-induced increase in retinoic acid receptor-β expression and accumulation of hypoxia-inducible factor-1α was also blocked by the inhibitors tested. This is the first time, to our knowledge, that retinoic acid receptor-β signalling is involved in the control of the expression of transcription factor hypoxia-inducible factor-1α in both normoxia and hypoxia and that retinoic acid receptor-β expression is found to be strictly regulated by intracellular prostaglandin E(2). Given the relevance of hypoxia-inducible factor-1α in the kidney in terms of tumorigenesis, progressive renal failure, production

  4. Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1.

    PubMed

    Liu, Yu; Higashitsuji, Hiroaki; Higashitsuji, Hisako; Itoh, Katsuhiko; Sakurai, Toshiharu; Koike, Kazuhiko; Hirota, Kiichi; Fukumoto, Manabu; Fujita, Jun

    2013-03-01

    Gankyrin (also called p28 or PSMD10) is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It consists of 7 ankyrin repeats and interacts with multiple proteins including Rb, Cdk4, MDM2 and NF-κB. To assess the oncogenic activity in vivo, we produced transgenic mice that overexpress gankyrin specifically in the hepatocytes. Unexpectedly, 5 of 7 F2 transgenic mice overexpressing hepatitis B virus X protein (HBX) promoter-driven gankyrin, and one of 3 founder mice overexpressing serum amyloid P component (SAP) promoter-driven gankyrin developed hepatic vascular neoplasms (hemangioma/hemangiosarcomas) whereas none of the wild-type mice did. Endothelial overgrowth was more frequent in the livers of diethylnitrosamine-treated transgenic mice than wild-type mice. Mouse hepatoma Hepa1-6 cells overexpressing gankyrin formed tumors with more vascularity than parental Hepa1-6 cells in the transplanted mouse skin. We found that gankyrin binds to and sequester factor inhibiting hypoxia-inducible factor-1 (FIH-1), which results in decreased interaction between FIH-1 and hypoxia-inducible factor-1α (HIF-1α) and increased activity of HIF-1 to promote VEGF production. The effects of gankyrin were more prominent under 3% O2 than 1% or 20% O2 conditions. Thus, the present study clarified, at least partly, mechanisms of vascular tumorigenesis, and suggests that gankyrin might play a physiological role in hypoxic responses besides its roles as an oncoprotein. PMID:23376718

  5. Selective inhibition of the hypoxia-inducible factor prolyl hydroxylase PHD3 by Zn(II).

    PubMed

    Na, Yu-Ran; Woo, Dustin J; Choo, Hyunah; Chung, Hak Suk; Yang, Eun Gyeong

    2015-07-01

    We report herein that Zn(II) selectively inhibits the hypoxia-inducible factor prolyl hydroxylase PHD3 over PHD2, and does not compete with Fe(II). Independent of the oligomer formation induced by Zn(II), inhibition of the activity of PHD3 by Zn(II) involves Cys42 and Cys52 residues distantly located from the active site. PMID:26051901

  6. Hydrogen sulfide alleviates hypoxia-induced root tip death in Pisum sativum.

    PubMed

    Cheng, Wei; Zhang, Liang; Jiao, Chengjin; Su, Miao; Yang, Tao; Zhou, Lina; Peng, Renyi; Wang, Ranran; Wang, Chongying

    2013-09-01

    Flooding of soils often results in hypoxic conditions surrounding plant roots, which is a harmful abiotic stress to crops. Hydrogen sulfide (H2S) is a highly diffusible, gaseous molecule that modulates cell signaling and is involved in hypoxia signaling in animal cells. However, there have been no previous studies of H2S in plant cells in response to hypoxia. The effects of H2S on hypoxia-induced root tip death were studied in pea (Pisum sativum) via analysis of endogenous H2S and reactive oxygen species (ROS) levels. The activities of key enzymes involved in antioxidative and H2S metabolic pathways were determined using spectrophotometric assays. Ethylene was measured by gas chromatography. We found that exogenous H2S pretreatment dramatically alleviated hypoxia-induced root tip death by protecting root tip cell membranes from ROS damage induced by hypoxia and by stimulating a quiescence strategy through inhibiting ethylene production. Conversely, root tip death induced by hypoxia was strongly enhanced by inhibition of the key enzymes responsible for endogenous H2S biosynthesis. Our results demonstrated that exogenous H2S pretreatment significantly alleviates hypoxia-induced root tip death in pea seedlings and, therefore, enhances the tolerance of the plant to hypoxic stress.

  7. Hypoxia-induced Bcl-2 expression in endothelial cells via p38 MAPK pathway

    SciTech Connect

    Zhang, Cui-Li; Song, Fei; Zhang, Jing; Song, Q.H.

    2010-04-16

    Angiogenesis and apoptosis are reciprocal processes in endothelial cells. Bcl-2, an anti-apoptotic protein, has been found to have angiogenic activities. The purpose of this study was to determine the role of Bcl-2 in hypoxia-induced angiogenesis in endothelial cells and to investigate the underlying mechanisms. Human aortic endothelial cells (HAECs) were exposed to hypoxia followed by reoxygenation. Myocardial ischemia and reperfusion mouse model was used and Bcl-2 expression was assessed. Bcl-2 expression increased in a time-dependent manner in response to hypoxia from 2 to 72 h. Peak expression occurred at 12 h (3- to 4-fold, p < 0.05). p38 inhibitor (SB203580) blocked hypoxia-induced Bcl-2 expression, whereas PKC, ERK1/2 and PI3K inhibitors did not. Knockdown of Bcl-2 resulted in decreased HAECs' proliferation and migration. Over-expression of Bcl-2 increased HAECs' tubule formation, whereas knockdown of Bcl-2 inhibited this process. In this model of myocardial ischemia and reperfusion, Bcl-2 expression was increased and was associated with increased p38 MAPK activation. Our results showed that hypoxia induces Bcl-2 expression in HAECs via p38 MAPK pathway.

  8. Sodium hydrosulfide prevents hypoxia-induced behavioral impairment in neonatal mice.

    PubMed

    Wang, Zhen; Zhan, Jingmin; Wang, Xueer; Gu, Jianhua; Xie, Kai; Zhang, Qingrui; Liu, Dexiang

    2013-11-13

    Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological abnormalities. Endogenous hydrogen sulfide (H2S) may have multiple functions in brain. The aim of this study is to investigate whether sodium hydrosulfide (NaHS), a H2S donor, provides protection against neonatal hypoxia-induced neurobehavioral deficits. Neonatal mice were subjected to hypoxia (5% oxygen for 120min) at postnatal day 1 and received NaHS (5.6mg/kg) once daily for 3d. Neurobehavioral toxicity was examined at 3-30d after hypoxia. Treatment with NaHS significantly attenuated the delayed development of sensory and motor reflexes induced by hypoxia up to two weeks after the insult. Moreover, NaHS improved the learning and memory performance of hypoxic animals as indicated in Morris water maze test at 30d after hypoxia. In mice exposed to hypoxia, treatment with NaHS enhanced expression of brain derived neurotrophic factor (BDNF) in the hippocampus. Furthermore, the protective effects of NaHS were associated with its ability to repress the hypoxia-induced nitric oxide synthase (NOS) activity and nitric oxide production in the hippocampus of mice brain. Taken together, these results suggest that the long-lasting beneficial effects of NaHS on hypoxia-induced neurobehavioral deficits are mediated, at least in part, by inducing BDNF expression and suppressing NOS activity in the brain of mice.

  9. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment.

    PubMed

    Hota, Sunil Kumar; Barhwal, Kalpana; Baitharu, Iswar; Prasad, Dipti; Singh, Shashi Bala; Ilavazhagan, Govindasamy

    2009-04-01

    Hypobaric hypoxia induced memory impairment has been attributed to several factors including increased oxidative stress, depleted mitochondrial bioenergetics, altered neurotransmission and apoptosis. This multifactorial response of the brain to hypobaric hypoxia limits the use of therapeutic agents that target individual pathways for ameliorating hypobaric hypoxia induced memory impairment. The present study aimed at exploring the therapeutic potential of a bacoside rich leaf extract of Bacopa monniera in improving the memory functions in hypobaric conditions. The learning ability was evaluated in male Sprague Dawley rats along with memory retrieval following exposure to hypobaric conditions simulating an altitude of 25,000 ft for different durations. The effect of bacoside administration on apoptosis, cytochrome c oxidase activity, ATP levels, and oxidative stress markers and on plasma corticosterone levels was investigated. Expression of NR1 subunit of N-methyl-d-aspartate receptors, neuronal cell adhesion molecules and was also studied along with CREB phosphorylation to elucidate the molecular mechanisms of bacoside action. Bacoside administration was seen to enhance learning ability in rats along with augmentation in memory retrieval and prevention of dendritic atrophy following hypoxic exposure. In addition, it decreased oxidative stress, plasma corticosterone levels and neuronal degeneration. Bacoside administration also increased cytochrome c oxidase activity along with a concomitant increase in ATP levels. Hence, administration of bacosides could be a useful therapeutic strategy in ameliorating hypobaric hypoxia induced cognitive dysfunctions and other related neurological disorders.

  10. STAT3 regulates hypoxia-induced epithelial mesenchymal transition in oesophageal squamous cell cancer

    PubMed Central

    CUI, YAO; LI, YUN-YUN; LI, JIAN; ZHANG, HONG-YAN; WANG, FENG; BAI, XUE; LI, SHAN-SHAN

    2016-01-01

    Hypoxia plays a key role in tumour initiation and metastasis; one of the mechanisms is to induce epithelial-mesenchymal transition (EMT). Signal transducer and activator of transcription 3 (STAT3) is involved in EMT by regulating the transcriptional regulators of E-cadherin, the biomarker of EMT. Until now, however, few studies have focused on the effects of STAT3 in hypoxia-induced EMT in tumour cells. The goal of this study was to investigate the roles of STAT3 in hypoxia-induced EMT in oesophageal squamous cell carcinoma (ESCC). The ESCC cells, TE-1 and EC-1, were incubated in normoxia, or in CoCl2, which was used to mimic hypoxia. With CoCl2, the ESCC cells showed increased migration and invasion abilities, accompanied with upregulation of HIF-1α, STAT3, and vimentin, and downregulation of E-cadherin. Knockdown of STAT3 inhibited EMT of ESCC cells and downregulated HIF-1α in vitro and in vivo. In ChIP assays, STAT3 bound to the promoter of HIF-1α, suggesting that STAT3 regulates transcription of HIF-1α. In conclusion, hypoxia induces EMT of ESCC, and STAT3 regulates this process by promoting HIF-1α expression. PMID:27220595

  11. HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells

    SciTech Connect

    Liu, Junye; Zhang, Jing; Wang, Xiaowu; Li, Yan; Chen, Yongbin; Li, Kangchu; Zhang, Jian; Yao, Libo; Guo, Guozhen

    2010-07-15

    Hypoxia inducible factor 1 (HIF-1), the key mediator of hypoxia signaling pathways, has been shown involved in hypoxia-induced radioresistance. However, the underlying mechanisms are unclear. The present study demonstrated that both hypoxia and hypoxia mimetic cobalt chloride could increase the radioresistance of human cervical cancer Hela cells. Meanwhile, ectopic expression of HIF-1 could enhance the resistance of Hela cells to radiation, whereas knocking-down of HIF-1 could increase the sensitivity of Hela cells to radiation in the presence of hypoxia. N-Myc downstream-regulated gene 2 (NDRG2), a new HIF-1 target gene identified in our lab, was found to be upregulated by hypoxia and radiation in a HIF-1-dependent manner. Overexpression of NDRG2 resulted in decreased sensitivity of Hela cells to radiation while silencing NDRG2 led to radiosensitization. Moreover, NDRG2 was proved to protect Hela cells from radiation-induced apoptosis and abolish radiation-induced upregulation of Bax. Taken together, these data suggest that both HIF-1 and NDRG2 contribute to hypoxia-induced tumor radioresistance and that NDRG2 acts downstream of HIF-1 to promote radioresistance through suppressing radiation-induced Bax expression. It would be meaningful to further explore the clinical application potential of HIF-1 and NDRG2 blockade as radiosensitizer for tumor therapy.

  12. Neuronal pentraxin 1 expression is regulated by hypoxia inducible factor-1α.

    PubMed

    Botlagunta, Mahendran

    2015-01-01

    Neuronal pentraxins (NPs) are belong to sub family of long pentraxin proteins consist of neuronal pentraxin 1 (NP1), neuronal pentraxin 2 (NP2), and neuronal pentraxin receptor (NPR). Enhanced expression of NP1 in hypoxic conditions has shown to induce cell death in neuronal cells, however, the underlying mechanism of NP1 regulation by hypoxia remains elusive. To demonstrate that, we have cloned human NP1 gene promoter upstream of the luciferase gene and the activity of NP1 promoter was studied using HEK cell lines. Within the promoter region of the human NP1 gene, we identified six putative hypoxia inducible factor (HIF) responsive elements. By luciferase reporter assays we determined that the hypoxia inducible factor responsive element is located between -332 to -215 positions relative to the translation start site are essential for transcriptional activation of NP1 under hypoxic conditions. To further confirm the activity is solely due to hypoxia, we transiently transfected green fluorescent protein (EGFP) under transcriptional control of five copies of a hypoxia response element (HRE). The intensity of GFP was recorded at normal and hypoxic conditions. Taken together, our results demonstrate that NP1 gene is a target of as a hypoxia-inducible factor and it regulate NP1 expression by binding to hypoxia responsive elements (HREs) in its promoter region.

  13. Erythropoietin gene expression: developmental-stage specificity, cell-type specificity, and hypoxia inducibility.

    PubMed

    Suzuki, Norio

    2015-01-01

    Erythrocytes play an essential role in the delivery of oxygen from the lung to every organ; a decrease in erythrocytes (anemia) causes hypoxic stress and tissue damage. To maintain oxygen homeostasis in adult mammals, when the kidney senses hypoxia, it secretes an erythroid growth factor, erythropoietin (Epo), which stimulates erythropoiesis in the bone marrow. Recently, studies using genetically modified mice have shown that the in vivo expression profile of the Epo gene changes dramatically during development. The first Epo-producing cells emerge in the neural crest and neuroepithelium of mid-stage embryos and support primitive erythropoiesis in the yolk sac. Subsequently, Epo from the hepatocytes stimulates erythropoiesis in the fetal liver of later stage embryos in a paracrine manner. In fact, erythroid lineage cells comprise the largest cell population in the fetal liver, and hepatocytes are distributed among the erythroid cell clusters. Adult erythropoiesis in the bone marrow requires Epo that is secreted by renal Epo-producing cells (REP cells). REP cells are widely distributed in the renal cortex and outer medulla. Hypoxia-inducible Epo production both in hepatocytes and REP cells is controlled at the gene transcription level that is mainly mediated by the hypoxia-inducible transcription factor (HIF) pathway. These mouse studies further provide insights into the molecular mechanisms of the cell-type specific, hypoxia-inducible expression of the Epo gene, which involves multiple sets of cis- and trans-regulatory elements. PMID:25786542

  14. Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system.

    PubMed

    Matsuyama, Tomonori; Tanaka, Tomoharu; Tatsumi, Kenichiro; Daijo, Hiroki; Kai, Shinichi; Harada, Hiroshi; Fukuda, Kazuhiko

    2015-08-15

    Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1α and HIF-2α proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro. PMID:26001375

  15. The Role of Hypoxia-Induced miR-210 in Cancer Progression

    PubMed Central

    Dang, Kyvan; Myers, Kenneth A.

    2015-01-01

    Prolonged hypoxia, the event of insufficient oxygen, is known to upregulate tumor development and growth by promoting the formation of a neoplastic environment. The recent discovery that a subset of cellular microRNAs (miRs) are upregulated during hypoxia, where they function to promote tumor development, highlights the importance of hypoxia-induced miRs as targets for continued investigation. miRs are short, non-coding transcripts involved in gene expression and regulation. Under hypoxic conditions, miR-210 becomes highly upregulated in response to hypoxia inducing factors (HIFs). HIF-1α drives miR-210’s overexpression and the resultant alteration of cellular processes, including cell cycle regulation, mitochondria function, apoptosis, angiogenesis and metastasis. Here we discuss hypoxia-induced dysregulation of miR-210 and the resultant changes in miR-210 protein targets that regulate cancer progression. Potential methods of targeting miR-210 as a therapeutic tool are also explored. PMID:25809609

  16. REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling

    PubMed Central

    Lin, Tzu-Ping; Chang, Yi-Ting; Lee, Sung-Yuan; Campbell, Mel; Wang, Tien-Chiao; Shen, Shu-Huei; Chung, Hsiao-Jen; Chang, Yen-Hwa; Chiu, Allen W.; Pan, Chin-Chen; Lin, Chi-Hung; Chu, Cheng-Ying; Kung, Hsing-Jien; Cheng, Chia-Yang; Chang, Pei-Ching

    2016-01-01

    Prostate cancer (PCa) with neuroendocrine differentiation (NED) is tightly associated with hormone refractory PCa (HRPC), an aggressive form of cancer that is nearly impossible to treat. Determining the mechanism of the development of NED may yield novel therapeutic strategies for HRPC. Here, we first demonstrate that repressor element-1 silencing transcription factor (REST), a transcriptional repressor of neuronal genes that has been implicated in androgen-deprivation and IL-6 induced NED, is essential for hypoxia-induced NED of PCa cells. Bioinformatics analysis of transcriptome profiles of REST knockdown during hypoxia treatment demonstrated that REST is a master regulator of hypoxia-induced genes. Gene set enrichment analysis (GSEA) of hypoxia and REST knockdown co-upregulated genes revealed their correlation with HRPC. Consistently, gene ontology (GO) analysis showed that REST reduction potential associated with hypoxia-induced tumorigenesis, NE development, and AMPK pathway activation. Emerging reports have revealed that AMPK activation is a potential mechanism for hypoxia-induced autophagy. In line with this, we demonstrate that REST knockdown alone is capable of activating AMPK and autophagy activation is essential for hypoxia-induced NED of PCa cells. Here, making using of in vitro cell-based assay for NED, we reveal a new role for the transcriptional repressor REST in hypoxia-induced NED and characterized a sequential molecular mechanism downstream of REST resulting in AMPK phosphorylation and autophagy activation, which may be a common signaling pathway leading to NED of PCa. PMID:27034167

  17. Lysyl oxidase mediates hypoxia-induced radioresistance in non-small cell lung cancer A549 cells

    PubMed Central

    Gong, Chongwen; Gu, Runxia; Jin, Honglin; Sun, Yao; Li, Zhenyu; Wu, Gang

    2016-01-01

    Hypoxia-induced radioresistance has been well known as the main obstacle in cancer radiotherapy. Lysyl oxidase (LOX) was previously demonstrated to play an important role in hypoxia-induced biological behaviors, such as metastasis and angiogenesis, through hypoxia-inducible factor-1α (HIF-1α), which is an important contributing factor to radioresistance in tumor cells. However, how LOX plays a role in hypoxia-induced radioresistance has yet to be determined. Here, we found that LOX expression was in accordance with HIF-1α expression, and LOX expression at the mRNA and protein level, and enzymatic activity were remarkably upregulated in the hypoxic A549 cells, compared with normoxic A549 cells. Inhibition of LOX resulted in the reduction of the ability to repair double-stranded breaks (DSBs), promotion of apoptosis, relief of G2/M cycle arrest, and eventually reduction of hypoxia-induced radioresistance in the hypoxic A549 cells. This suggests that LOX may play an important role in hypoxia-induced radioresistance. Together, our results might suggest a novel potential therapeutic target in the management of non-small cell lung cancer (NSCLC). PMID:26515140

  18. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway.

    PubMed

    Tramontano, Anthony F; Muniyappa, Ranganath; Black, Aislinn D; Blendea, Mihaela C; Cohen, Inna; Deng, Lili; Sowers, James R; Cutaia, Michael V; El-Sherif, Nabil

    2003-09-01

    Apoptosis is a contributing cause of myocyte loss in ischemic heart disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that the erythropoietin receptor (EPOR) is expressed in the neonatal rat ventricular myocyte (NRVM). Exposure of NRVMs to hypoxia, with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL, flow cytometry, and caspase 3/7 like activity when compared to hypoxia treatment alone. EPO administered at the initiation of coronary artery occlusion in the rat significantly decreased apoptosis in the myocardial ischemic region. In the NRVM, EPO increased the activity of Akt. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, a specific blocker of phosphatidylinositol 3-kinase (PI3-K). Our study demonstrates that EPO inhibits apoptosis in the NRVM exposed to hypoxia, through an Akt-dependent pathway. EPO also inhibits apoptosis in the in vivo rat model of myocardial ischemia.

  19. Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

    PubMed Central

    KUBO, HIROSHI; KITAJIMA, YOSHIHIKO; KAI, KEITA; NAKAMURA, JUN; MIYAKE, SHUUSUKE; YANAGIHARA, KAZUYOSHI; MORITO, KIYOTO; TANAKA, TOMOKAZU; SHIDA, MASAAKI; NOSHIRO, HIROKAZU

    2016-01-01

    Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting

  20. O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy.

    PubMed

    Facundo, Heberty T; Brainard, Robert E; Watson, Lewis J; Ngoh, Gladys A; Hamid, Tariq; Prabhu, Sumanth D; Jones, Steven P

    2012-05-15

    The regulation of cardiomyocyte hypertrophy is a complex interplay among many known and unknown processes. One specific pathway involves the phosphatase calcineurin, which regulates nuclear translocation of the essential cardiac hypertrophy transcription factor, nuclear factor of activated T-cells (NFAT). Although metabolic dysregulation is frequently described during cardiac hypertrophy, limited insights exist regarding various accessory pathways. One metabolically derived signal, beta-O-linked N-acetylglucosamine (O-GlcNAc), has emerged as a highly dynamic posttranslational modification of serine and threonine residues regulating physiological and stress processes. Given the metabolic dysregulation during hypertrophy, we hypothesized that NFAT activation is dependent on O-GlcNAc signaling. Pressure overload-induced hypertrophy (via transverse aortic constriction) in mice or treatment of neonatal rat cardiac myocytes with phenylephrine significantly enhanced global O-GlcNAc signaling. NFAT-luciferase reporter activity revealed O-GlcNAc-dependent NFAT activation during hypertrophy. Reversal of enhanced O-GlcNAc signaling blunted cardiomyocyte NFAT-induced changes during hypertrophy. Taken together, these results demonstrate a critical role of O-GlcNAc signaling in NFAT activation during hypertrophy and provide evidence that O-GlcNAc signaling is coordinated with the onset and progression of cardiac hypertrophy. This represents a potentially significant and novel mechanism of cardiac hypertrophy, which may be of particular interest in future in vivo studies of hypertrophy.

  1. Neonatal epithelial hypoxia inducible factor-1α expression regulates the response of the lung to experimental asthma.

    PubMed

    Greenwood, Krista K; Proper, Steven P; Saini, Yogesh; Bramble, Lori A; Jackson-Humbles, Daven N; Wagner, James G; Harkema, Jack R; LaPres, John J

    2012-03-01

    Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early postnatal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α-deficient mice display increased airway resistance when compared with their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung and epithelial-specific deficiency in the transcription factor, during early postnatal development, increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Finally, these results might explain some of the chronic respiratory pathology observed in premature infants, especially those that receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described.

  2. Neonatal epithelial hypoxia inducible factor-1α expression regulates the response of the lung to experimental asthma.

    PubMed

    Greenwood, Krista K; Proper, Steven P; Saini, Yogesh; Bramble, Lori A; Jackson-Humbles, Daven N; Wagner, James G; Harkema, Jack R; LaPres, John J

    2012-03-01

    Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early postnatal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α-deficient mice display increased airway resistance when compared with their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung and epithelial-specific deficiency in the transcription factor, during early postnatal development, increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Finally, these results might explain some of the chronic respiratory pathology observed in premature infants, especially those that receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described. PMID:22180657

  3. MicroRNA-96 promotes myocardial hypertrophy by targeting mTOR

    PubMed Central

    Sun, Xuemei; Zhang, Chunlai

    2015-01-01

    As a main cause of cardiac hypertrophy, myocardial hypertrophy includes the proliferation and enlongation of myocardial cell, resulting in abnormally cardiac enlargement. However, the pathogenesis and the molecular mechanism that regulate gene expression of myocardial hypertrophy remain incompletely understood. MiRNAs were deemed as an important molecules involved in a variety of pathological processes. MiR-96 has been reported being associated with the tumor proliferation, but whether miR-96 is involved in cardiac hypertrophy remains uncertain. In this study, we have confirmed that, as the myocardial hypertrophy gene, mTOR was a target gene of miR-96, who would promote the occurrence of myocardial hypertrophy. Thus, we got the conclusion that miR-96 could promote myocardial hypertrophy by inhibiting mTOR, miR-96 and mTOR were negatively correlated. PMID:26823769

  4. Using OPLS-DA to find new hypotheses in vast amounts of gene expression data - studying the progression of cardiac hypertrophy in the heart of aorta ligated rat.

    PubMed

    Gennebäck, Nina; Malm, Linus; Hellman, Urban; Waldenström, Anders; Mörner, Stellan

    2013-06-10

    One of the great problems facing science today lies in data mining of the vast amount of data. In this study we explore a new way of using orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze multidimensional data. Myocardial tissues from aorta ligated and control rats (sacrificed at the acute, the adaptive and the stable phases of hypertrophy) were analyzed with whole genome microarray and OPLS-DA. Five functional gene transcript groups were found to show interesting clusters associated with the aorta ligated or the control animals. Clustering of "ECM and adhesion molecules" confirmed previous results found with traditional statistics. The clustering of "Fatty acid metabolism", "Glucose metabolism", "Mitochondria" and "Atherosclerosis" which are new results is hard to interpret, thereby being possible subject to new hypothesis formation. We propose that OPLS-DA is very useful in finding new results not found with traditional statistics, thereby presenting an easy way of creating new hypotheses. PMID:23523859

  5. Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways.

    PubMed

    Chen, Jinghai; Chen, Yuefeng; Zhu, Weiquan; Han, Yu; Han, Bianmei; Xu, Ruixia; Deng, Linzi; Cai, Yan; Cong, Xiangfeng; Yang, Yuejing; Hu, Shengshou; Chen, Xi

    2008-04-15

    Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth. PMID:17891781

  6. Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol.

    PubMed

    Hur, Eunseon; Kim, Hong-Hee; Choi, Su Mi; Kim, Jin Hee; Yim, Sujin; Kwon, Ho Jeong; Choi, Youngyeon; Kim, Dae Kyong; Lee, Mi-Ock; Park, Hyunsung

    2002-11-01

    Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the alpha subunit of hypoxia-inducible factor-1 (HIF-1alpha), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1alpha/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 microg/ml) does not significantly change the stability of the HIF-1alpha protein and does not inhibit the nuclear localization of HIF-1alpha. However, this dose of radicicol significantly reduces HRE binding by the HIF-1alpha/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1alpha/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1alpha/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.

  7. Accelerated Development of Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction in a RyR2-R176Q Knockin Mouse Model

    PubMed Central

    van Oort, Ralph J.; Respress, Jonathan L.; Li, Na; Reynolds, Corey; De Almeida, Angela C.; Skapura, Darlene G.; De Windt, Leon J.; Wehrens, Xander H.T.

    2010-01-01

    In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although Ca2+ has a central role in hypertrophic signaling pathways, the Ca2+ source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca2+ leak through defective cardiac intracellular Ca2+ release channels/ ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca2+-dependent hypertrophic signaling. Mice heterozygous for the gain-of-function mutation R176Q/+ in RyR2 and wildtype (WT) mice were subjected to transverse aortic constriction (TAC). Cardiac function was significantly lower, and cardiac dimensions were larger at 8 weeks after TAC in R176Q/+ compared with WT mice. R176Q/+ mice displayed an enhanced hypertrophic response compared to WT mice as assessed by heart weight to body weight ratios and cardiomyocyte cross sectional areas after TAC. Quantitative PCR revealed increased transcriptional activation of cardiac stress genes in R176Q/+ mice after TAC. Moreover, pressure overload resulted in an increased SR Ca2+ leak, associated with higher expression levels of the exon 4 splice form of regulator of calcineurin-1 (RCAN1-4), and a decrease in nuclear factor of activated T-cells (NFAT) phosphorylation in R176Q/+ mice compared to WT. Taken together, our results suggest that RyR2-dependent SR Ca2+ leak activates the pro-hypertrophic calcineurin/NFAT pathway under conditions of pressure overload. PMID:20157052

  8. CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death.

    PubMed

    Chen, Wei-Kung; Kuo, Wei-Wen; Hsieh, Dennis Jine-Yuan; Chang, Hsin-Nung; Pai, Pei-Ying; Lin, Kuan-Ho; Pan, Lung-Fa; Ho, Tsung-Jung; Viswanadha, Vijaya Padma; Huang, Chih-Yang

    2015-01-01

    During hypoxia, gene expression is altered by various transcription factors. Insulin-like growth factor-II (IGF2) is known to be induced by hypoxia, which binds to IGF2 receptor IGF2R that acts like a G protein-coupled receptor, might cause pathological hypertrophy or activation of the mitochondria-mediated apoptosis pathway. Cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) is central to second messenger-regulated transcription and plays a critical role in the cardiomyocyte survival pathway. In this study, we found that IGF2R level was enhanced in H9c2 cardiomyoblasts exposed to hypoxia in a time-dependent manner but was down-regulated by CREB expression. The over-expression of CREB in H9c2 cardiomyoblasts suppressed the induction of hypoxia-induced IGF2R expression levels and reduced cell apoptosis. Gel shift assay results further indicated that CREB binds to the promoter sequence of IGF2R. With a luciferase assay method, we further observed that CREB represses IGF2R promoter activity. These results suggest that CREB plays an important role in the inhibition of IGF2R expression by binding to the IGF2R promoter and further suppresses H9c2 cardiomyoblast cell apoptosis induced by IGF2R signaling under hypoxic conditions. PMID:26610485

  9. Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.

    PubMed

    Amirkhosravi, A; Meyer, T; Warnes, G; Amaya, M; Malik, Z; Biggerstaff, J P; Siddiqui, F A; Sherman, P; Francis, J L

    1998-10-01

    Tissue factor (TF), the membrane glycoprotein that initiates blood coagulation, is constitutively expressed by many tumor cells and is implicated in peri-tumor fibrin deposition and hypercoagulability in cancer. Upregulation of tumor TF correlates with enhanced metastatic potential. Furthermore, TF has been colocalized with VEGF in breast cancer, specially at sites of early angiogenesis. There are no data on the effect of hypoxia on tumor cell TF expression. Since hypoxia is known to stimulate VEGF production, we studied whether this also induces tumor cell TF expression. Confluent monolayers of A375 melanoma, MCF-7 breast carcinoma and A549 lung carcinoma were cultured in either 95% air, 5% CO2 (normoxic) or 95% N2, 5% CO2 (hypoxic; 25-30 mmHg) for 24 h. Procoagulant activity (PCA) was measured by amidolytic and clotting assays, surface TF antigen by flow cytometry, early apoptosis by annexin V binding and VEGF levels in culture supernatants by ELISA. Hypoxia significantly increased tumor cell PCA in all three cell lines tested and TF antigen on A375 cells was increased four-fold (P <0.05). Pentoxifylline (PTX), a methylxanthine derivative, significantly inhibited the hypoxia-induced increase in PCA as well as VEGF release in all three cell lines tested. In A375 cells, PTX significantly inhibited TF antigen expression by both normoxic and hypoxic cells. Hypoxia induced a slight (5%) but not significant, increase in early apoptosis. Intravenous injection of hypoxic A375 cells into nude rats produced more pronounced thrombocytopenia (n = 5, P <0.01) and more lung metastases (n = 3, P <0.05) compared to normoxic cells. We conclude that hypoxia increases TF expression by malignant cells which enhances tumor cell-platelet binding and hematogenous metastasis. Hypoxia-induced upregulation of TF appears to parallel that of VEGF, although the mechanism remains unclear.

  10. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics. PMID:27698790

  11. Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy.

    PubMed

    de Theije, C C; Langen, R C J; Lamers, W H; Gosker, H R; Schols, A M W J; Köhler, S E

    2015-01-15

    Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor (Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers.

  12. Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.

    PubMed

    Amirkhosravi, A; Meyer, T; Warnes, G; Amaya, M; Malik, Z; Biggerstaff, J P; Siddiqui, F A; Sherman, P; Francis, J L

    1998-10-01

    Tissue factor (TF), the membrane glycoprotein that initiates blood coagulation, is constitutively expressed by many tumor cells and is implicated in peri-tumor fibrin deposition and hypercoagulability in cancer. Upregulation of tumor TF correlates with enhanced metastatic potential. Furthermore, TF has been colocalized with VEGF in breast cancer, specially at sites of early angiogenesis. There are no data on the effect of hypoxia on tumor cell TF expression. Since hypoxia is known to stimulate VEGF production, we studied whether this also induces tumor cell TF expression. Confluent monolayers of A375 melanoma, MCF-7 breast carcinoma and A549 lung carcinoma were cultured in either 95% air, 5% CO2 (normoxic) or 95% N2, 5% CO2 (hypoxic; 25-30 mmHg) for 24 h. Procoagulant activity (PCA) was measured by amidolytic and clotting assays, surface TF antigen by flow cytometry, early apoptosis by annexin V binding and VEGF levels in culture supernatants by ELISA. Hypoxia significantly increased tumor cell PCA in all three cell lines tested and TF antigen on A375 cells was increased four-fold (P <0.05). Pentoxifylline (PTX), a methylxanthine derivative, significantly inhibited the hypoxia-induced increase in PCA as well as VEGF release in all three cell lines tested. In A375 cells, PTX significantly inhibited TF antigen expression by both normoxic and hypoxic cells. Hypoxia induced a slight (5%) but not significant, increase in early apoptosis. Intravenous injection of hypoxic A375 cells into nude rats produced more pronounced thrombocytopenia (n = 5, P <0.01) and more lung metastases (n = 3, P <0.05) compared to normoxic cells. We conclude that hypoxia increases TF expression by malignant cells which enhances tumor cell-platelet binding and hematogenous metastasis. Hypoxia-induced upregulation of TF appears to parallel that of VEGF, although the mechanism remains unclear. PMID:9798977

  13. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability

    PubMed Central

    Aslam, Muhammad; Paddenberg, Renate; Quanz, Karin; Chang, Chia L.; Park, Jae-Il; Gries, Barbara; Rafiq, Amir; Faulhammer, Petra; Goldenberg, Anna; Papadakis, Tamara; Noll, Thomas; Hsu, Sheau Y. T.; Weissmann, Norbert; Kummer, Wolfgang

    2009-01-01

    Accumulating evidence suggests a pivotal role of the calcitonin receptor-like receptor (CRLR) signaling pathway in preventing damage of the lung by stabilizing pulmonary barrier function. Intermedin (IMD), also termed adrenomedullin-2, is the most recently identified peptide targeting this receptor. Here we investigated the effect of hypoxia on the expression of IMD in the murine lung and cultured murine pulmonary microvascular endothelial cells (PMEC) as well as the role of IMD in regulating vascular permeability. Monoclonal IMD antibodies were generated, and transcript levels were assayed by quantitative RT-PCR. The promoter region of IMD gene was analyzed, and the effect of hypoxia-inducible factor (HIF)-1α on IMD expression was investigated in HEK293T cells. Isolated murine lungs and a human lung microvascular endothelial cell monolayer model were used to study the effect of IMD on vascular permeability. IMD was identified as a pulmonary endothelial peptide by immunohistochemistry and RT-PCR. Hypoxia caused an upregulation of IMD mRNA in the murine lung and PMEC. As shown by these results, HIF-1α enhances IMD promoter activity. Our functional studies showed that IMD abolished the increase in pressure-induced endothelial permeability. Moreover, IMD decreased basal and thrombin-induced hyperpermeability of an endothelial cell monolayer in a receptor-dependent manner and activated PKA in these cells. In conclusion, IMD is a novel hypoxia-induced gene and a potential interventional agent for the improvement of endothelial barrier function in systemic inflammatory responses and hypoxia-induced vascular leakage. PMID:19684198

  14. Hypoxia-induced hypothermia mediated by GABA in the rostral parapyramidal area of the medulla oblongata.

    PubMed

    Osaka, T

    2014-05-16

    Hypoxia evokes a regulated decrease in the body core temperature (Tc) in a variety of animals. The neuronal mechanisms of this response include, at least in part, glutamatergic activation in the lateral preoptic area (LPO) of the hypothalamus. As the sympathetic premotor neurons in the medulla oblongata constitute a cardinal relay station in the descending neuronal pathway from the hypothalamus for thermoregulation, their inhibition can also be critically involved in the mechanisms of the hypoxia-induced hypothermia. Here, I examined the hypothesis that hypoxia-induced hypothermia is mediated by glutamate-responsive neurons in the LPO that activate GABAergic transmission in the rostral raphe pallidus (rRPa) and neighboring parapyramidal region (PPy) of the medulla oblongata in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. Unilateral microinjection of GABA (15nmol) into the rRPa and PPy regions elicited a prompt increase in tail skin temperature (Ts) and decreases in Tc, oxygen consumption rate (VO2), and heart rate. Next, when the GABAA receptor blocker bicuculline methiodide (bicuculline methiodide (BMI), 10pmol) alone was microinjected into the rRPa, it elicited unexpected contradictory responses: simultaneous increases in Ts, VO2 and heart rate and a decrease in Tc. Then, when BMI was microinjected bilaterally into the PPy, no direct effect on Ts was seen; and thermogenic and tachycardic responses were slight. However, pretreatment of the PPy with BMI, but not vehicle saline, greatly attenuated the hypothermic responses evoked by hypoxic (10%O2-90%N2, 5min) ventilation or bilateral microinjections of glutamate (5nmol, each side) into the LPO. The results suggest that hypoxia-induced hypothermia was mediated, at least in part, by the activation of GABAA receptors in the PPy. PMID:24607346

  15. Cytoprotective effects of fisetin against hypoxia-induced cell death in PC12 cells.

    PubMed

    Chen, Pei-Yi; Ho, Yi-Ru; Wu, Ming-Jiuan; Huang, Shun-Ping; Chen, Po-Kong; Tai, Mi-Hsueh; Ho, Chi-Tang; Yen, Jui-Hung

    2015-01-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), a flavonol compound of flavonoids, exhibits a broad spectrum of biological activities including anti-oxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The aim of this study is to investigate the cytoprotective effect of fisetin and the underlying molecular mechanism against hypoxia-induced cell death in PC12 cells. The results of this study showed that fisetin significantly restored the cell viability of PC12 cells under both cobalt chloride (CoCl₂)- and low oxygen-induced hypoxic conditions. Treatment with fisetin successfully reduced the CoCl₂-mediated reactive oxygen species (ROS) production, which was accompanied by an increase in the cell viability of PC12 cells. Furthermore, we found that treatment of PC12 cells with fisetin markedly upregulated hypoxia-inducible factor 1α (HIF-1α), its nuclear accumulation and the hypoxia-response element (HRE)-driven transcriptional activation. The fisetin-mediated cytoprotection during CoCl₂ exposure was significantly attenuated through the administration of HIF-1α siRNA. Moreover, we demonstrated that MAPK/ERK kinase 1/2 (MEK1/2), p38 MAPK and phosphatidylinositol 3-kinase (PI3 K) inhibitors significantly blocked the increase in cell survival that was induced by fisetin treatment under hypoxic conditions. Consistently, increased phosphorylation of ERK, p38 and Akt proteins was observed in PC12 cells treated with fisetin. However, the fisetin-induced HRE-driven transcription was not affected by inhibition of these kinase signaling pathways. Current results reveal for the first time that fisetin promotes cell survival and protects against hypoxia-induced cell death through ROS scavenging and the activation of HIF1α-, MAPK/ERK-, p38 MAPK- and PI3 K/Akt-dependent signaling pathways in PC12 cells.

  16. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  17. Regression of Copper-Deficient Heart Hypertrophy: Reduction in the Size of Hypertrophic Cardiomyocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary copper deficiency causes cardiac hypertrophy and its transition to heart failure in a mouse model. Copper repletion results in a rapid regression of cardiac hypertrophy and prevention of heart failure. The present study was undertaken to understand dynamic changes of cardiomyocytes in the hy...

  18. Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGFBP3 in cancer.

    PubMed

    Le Jan, Sébastien; Le Meur, Nolwenn; Cazes, Aurélie; Philippe, Josette; Le Cunff, Martine; Léger, Jean; Corvol, Pierre; Germain, Stéphane

    2006-06-12

    By triggering an adaptive response to hypoxia which is a common feature of tumor microenvironments, endothelial cells contribute to the onset of angiogenic responses involved in tumor growth. Therefore, identifying hypoxic markers represent a challenge for a better understanding of tumor angiogenesis and for the optimization of anti-angiogenic therapeutic strategy. Using representational difference analysis combined with microarray, we here report the identification of 133 hypoxia-induced transcripts in human microendothelial cells (HMEC-1). By Northern blot, we confirm hypoxia-induced expression of insulin-like growth factor binding protein 3 (igfbp3), thioredoxin-interacting protein (txnip), neuritin (nrn1). Finally, by performing in situ hybridization on several types of human tumors, we provide evidence for nrn1 and txnip as hypoxic perinecrotic markers and for igfbp3 as a tumor endothelial marker. We propose these hypoxia-induced genes could represent relevant prognostic tools and targets for therapeutic intervention in cancers. PMID:16723126

  19. Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish

    PubMed Central

    Dahl Ejby Jensen, Lasse; Cao, Renhai; Hedlund, Eva-Maria; Söll, Iris; Lundberg, Jon O.; Hauptmann, Giselbert; Steffensen, John Fleng; Cao, Yihai

    2009-01-01

    The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system. PMID:19822749

  20. Apelin Protects Primary Rat Retinal Pericytes from Chemical Hypoxia-Induced Apoptosis

    PubMed Central

    Chen, Li; Tao, Yong; Feng, Jing; Jiang, Yan Rong

    2015-01-01

    Pericytes are a population of cells that participate in normal vessel architecture and regulate permeability. Apelin, as the endogenous ligand of G protein-coupled receptor APJ, participates in a number of physiological and pathological processes. To date, the effect of apelin on pericyte is not clear. Our study aimed to investigate the potential protection mechanisms of apelin, with regard to primary rat retinal pericytes under hypoxia. Immunofluorescence staining revealed that pericytes colocalized with APJ in the fibrovascular membranes dissected from proliferative diabetic retinopathy patients. In the in vitro studies, we first demonstrated that the expression of apelin/APJ was upregulated in pericytes under hypoxia, and apelin increased pericytes proliferation and migration. Moreover, knockdown of apelin in pericyte was achieved via lentivirus-mediated RNA interference. After the inhibition of apelin, pericytes proliferation was inhibited significantly in hypoxia culture condition. Furthermore, exogenous recombinant apelin effectively prevented hypoxia-induced apoptosis through downregulating active-caspase 3 expression and increasing the ratio of B cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax) in pericytes. These results suggest that apelin suppressed hypoxia-induced pericytes injury, which indicated that apelin could be a potential therapeutic target for retinal angiogenic diseases. PMID:26491547

  1. HYPOXIA-INDUCED CHANGES IN PULMONARY AND SYSTEMIC VASCULAR RESISTANCE: WHERE IS THE O2 SENSOR?

    PubMed Central

    Waypa, Gregory B.; Schumacker, Paul T.

    2010-01-01

    Pulmonary arteries (PA) constrict in response to alveolar hypoxia, whereas systemic arteries (SA) undergo dilation. These physiological responses reflect the need to improve gas exchange in the lung, and to enhance the delivery of blood to hypoxic systemic tissues. An important unresolved question relates to the underlying mechanism by which the vascular cells detect a decrease in oxygen tension and translate that into a signal that triggers the functional response. A growing body of work implicates the mitochondria, which appear to function as O2 sensors by initiating a redox-signaling pathway that leads to the activation of downstream effectors that regulate vascular tone. However, the direction of this redox signal has been the subject of controversy. Part of the problem has been the lack of appropriate tools to assess redox signaling in live cells. Recent advancements in the development of redox sensors have led to studies that help to clarify the nature of the hypoxia-induced redox signaling by reactive oxygen species (ROS). Moreover, these studies provide valuable insight regarding the basis for discrepancies in earlier studies of the hypoxia-induced mechanism of redox signaling. Based on recent work, it appears that the O2 sensing mechanism in both the PA and SA are identical, that mitochondria function as the site of O2 sensing, and that increased ROS release from these organelles leads to the activation of cell-specific, downstream vascular responses. PMID:20713189

  2. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

    PubMed Central

    Zhou, Tian-yi; Zhuang, Lin-han; Hu, Yan; Zhou, Yu-lu; Lin, Wen-kai; Wang, Dan-dan; Wan, Zi-qian; Chang, Lin-lin; Chen, Ying; Ying, Mei-dan; Chen, Zi-bo; Ye, Song; Lou, Jian-shu; He, Qiao-jun; Zhu, Hong; Yang, Bo

    2016-01-01

    Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients. PMID:27476430

  3. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells.

    PubMed

    Zhou, Tian-Yi; Zhuang, Lin-Han; Hu, Yan; Zhou, Yu-Lu; Lin, Wen-Kai; Wang, Dan-Dan; Wan, Zi-Qian; Chang, Lin-Lin; Chen, Ying; Ying, Mei-Dan; Chen, Zi-Bo; Ye, Song; Lou, Jian-Shu; He, Qiao-Jun; Zhu, Hong; Yang, Bo

    2016-01-01

    Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients. PMID:27476430

  4. Hypoxia Induces Autophagy through Translational Up-Regulation of Lysosomal Proteins in Human Colon Cancer Cells

    PubMed Central

    Lai, Ming-Chih; Chang, Chiao-May; Sun, H. Sunny

    2016-01-01

    Hypoxia occurs in a wide variety of physiological and pathological conditions, including tumorigenesis. Tumor cells have to adapt to hypoxia by altering their gene expression and protein synthesis. Here, we showed that hypoxia inhibits translation through activation of PERK and inactivation of mTOR in human colon cancer HCT116 cells. Prolonged hypoxia (1% O2, 16 h) dramatically inhibits general translation in HCT116 cells, yet selected mRNAs remain efficiently translated under such a condition. Using microarray analysis of polysome- associated mRNAs, we identified a large number of hypoxia-regulated genes at the translational level. Efficiently translated mRNAs during hypoxia were validated by polysome profiling and quantitative real-time RT-PCR. Pathway enrichment analysis showed that many of the up-regulated genes are involved in lysosome, glycan and lipid metabolism, antigen presentation, cell adhesion, and remodeling of the extracellular matrix and cytoskeleton. The majority of down-regulated genes are involved in apoptosis, ubiquitin-mediated proteolysis, and oxidative phosphorylation. Further investigation showed that hypoxia induces lysosomal autophagy and mitochondrial dysfunction through translational regulation in HCT116 cells. The abundance of several translation factors and the mTOR kinase activity are involved in hypoxia-induced mitochondrial autophagy in HCT116 cells. Our studies highlight the importance of translational regulation for tumor cell adaptation to hypoxia. PMID:27078027

  5. Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition

    PubMed Central

    2015-01-01

    To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin’s structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers. PMID:26394152

  6. Hypoxia induced the differentiation of Tbx18-positive epicardial cells to CoSMCs

    PubMed Central

    Jing, Xiaodong; Gao, Yulin; Xiao, Songlin; Qin, Qin; Wei, Xiaoming; Yan, Yuling; Wu, Ling; Deng, Songbai; Du, Jianlin; Liu, Yajie; She, Qiang

    2016-01-01

    Understanding the origin and differentiation mechanism of coronary vascular smooth muscle cells (CoSMCs) is very important to cardiovascular biology. The early cardiovascular system is formed in a hypoxic microenvironment, and Tbx18-positive epicardial cells are a source of CoSMCs. However, the effects of hypoxia on the differentiation of Tbx18-positive epicardial cells to CoSMCs and the primary regulatory mechanism are insufficiently understood. Using Tbx18:Cre/R26REYFP/LacZ fate-tracing mice, we cultured highly purified Tbx18-positive epicardial cells. We further showed that hypoxia induced Tbx18-positive epicardial cells to differentiate into CoSMCs and promoted the epithelial-mesenchymal transition (EMT) process of the cells in vitro. The induction of differentiation was primarily achieved via the hypoxia inducible factor-1α (HIF-1α)-mediated effects exerted on Snail. Using a cell migration assay, we showed that hypoxia enhanced the motility of Tbx18-positive epicardial cells. By constructing a hypoxic model of the embryonic epicardium in vivo, we showed that hypoxia led to premature in situ differentiation of Tbx18-positive epicardial cells to CoSMCs. Furthermore, hypoxia was sufficient to induce Snail expression in Tbx18-positive epicardial cells in vivo. Our study suggests that hypoxia intervention was sufficient to induce the differentiation of Tbx18-positive epicardial cells to CoSMCs. Furthermore, this differentiation was achieved primarily via HIF-1α-mediated regulation of Snail. PMID:27456656

  7. Curcumin inhibits hypoxia-induced migration in K1 papillary thyroid cancer cells

    PubMed Central

    Tan, Cheng; Zhang, Li; Cheng, Xian; Lin, Xiu-Feng; Lu, Rong-Rong; Bao, Jian-Dong

    2014-01-01

    Curcumin, traditionally used as food and medicinal purposes, has recently been reported to have protective efficacy against hypoxia. Hypoxia is one of the important reactive factors in tumor metastasis, which is a key problem in clinical thyroid cancer therapy. In present study, we investigate the anti-metastatic effect of curcumin on the K1 papillary thyroid cancer cells as well as its potential mechanisms. The results show that curcumin effectively inhibits hypoxia-induced reactive oxygen species (ROS) upregulation and significantly decreases the mRNA and protein expression levels of hypoxia-inducible factor-1α (HIF-1α) in K1 cells. Curcumin also decreases the DNA binding ability of HIF-1α to hypoxia response element (HRE). Furthermore, curcumin enhances E-cadherin expression, inhibits metalloproteinase-9 (MMP-9) enzyme activity, and weakens K1 cells migration under hypoxic conditions. In summary, these results indicate that curcumin possesses a potent anti-metastatic effect and might be an effective tumoristatic agent for the treatment of aggressive papillary thyroid cancers. PMID:25349216

  8. Hypoxia-Induced Endothelial Progenitor Cell Function Is Blunted in Angiotensinogen Knockout Mice

    PubMed Central

    Choi, Jin-Hwa; Nguyen, Minh-Phuong; Lee, Dongjin; Oh, Goo-Taeg; Lee, You-Mie

    2014-01-01

    Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT+/−) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT+/− EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT+/− EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT+/− early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT+/− EPCs. In AGT+/− mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis. PMID:24938229

  9. p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death

    PubMed Central

    Feng, Xi; Liu, Xing; Zhang, Wei; Xiao, Wuhan

    2011-01-01

    Hypoxia stabilizes the tumour suppressor p53, allowing it to function primarily as a transrepressor; however, the function of p53 during hypoxia remains unclear. In this study, we showed that p53 suppressed BNIP3 expression by directly binding to the p53-response element motif and recruiting corepressor mSin3a to the BNIP3 promoter. The DNA-binding site of p53 must remain intact for the protein to suppress the BNIP3 promoter. In addition, taking advantage of zebrafish as an in vivo model, we confirmed that zebrafish nip3a, a homologous gene of mammalian BNIP3, was indeed induced by hypoxia and p53 mutation/knockdown enhanced nip3a expression under hypoxia resulted in cell death enhancement in p53 mutant embryos. Furthermore, p53 protected against hypoxia-induced cell death mediated by p53 suppression of BNIP3 as illustrated by p53 knockdown/loss assays in both human cell lines and zebrafish model, which is in contrast to the traditional pro-apoptotic role of p53. Our results suggest a novel function of p53 in hypoxia-induced cell death, leading to the development of new treatments for ischaemic heart disease and cerebral stoke. PMID:21792176

  10. Involvement of Hypoxia-Inducible Factors in the Dysregulation of Oxygen Homeostasis in Sepsis

    PubMed Central

    Hirota, Kiichi

    2015-01-01

    Sepsis is a state of infection with serious systemic manifestations, and if severe enough, can be associated with multiple organ dysfunction and systemic hypotension, which can cause tissues to be hypoxic. Inflammation, as part of the multifaceted biological response to injurious stimuli, such as pathogens or damaged tissues and cells, underlies these biological processes. Prolonged and persistent inflammation, also known as chronic inflammation, results in progressive alteration in the various types of cells at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue during the process. Tissue hypoxia during inflammation is not just a simple bystander process, but can considerably affect the development or attenuation of inflammation by causing the regulation of hypoxia-dependent gene expression. Indeed, the study of transcriptionally regulated tissue adaptation to hypoxia requires intense investigation to help control hypoxia-induced inflammation and organ failure. In this review, I have described the pathophysiology of sepsis with respect to oxygen metabolism and expression of hypoxia-inducible factor 1. PMID:25567333

  11. Hypoxia induces TFE3 expression in head and neck squamous cell carcinoma

    PubMed Central

    Sun, Zhi-Jun; Yu, Guang-Tao; Huang, Cong-Fa; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Zhang, Wen-Feng; Liu, Bing; Zhang, Lu

    2016-01-01

    To assess the role of transcription factor μE3 (TFE3) in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), human HNSCC tissue arrays were investigated for TFE3 expression. Human HNSCC tissues with neoadjuvant inductive chemotherapey (docetaxel, cisplatin and fluorouracil, TPF) and mice HNSCC tissues from transgenic mice model were evaluated for TFE3 expression and the hypoxia pathway. The roles of EGF/EGFR mediated hypoxia in TFE3 nuclear expression were analyzed in vitro and in vivo. TFE3 expression was higher in human HNSCC tissues compared with that in normal oral mucosa. Moreover, high TFE3 expression was related to HIF-1α, PAI-1, and EGFR, which demonstrated the activation of the hypoxia pathway in HNSCC tissues. Furthermore, elevated TFE3 expression was observed in HNSCC after cisplatin-based chemotherapy, and high TFE3 expression may indicate poor response to TPF inductive chemotherapy. Furthermore, similar changes with increased TFE3 were observed in HNSCC of the transgenic mouse HNSCC model. Hypoxic culture in the human HNSCC cell line increased TFE3 expression, which promoted cell survival under hypoxia. EGFR inhibiton by cetuximab could attenuate hypoxia-induced TFE3 in the HNSCC cell line and transgenic mouse HNSCC model. These findings indicated that TFE3 was an important hypoxia-induced transcriptional factor in HNSCC. TFE3 could be regarded as a durgable therapeutic oncotarget by EGFR inhibition. PMID:26872381

  12. The Hypoxia-Inducible Factor 1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia▿

    PubMed Central

    Martorell, Lluis; Gentile, Maurizio; Rius, Jordi; Rodríguez, Cristina; Crespo, Javier; Badimon, Lina; Martínez-González, José

    2009-01-01

    Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1α protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca2+ was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia. PMID:19720740

  13. Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

    PubMed Central

    Villegas, Leah R.; Kluck, Dylan; Field, Carlie; Oberley-Deegan, Rebecca E.; Woods, Crystal; Yeager, Michael E.; El Kasmi, Karim C.; Savani, Rashmin C.; Bowler, Russell P.

    2013-01-01

    Abstract Aims: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species, such as superoxide (O2•−), contribute to the pathogenesis of PH and vascular responses, including vascular remodeling and inflammation. This study sought to investigate the protective role of a pharmacological catalytic antioxidant, a superoxide dismutase (SOD) mimetic (MnTE-2-PyP), in hypoxia-induced PH, vascular remodeling, and NALP3 (NACHT, LRR, and PYD domain-containing protein 3)–mediated inflammation. Results: Mice (C57/BL6) were exposed to hypobaric hypoxic conditions, while subcutaneous injections of MnTE-2-PyP (5 mg/kg) or phosphate-buffered saline (PBS) were given 3× weekly for up to 35 days. SOD mimetic-treated groups demonstrated protection against increased right ventricular systolic pressure, indirect measurements of pulmonary artery pressure, and RV hypertrophy. Vascular remodeling was assessed by Ki67 staining to detect vascular cell proliferation, α-smooth muscle actin staining to analyze small vessel muscularization, and hyaluronan (HA) measurements to assess extracellular matrix modulation. Activation of the NALP3 inflammasome pathway was measured by NALP3 expression, caspase-1 activation, and interleukin 1-beta (IL-1β) and IL-18 production. Hypoxic exposure increased PH, vascular remodeling, and NALP3 inflammasome activation in PBS-treated mice, while mice treated with MnTE-2-PyP showed an attenuation in each of these endpoints. Innovation: This study is the first to demonstrate activation of the NALP3 inflammasome with cleavage of caspase-1 and release of active IL-1 β and IL-18 in chronic hypoxic PH, as well as its attenuation by the SOD mimetic, MnTE-2-PyP. Conclusion: The ability of the SOD mimetic to scavenge extracellular O2•− supports our previous observations in EC-SOD-overexpressing mice that implicate extracellular oxidant/antioxidant imbalance in hypoxic PH

  14. Expression of hypoxia-inducible factor 1α mRNA in hearts and lungs of broiler chickens with ascites syndrome induced by excess salt in drinking water.

    PubMed

    Zhang, Jianjun; Feng, Xuejian; Zhao, Lihong; Wang, Wei; Gao, Mingyu; Wu, Boning; Qiao, Jian

    2013-08-01

    Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed heterodimeric transcription factor that mediates adaptive responses to hypoxia in all nucleated cells of metazoan organisms. Hypoxia-inducible factor 1α is involved in the pathogenesis of pulmonary hypertension in humans and animals, but whether HIF-1α is associated with the development of pulmonary hypertension syndrome (also known as ascites syndrome, AS) in broiler chickens has not been determined. In the present paper we addressed this issue by measuring the expression of HIF-1α mRNA in hearts and lungs of broiler chickens with AS induced by excess salt in drinking water. We conducted 2 experiments. The first experiment was used to observe the effects of excess salt on AS incidence. The results indicated that total incidence (20%) of AS in excess salt group (receiving 0.3% NaCl in drinking water) was much higher compared with the control group (receiving tap water) over a 43-d time course (P < 0.05). In the second experiment, we determined mean pulmonary arterial pressure (mPAP), ascites heart index (AHI), and expression of HIF-1α mRNA in lungs and hearts of broiler chickens after the excess salt treatment. Our results showed that excess salt induced pulmonary hypertension (indicated by higher mPAP) and right ventricular hypertrophy (greater ascites heart index) in broiler chickens. Meanwhile, the expression levels of HIF-1α mRNA in lungs and hearts were significantly increased at different time points in the excess salt group compared with the control group. Linear correlation analysis showed that the expression of HIF-1α mRNA in lungs was significantly positively correlated with mPAP (correlation coefficient = 0.79, P < 0.001), demonstrating that expression of HIF-1α mRNA was gradually increased in the excess salt group with the increase of pulmonary arterial pressure. In addition, the ascitic chickens showed significantly higher transcriptional levels of HIF-1α in hearts and lungs

  15. Left ventricular hypertrophy index based on a combination of frontal and transverse planes in the ECG and VCG: Diagnostic utility of cardiac vectors

    NASA Astrophysics Data System (ADS)

    Bonomini, Maria Paula; Juan Ingallina, Fernando; Barone, Valeria; Antonucci, Ricardo; Valentinuzzi, Max; Arini, Pedro David

    2016-04-01

    The changes that left ventricular hypertrophy (LVH) induces in depolarization and repolarization vectors are well known. We analyzed the performance of the electrocardiographic and vectorcardiographic transverse planes (TP in the ECG and XZ in the VCG) and frontal planes (FP in the ECG and XY in the VCG) to discriminate LVH patients from control subjects. In an age-balanced set of 58 patients, the directions and amplitudes of QRS-complexes and T-wave vectors were studied. The repolarization vector significantly decreased in modulus from controls to LVH in the transverse plane (TP: 0.45±0.17mV vs. 0.24±0.13mV, p<0.0005 XZ: 0.43±0.16mV vs. 0.26±0.11mV, p<0.005) while the depolarization vector significantly changed in angle in the electrocardiographic frontal plane (Controls vs. LVH, FP: 48.24±33.66° vs. 46.84±35.44°, p<0.005, XY: 20.28±35.20° vs. 19.35±12.31°, NS). Several LVH indexes were proposed combining such information in both ECG and VCG spaces. A subset of all those indexes with AUC values greater than 0.7 was further studied. This subset comprised four indexes, with three of them belonging to the ECG space. Two out of the four indexes presented the best ROC curves (AUC values: 0.78 and 0.75, respectively). One index belonged to the ECG space and the other one to the VCG space. Both indexes showed a sensitivity of 86% and a specificity of 70%. In conclusion, the proposed indexes can favorably complement LVH diagnosis

  16. Hypoxia-induced expression of RTEF-1 (related transcriptional enhancer factor-1) in endothelial cells is independent of HIF-1 (hypoxia-inducible factor-1)

    SciTech Connect

    Zhang, Cuili; Song, Q.H.; Li, Jian; Tian, Ye

    2009-04-10

    Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in transcriptional regulation of angiogenic genes in hypoxic endothelial cells. The mechanisms involved in the induction of RTEF-1 expression in hypoxia are poorly understood. In bovine aortic endothelial cells (BAEC) subjected to hypoxia, Western blot and quantitative PCR analysis revealed that RTEF-1 protein and mRNA levels were significantly increased by hypoxia. To address the potential role of the hypoxia-inducible factor-1 (HIF-1) in RTEF-1 induction, a hepatoma cell line deficient in HIF-1 (c4) and a control HIF-1 positive cell line (vT{l_brace}2{r_brace}) were exposed to hypoxia. We report that RTEF-1 protein expression assessed by either Western blotting or immunofluorescence was increased in both cell lines. This demonstrates that HIF-1 is not required for RTEF-1 upregulation by hypoxia. Conversely, RTEF-1 appeared to regulate the expression of HIF-1: HIF-1{alpha} promoter activity was increased (3.6-fold) by RTEF-1 overexpression in BAEC. Furthermore, RTEF-1 enhanced BAEC proliferation and tubule formation; these were inhibited by RTEF-1 knockdown with siRNA. We propose that RTEF-1, acting via HIF-1, is a key regulator of angiogenesis in response to hypoxia.

  17. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha.

    PubMed

    Yuan, Yong; Hilliard, George; Ferguson, Tsuneo; Millhorn, David E

    2003-05-01

    The hypoxia-inducible factor (HIF) activates the expression of genes that contain a hypoxia response element. The alpha-subunits of the HIF transcription factors are degraded by proteasomal pathways during normoxia but are stabilized under hypoxic conditions. The von Hippel-Lindau protein (pVHL) mediates the ubiquitination and rapid degradation of HIF-alpha (including HIF-1alpha and HIF-2alpha). Post-translational hydroxylation of a proline residue in the oxygen-dependent degradation (ODD) domain of HIF-alpha is required for the interaction between HIF and VHL. It has previously been established that cobalt mimics hypoxia and causes accumulation of HIF-1alpha and HIF-2alpha. However, little is known about the mechanism by which this occurs. In an earlier study, we demonstrated that cobalt binds directly to the ODD domain of HIF-2alpha. Here we provide the first evidence that cobalt inhibits pVHL binding to HIF-alpha even when HIF-alpha is hydroxylated. Deletion of 17 amino acids within the ODD domain of HIF-2alpha that are required for pVHL binding prevented the binding of cobalt and stabilized HIF-2alpha during normoxia. These findings show that cobalt mimics hypoxia, at least in part, by occupying the VHL-binding domain of HIF-alpha and thereby preventing the degradation of HIF-alpha. PMID:12606543

  18. Splice-variant changes of the CaV3.2 T-type calcium channel mediate voltage-dependent facilitation and associate with cardiac hypertrophy and development

    PubMed Central

    David, Laurence S; Garcia, Esperanza; Cain, Stuart M; Thau, Elana M; Tyson, John R

    2010-01-01

    Low voltage-activated T-type calcium (Ca) channels contribute to the normal development of the heart and are also implicated in pathophysiological states such as cardiac hypertrophy. Functionally distinct T-type Ca channel isoforms can be generated by alternative splicing from each of three different T-type genes (CaV3.1, CaV3.2, CaV3.3), although it remains to be described whether specific splice variants are associated with developmental states and pathological conditions. We aimed to identify and functionally characterize CaV3.2 T-type Ca channel alternatively spliced variants from newborn animals and to compare with adult normotensive and spontaneously hypertensive rats (SHR). DNA sequence analysis of full-length CaV3.2 cDNA generated from newborn heart tissue identified ten major regions of alternative splicing, the more common variants of which were analyzed by quantitative real-time PCR (qRT-PCR) and also subject to functional examination by whole-cell patch clamp. The main findings are that: (1) cardiac CaV3.2 T-type Ca channels are subject to considerable alternative splicing, (2) there is preferential expression of CaV3.2(−25) splice variant channels in newborn rat heart with a developmental shift in adult heart that results in approximately equal levels of expression of both (+25) and (−25) exon variants, (3) in the adult stage of hypertensive rats there is both an increase in overall CaV3.2 expression and a shift towards expression of CaV3.2(+25) containing channels as the predominant form and (4) alternative splicing confers a variant-specific voltage-dependent facilitation of CaV3.2 channels. We conclude that CaV3.2 alternative splicing generates significant T-type Ca channel structural and functional diversity with potential implications relevant to cardiac developmental and pathophysiological states. PMID:20699644

  19. Identification of crucial microRNAs and genes in hypoxia-induced human lung adenocarcinoma cells

    PubMed Central

    Geng, Ying; Deng, Lili; Su, Dongju; Xiao, Jinling; Ge, Dongjie; Bao, Yongxia; Jing, Hui

    2016-01-01

    Background Variations of microRNA (miRNA) expression profile in hypoxic lung cancer cells have not been studied so far. Therefore, using miRNA microarray technology, this study aimed to study the miRNA expression profile and investigate the potential crucial miRNAs and their target genes in hypoxia-induced human lung adenocarcinoma cells. Materials and methods Based on miRNA microarray, miRNA expression profiling of hypoxia-induced lung adenocarcinoma A549 cells was obtained. After identification of differentially expressed miRNAs (DE-miRNAs) in hypoxic cells, target genes of DE-miRNAs were predicted, and functional enrichment analysis of targets was conducted. Furthermore, the expression levels of DE-miRNAs and their target genes were validated by real-time quantitative polymerase chain reaction. In addition, using miRNA mimics, the effect of overexpressed DE-miRNAs on A549 cell behaviors (cell proliferation, cell cycle, and apoptosis) was evaluated. Results In total, 14 DE-miRNAs (nine upregulated miRNAs and five downregulated miRNAs) were identified in hypoxic cells, compared with normoxic cells. Target genes of both upregulated and downregulated miRNAs were enriched in the functions such as chromatin modification, and pathways such as Wnt signaling pathway and transforming growth factor (TGF)-β signaling pathway. The expression levels of several miRNAs and their target genes were confirmed, including hsa-miR-301b/FOXF2, hsa-miR-148b-3p/WNT10B, hsa-miR-769-5p/(SMAD2, ARID1A), and hsa-miR-622. Among them, hsa-miR-301b was verified to regulate FOXF2, and hsa-miR-769-5p was verified to modulate ARID1A. In addition, the overexpression of hsa-miR-301b and hsa-miR-769-5p significantly affected the cell cycle of A549 cells, but not cell proliferation and apoptosis. Conclusion miRNA expression profile was changed in hypoxia-induced lung cancer cells. Those validated miRNAs and genes may play crucial roles in the response of lung cancer cells to hypoxia. PMID:27524914

  20. Hypoxia-induced neuronal apoptosis is mediated by de novo synthesis of ceramide through activation of serine palmitoyltransferase.

    PubMed

    Kang, Mi Sun; Ahn, Kyong Hoon; Kim, Seok Kyun; Jeon, Hyung Jun; Ji, Jung Eun; Choi, Jong Min; Jung, Kwang Mook; Jung, Sung Yun; Kim, Dae Kyong

    2010-04-01

    Cellular hypoxia can lead to cell death or adaptation and has important effects on development, physiology, and pathology. Here, we investigated the role and regulation of ceramide in hypoxia-induced apoptosis of SH-SY5Y neuroblastoma cells. Hypoxia increased the ceramide concentration; subsequently, we observed biochemical changes indicative of apoptosis, such as DNA fragmentation, nuclear staining, and poly ADP-ribose polymerase (PARP) cleavage. The hypoxic cell death was potently inhibited by a caspase inhibitor, zVAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone). l-Cycloserine, a serine palmitoyltransferase (SPT) inhibitor, and fumonisin B(1) (FB(1)), a ceramide synthase inhibitor, inhibited the hypoxia-induced increase in ceramide, indicating that the increase occurred via the de novo pathway. Hypoxia increased the activity and protein levels of SPT2, suggesting that the hypoxia-induced increase in ceramide is due to the transcriptional up-regulation of SPT2. Specific siRNA of SPT2 prevented hypoxia-induced cell death and ceramide production. However, hypoxia also increased the cellular level of glucosylceramide, which was inhibited by a glucosylceramide synthase (GCS) inhibitor and specific siRNA, but not a ceramidase inhibitor. The increase in glucosylceramide was accompanied by increases in both PARP cleavage and DNA fragmentation. Together, the current results suggest that both SPT and GCS may regulate the cellular level of ceramide, and thus may be critical enzymes for deciding the fate of the cells exposed to hypoxia.

  1. Inhibitory effect of Bailing capsule on hypoxia-induced proliferation of rat pulmonary arterial smooth muscle cells

    PubMed Central

    Li, Xiaohui; Peng, Kejun; Zhou, Yutian; Deng, Fengmei; Ma, Jiao

    2016-01-01

    Objectives: To investigated the effects of Bailing capsule on hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). Methods: This prospective study was performed at the Central Laboratory, Chengdu Medical College, Chengdu, China between April 2012 and November 2014. Ten healthy adult male Wistar rats were administrated with gastric perfusion of Bailing capsule to obtain serum containing the tested drugs. Proliferation of pulmonary arterial smooth muscle cells proliferation was measured using cell counting kit-8 assay. Production of reactive oxygen species (ROS) in rat PASMCs was determined through a fluorometric assay, whereas production of endothelin-1 (ET-1) was detected by ELISA and quantitative real-time PCR (qRT-PCR). Expression of proliferating cell nuclear antigen (PCNA), c-fos, and c-jun in PASMCs was also determined using immunohistochemistry staining and qRT-PCR. Results: We observed that the medicated serum obviously inhibited hypoxia-induced cell proliferation in a concentration-dependent manner. Moreover, the medicated serum significantly reduced hypoxia-induced production of ROS and ET-1, as well as expression of PCNA, c-fos, and c-jun, in PASMCs. Conclusion: Results demonstrated that Bailing capsule can inhibit hypoxia-induced PASMC proliferation possibly by suppressing ET-1 and ROS production and by inhibiting expression of PCNA, c-fos, and c-jun. These results suggest that Bailing possess antiproliferative property, which is probably one of the underlying mechanisms of Bailing capsule for the clinical treatment of chronic obstructive pulmonary disease. PMID:27146611

  2. Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells.

    PubMed

    Schödel, Johannes; Bohr, Daniela; Klanke, Bernd; Schley, Gunnar; Schlötzer-Schrehardt, Ursula; Warnecke, Christina; Kurtz, Armin; Amann, Kerstin; Eckardt, Kai-Uwe; Willam, Carsten

    2010-11-01

    The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and -independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia-inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1α expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia-inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and -independent mechanisms.

  3. TIPE2 Inhibits Hypoxia-Induced Wnt/β-Catenin Pathway Activation and EMT in Glioma Cells.

    PubMed

    Liu, Zhi-Jun; Liu, Hong-Lin; Zhou, Hai-Cun; Wang, Gui-Cong

    2016-01-01

    Hypoxia-induced epithelial-to-mesenchymal transition (EMT) could facilitate tumor progression. TIPE2, the tumor necrosis factor-α (TNF-α)-induced protein 8-like 2 (also known as TNFAIP8L2), is a member of the TNF-α-induced protein 8 (TNFAIP8, TIPE) family and has been involved in the development and progression of several tumors. However, the effects of TIPE2 on the EMT process in glioma cells and the underlying mechanisms of these effects have not been previously reported. In our study, we assessed the roles of TIPE2 in the EMT process in glioma cells in response to hypoxia. Our results indicated that TIPE2 expression was significantly decreased in human glioma cell lines. TIPE2 overexpression significantly inhibited hypoxia-induced migration and invasion, as well as suppressed the EMT process in glioma cells. Furthermore, TIPE2 overexpression prevented hypoxia-induced expression of β-catenin, cyclin D1, and c-myc in human glioma cells. In summary, these data suggest that TIPE2 overexpression inhibited hypoxia-induced Wnt/β-catenin pathway activation and EMT in glioma cells. PMID:27656836

  4. Telmisartan regresses left ventricular hypertrophy in caveolin-1 deficient mice

    PubMed Central

    Kreiger, Marta H; Di Lorenzo, Annarita; Teutsch, Christine; Kauser, Katalin; Sessa, William C.

    2011-01-01

    The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known, however the role of the Ang II in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav- KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan, and cardiac function assessed by echocardiography. Treatment of Cav-1 KO mice with telmisartan significantly improved cardiac function compared to age-matched, vehicle treated Cav-1 KO mice, while telmisartan did not affected cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by telmisartan in Cav-1 KO but not WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides-A and –B, β-myosin heavy chain and TGF-β and telmisartan treatment normalized the expression of these genes. Telmisartan reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, telmisartan treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy. PMID:20585312

  5. Telmisartan regresses left ventricular hypertrophy in caveolin-1-deficient mice.

    PubMed

    Krieger, Marta H; Di Lorenzo, Annarita; Teutsch, Christine; Kauser, Katalin; Sessa, William C

    2010-11-01

    The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known; however, its role in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav-1 KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan (Telm), and cardiac function was assessed by echocardiography. Treatment of Cav-1 KO mice with Telm significantly improved cardiac function compared with age-matched vehicle-treated Cav-1 KO mice, whereas Telm did not affect cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by Telm in Cav-1 KO but not in WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides A and B, β-myosin heavy chain and TGF-β, and Telm treatment normalized the expression of these genes. Telm reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, Telm treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy. PMID:20585312

  6. Hypoxia-inducible factor-1α as a predictive marker in pre-eclampsia

    PubMed Central

    AKHILESH, MEENAKSHI; MAHALINGAM, VIVEKANANDA; NALLIAH, SIVALINGAM; ALI, ROSALINA MOHD; GANESALINGAM, MURALI; HALEAGRAHARA, NAGARAJA

    2013-01-01

    The aim of this study was to determine whether or not the increased levels of hypoxia-inducible factor-1α (HIF-1α) could be used to demonstrate failed placentation in pre-eclamptic mothers. Twenty pregnant females with (pre-eclampsia group) or without pre-eclampsia (control group) were included in the present study. Antenatal and post-delivery HIF-1α transcription factor levels were measured. A significant increase was observed in the HIF-1α levels in the pre- and post-natal pre-eclampsia mothers. The findings suggest that the levels of HIF-1α in the blood of mothers with pre-eclampsia decrease after delivery of the placenta. The results confirm that there is increased HIF-1α in pre-eclampsia and a steady increase in the levels of HIF-1α could be commensurate with the possibility of a patient developing pre-eclampsia at a later trimester. PMID:24648931

  7. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1.

    PubMed

    Ruthenborg, Robin J; Ban, Jae-Jun; Wazir, Anum; Takeda, Norihiko; Kim, Jung-Whan

    2014-09-01

    Wound healing is a complex multi-step process that requires spatial and temporal orchestration of cellular and non-cellular components. Hypoxia is one of the prominent microenvironmental factors in tissue injury and wound healing. Hypoxic responses, mainly mediated by a master transcription factor of oxygen homeostasis, hypoxia-inducible factor-1 (HIF-1), have been shown to be critically involved in virtually all processes of wound healing and remodeling. Yet, mechanisms underlying hypoxic regulation of wound healing are still poorly understood. Better understanding of how the wound healing process is regulated by the hypoxic microenvironment and HIF-1 signaling pathway will provide insight into the development of a novel therapeutic strategy for impaired wound healing conditions such as diabetic wound and fibrosis. In this review, we will discuss recent studies illuminating the roles of HIF-1 in physiologic and pathologic wound repair and further, the therapeutic potentials of HIF-1 stabilization or inhibition.

  8. Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity

    PubMed Central

    Kietzmann, Thomas; Mennerich, Daniela; Dimova, Elitsa Y.

    2016-01-01

    The hypoxia-inducible factor α-subunits (HIFα) are key transcription factors in the mammalian response to oxygen deficiency. The HIFα regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation and proteasomal degradation. However, HIF α-subunits also respond to various growth factors, hormones, or cytokines under normoxia indicating involvement of different kinase pathways in their regulation. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIFα regulating kinases are attractive therapeutic targets. Although numerous kinases were reported to regulate HIFα indirectly, direct phosphorylation of HIFα affects HIFα stability, nuclear localization, and transactivity. Herein, we review the role of phosphorylation-dependent HIFα regulation with emphasis on protein stability, subcellular localization, and transactivation. PMID:26942179

  9. Pyrithione Zn selectively inhibits hypoxia-inducible factor prolyl hydroxylase PHD3.

    PubMed

    Na, Yu-Ran; Woo, Dustin J; Kim, So Yeon; Yang, Eun Gyeong

    2016-04-01

    Increasing evidence emphasizes the role of the hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) isoforms in regulating non-HIF substrates, but isoform selective PHD inhibitors under physiological conditions have not yet been reported. Here we have identified pyrithione Zn (PZ) as a potent, isoform-selective PHD3 inhibitor. The IC50 value of PZ was determined as 0.98 μM for PHD3, while it did not show any inhibitory activity toward full length and truncated PHD2 up to 1 mM. The selective efficacy of PZ was further demonstrated at the cellular level by observing inhibition of the PHD3-dependent DNA damage response pathway without stabilization of HIF-1α. PMID:26940742

  10. Current advances in the novel functions of hypoxia-inducible factor and prolyl hydroxylase in invertebrates.

    PubMed

    Wang, L; Cui, S; Ma, L; Kong, L; Geng, X

    2015-12-01

    Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia-inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs). However, recent findings have uncovered novel HIF-independent functions of PHDs. This review provides an overview of how invertebrates are able to sustain hypoxic damages, and highlights some recent discoveries in the regulation of cellular signalling by PHDs. Given that some core genes and major pathways are evolutionarily conserved, these research findings could provide insight into oxygen-sensitive signalling in mammals, and have biomedical implications for human diseases.

  11. Hypoxia inducible factor 1α expression and effects of its inhibitors in canine lymphoma

    PubMed Central

    KAMBAYASHI, Satoshi; IGASE, Masaya; KOBAYASHI, Kosuke; KIMURA, Ayana; SHIMOKAWA MIYAMA, Takako; BABA, Kenji; NOGUCHI, Shunsuke; MIZUNO, Takuya; OKUDA, Masaru

    2015-01-01

    Hypoxic conditions in various cancers are believed to relate with their malignancy, and hypoxia inducible factor-1α (HIF-1α) has been shown to be a major regulator of the response to low oxygen. In this study, we examined HIF-1α expression in canine lymphoma using cell lines and clinical samples and found that these cells expressed HIF-1α. Moreover, the HIF-1α inhibitors, echinomycin, YC-1 and 2-methoxyestradiol, suppressed the proliferation of canine lymphoma cell lines. In a xenograft model using NOD/scid mice, echinomycin treatment resulted in a dose-dependent regression of the tumor. Our results suggest that HIF-1α contributes to the proliferation and/or survival of canine lymphoma cells. Therefore, HIF-1α inhibitors may be potential agents to treat canine lymphoma. PMID:26050843

  12. Rv1894c is a novel hypoxia-induced nitronate monooxygenase required for Mycobacterium tuberculosis virulence.

    PubMed

    Klinkenberg, Lee G; Karakousis, Petros C

    2013-05-15

    Tuberculosis is difficult to cure, requiring a minimum of 6 months of treatment with multiple antibiotics. Small numbers of organisms are able to tolerate the antibiotics and persist in the lungs of infected humans, but they still require some metabolic activity to survive. We studied the role of the hypoxia-induced Rv1894c gene in Mycobacterium tuberculosis virulence in guinea pigs, which develop hypoxic, necrotic granulomas histologically resembling those in humans and found this gene to be necessary for full bacillary growth and survival. We characterized the function of the encoded enzyme as a nitronate monooxygenase, which is needed to prevent the buildup of toxic products during hypoxic metabolism and is negatively regulated by the transcriptional repressor KstR. Future studies will focus on developing small-molecule inhibitors that target Rv1894c and its homologs, with the goal of killing persistent bacteria, thereby shortening the time needed to treat tuberculosis. PMID:23408846

  13. Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis.

    PubMed

    Hua, Susan; Dias, Thilani H

    2016-01-01

    Hypoxia is an important micro-environmental characteristic of rheumatoid arthritis (RA). Hypoxia-inducible factors (HIF) are key transcriptional factors that are highly expressed in RA synovium to regulate the adaptive responses to this hypoxic milieu. Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Experimental and clinical data have confirmed the upregulation of both HIF-1α and HIF-2α in RA. This review will focus on the differential expression of HIFs within the synovial joint and its functional behavior in different cell types to regulate RA progression. Potential development of new therapeutic strategies targeting HIF-regulated pathways at sites of disease in RA will also be addressed. PMID:27445820

  14. Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis

    PubMed Central

    Hua, Susan; Dias, Thilani H.

    2016-01-01

    Hypoxia is an important micro-environmental characteristic of rheumatoid arthritis (RA). Hypoxia-inducible factors (HIF) are key transcriptional factors that are highly expressed in RA synovium to regulate the adaptive responses to this hypoxic milieu. Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Experimental and clinical data have confirmed the upregulation of both HIF-1α and HIF-2α in RA. This review will focus on the differential expression of HIFs within the synovial joint and its functional behavior in different cell types to regulate RA progression. Potential development of new therapeutic strategies targeting HIF-regulated pathways at sites of disease in RA will also be addressed. PMID:27445820

  15. The role of hypoxia-inducible factor-2 in digestive system cancers.

    PubMed

    Zhao, J; Du, F; Shen, G; Zheng, F; Xu, B

    2015-01-01

    Hypoxia is an all but ubiquitous phenomenon in cancers. Two known hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, primarily mediate the transcriptional response to hypoxia. Despite the high homology between HIF-1α and HIF-2α, emerging evidence suggests differences between both molecules in terms of transcriptional targets as well as impact on multiple physiological pathways and tumorigenesis. To date, much progress has been made toward understanding the roles of HIF-2α in digestive system cancers. Indeed, HIF-2α has been shown to regulate multiple aspects of digestive system cancers, including cell proliferation, angiogenesis and apoptosis, metabolism, metastasis and resistance to chemotherapy. These findings make HIF-2α a critical regulator of this malignant phenotype. Here we summarize the function of HIF-2 during cancer development as well as its contribution to tumorigenesis in digestive system malignancies.

  16. Coronary haemodynamics in left ventricular hypertrophy.

    PubMed Central

    Wallbridge, D. R.; Cobbe, S. M.

    1996-01-01

    BACKGROUND: Left ventricular hypertrophy is associated with an increased risk of cardiovascular morbidity and mortality. Previous studies have shown that patients with left ventricular hypertrophy develop electrocardiographic changes and left ventricular dysfunction during acute hypotension, and suggest that the lower end of autoregulation may be shifted upwards. AIM: To measure coronary blood flow (velocity) and flow reserve during acute hypotension in patients with left ventricular hypertrophy. PATIENTS: Eight patients with atypical chest pain and seven with hypertensive left ventricular hypertrophy; all with angiographically normal epicardial vessels. SETTING: Tertiary referral centre. METHODS: The physiological range of blood pressure was determined by previous ambulatory monitoring. Left ventricular mass was determined by echocardiography. At cardiac catheterisation, left coronary blood flow velocity was measured using a Judkins style Doppler tipped catheter. During acute hypotension with sodium nitroprusside, coronary blood flow velocity was recorded at rest and during maximal hyperaemia induced by intracoronary injection of adenosine. Quantitative coronary angiography was performed manually. RESULTS: For both groups coronary blood flow velocity remained relatively constant over a range of physiological diastolic blood pressures and showed a steep relation with diastolic blood pressure during maximal hyperaemia with intracoronary adenosine. Absolute coronary blood flow (calculated from quantitative angiographic data), standardised for left ventricular mass, showed reduced flow in the hypertensive group at rest and during maximal vasodilatation. CONCLUSION: The results are consistent with an inadequate blood supply to the hypertrophied heart, but no upward shift of the lower end of the autoregulatory range was observed. PMID:8705764

  17. Overexpression of ERβ is sufficient to inhibit hypoxia-inducible factor-1 transactivation

    SciTech Connect

    Park, Choa; Lee, YoungJoo

    2014-07-18

    Highlights: • We examined the effect of ERβ specific ligand on HIF-1 inhibition. • DPN down-regulates the ARNT protein levels in PC3 cells. • DPN did not show additional effect in ERβ transfected MCF-7 cells. • Our study shows that unliganded ERβ is sufficient to inhibit HIF-1 in systems of overexpression. - Abstract: Estrogen receptor (ER) β is predicted to play an important role in the prevention of breast cancer development and progression. We have previously shown that ERβ suppresses hypoxia inducible factor (HIF)-1-mediated transcription through aryl hydrocarbon receptor nuclear translocator (ARNT) degradation via ubiquitination processes. In this study, we attempted to examine the effect of ERβ specific ligand on HIF-1 inhibition in ERβ positive PC3 cells and ERβ transfected MCF-7 cells. ERβ specific agonist diarylpropionitrile (DPN) stimulated estrogen response element (ERE)-luciferase activity in a similar fashion to estradiol in PC3 cells. We observed that DPN down-regulates the ARNT protein levels leading to an attenuation of hypoxia-induced hypoxia response element (HRE)-driven luciferase reporter gene activation in PC3 cells. Treatment of DPN reduced vascular endothelial growth factor (VEGF) expression and co-treatment with ERβ specific antagonist PHTPP abrogated the effect in PC3 cells. We then examined the effect of DPN in ERβ transfected MCF-7 cells. HIF-1 transcriptional activity repression by ERβ was not further reduced by DPN, as examined by HRE-driven luciferase assays. Expression of ERβ significantly decreased VEGF secretion and ARNT expression under hypoxic conditions. However, DPN did not additionally affect this suppression in MCF-7 cells transfected with ERβ. This result shows that unliganded ERβ is sufficient to inhibit HIF-1 in systems of overexpression.

  18. Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types

    PubMed Central

    Sermeus, Audrey; Genin, Marie; Maincent, Amélie; Fransolet, Maude; Notte, Annick; Leclere, Lionel; Riquier, Hélène; Arnould, Thierry; Michiels, Carine

    2012-01-01

    Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIMEL. BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and –independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy. PMID:23139748

  19. Hypoxia inducible factor 1α contributes to regulation of autophagy in retinal detachment

    PubMed Central

    Shelby, Shameka J.; Angadi, Pavan S.; Zheng, Qiong-Duon; Yao, Jingyu; Jia, Lin; Zacks, David N.

    2015-01-01

    Photoreceptor (PR) cells receive oxygen and nutritional support from the underlying retinal pigment epithelium (RPE). Retinal detachment results in PR hypoxia and their time-dependent death. Detachment also activates autophagy within the PR, which serves to reduce the rate of PR apoptosis. In this study, we test the hypothesis that autophagy activation in the PR results, at least in part, from the detachment-induced activation of hypoxia-inducible factors (HIF). Retina-RPE separation was created in Brown-Norway rats and C57BL/6J mice by injection of 1% hyaluronic acid into the subretinal space. Retinas were harvested and assayed for HIF protein levels. Cultured 661W photoreceptor cells were subjected to hypoxic conditions and assayed for induction of HIF and autophagy. The requirement of HIF-1α and HIF-2α in regulating photoreceptor autophagy was tested using siRNA in vitro and in vivo. We observed increased levels of HIF-1α and HIF-2α within 1 day post-detachment, as well as increased levels of BNIP3, a downstream target of HIF-1α that contributes to autophagy activation. Exposing 661W cells to hypoxia resulted in increased HIF-1α and HIF-2α levels and increase in conversion of LC3-I to LC3-II. Silencing of HIF-1α, but not HIF-2α, reduced the hypoxia-induced increase in LC3-II formation and increased cell death in 661W cells. Silencing of HIF-1α in rat retinas prevented the detachment-induced increase in BNIP3 and LC3-II, resulting in increased PR cell death. Our data support the hypothesis that HIF-1α, but not HIF-2α, serves as an early response signal to induce autophagy and reduce photoreceptor cell death. PMID:26093278

  20. Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes.

    PubMed

    Laukka, Tuomas; Mariani, Christopher J; Ihantola, Tuukka; Cao, John Z; Hokkanen, Juho; Kaelin, William G; Godley, Lucy A; Koivunen, Peppi

    2016-02-19

    The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μm, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe(2+) and 2-oxoglutarate-binding residues increased the Km values for these factors 30-80-fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ∼400-500 μm. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization. PMID:26703470

  1. Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis.

    PubMed

    Höhne, Claudia; Boemke, Willehad; Schleyer, Nora; Francis, Roland C; Krebs, Martin O; Kaczmarczyk, Gabriele

    2002-05-01

    Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.

  2. Retinal hypoxia induces vascular endothelial growth factor through induction of estrogen-related receptor γ

    SciTech Connect

    Do, Ji Yeon; Choi, Young Keun; Kook, Hyun; Suk, Kyoungho; Lee, In-Kyu; Park, Dong Ho

    2015-05-01

    Ischemic retinopathies causing overexpression of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), are the most common cause of blindness. Thus, understanding the pathophysiology of targetable pathways that regulate retinal VEGF is of great interest. A conserved binding site for estrogen-related receptor γ (ERRγ) has been identified in the promoter of the Vegfa gene. ERRγ is a constitutively active orphan nuclear receptor and its expression is increased by hypoxic stimuli in metabolically active tissues. This study evaluated the role of ERRγ in the ischemic retina and the anti-VEGF potential of GSK5182, a selective inverse agonist of ERRγ. In an oxygen-induced retinopathy (OIR) mouse model, immunohistochemistry showed significantly increased ERRγ expression in the ganglion cell layer at postnatal day (P) 17. In a ganglion cell line (RGC-5), mRNA and protein levels of ERRγ were increased by desferrioxamine treatment and hypoxic conditions (1% O{sub 2}). Transient transfection of RGC-5 cells revealed that ERRγ regulated Vegfa expression and this was inhibited by GSK5182. Intravitreal injection of GSK5182 into the OIR model at P14 inhibited retinal Vegfa mRNA expression at P17. GSK5182 suppresses hypoxia-induced VEGF expression via ERRγ; therefore, ERRγ could be a treatment target for ischemic retinopathies. - Highlights: • OIR mice exhibited increased ERRγ expression in the ganglion cell layer. • Hypoxia-induced ERRγ expression was observed in retinal ganglion cells. • ERRγ overexpression increased VEGFA expression in retinal ganglion cells. • An ERRγ inverse agonist suppressed VEGFA expression in retinal ganglion cells. • Intravitreal injection of an ERRγ inverse agonist suppressed VEGFA in OIR mice.

  3. Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells.

    PubMed

    Chang, Chia-Yu; Lui, Tai-Ngar; Lin, Jia-Wei; Lin, Yi-Ling; Hsing, Chung-Hsi; Wang, Jhi-Joung; Chen, Ruei-Ming

    2016-01-01

    Hypoxia is a common occurrence in brain tumors and traumatic brain injury. microRNA (miR)-1 participates in the regulation of brain development and neuronal function. Interestingly, miR-1 can mediate ischemia-induced injury to cardiomyocytes. This study was designed to evaluate the roles of miR-1 in hypoxia-induced insults to neurons and the possible mechanisms. Exposure of neuro-2a cells to oxygen/glucose deprivation (OGD) or cobalt chloride decreased cell viability and induced cell apoptosis in time-dependent manners. In parallel, OGD caused augmentation of cellular Bax and cytochrome c levels, a reduction in the mitochondrial membrane potential (MMP), activation of caspase-3, and fragmentation of DNA. miR-1 was induced in neuro-2a cells by OGD. Knocking down miR-1 expression using specific antisense inhibitors significantly alleviated OGD-induced neuronal death. Administration of OGD to neuro-2a cells induced heat-shock protein (HSP)-70 messenger (m)RNA and protein expressions. A bioinformatic search revealed that miR-1-specific binding elements exist in the 3'-untranslated region of HSP-70 mRNA. Overexpression of miR-1 simultaneously attenuated OGD-induced HSP-70 mRNA and protein expressions. In comparison, knocking down miR-1 expression synergistically enhanced OGD-induced HSP-70 mRNA. As to the mechanism, reducing miR-1 expression lowered OGD-induced alterations in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study shows that miR-1 can target HSP-70 expression and consequently mediate hypoxia-induced apoptotic insults to neuro-2a cells via an intrinsic Bax-mitochondrion-caspase protease pathway. PMID:25238743

  4. Brazilian Green Propolis Suppresses the Hypoxia-Induced Neuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia

    PubMed Central

    Zhu, Aiqin; Takayama, Fumiko; Liu, Yicong; Harada, Yuka; Wu, Shizheng; Nakanishi, Hiroshi

    2013-01-01

    Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti-inflammatory effects, propolis may have protective effects against the hypoxia-induced neuroinflammatory responses. In this study, propolis (50 μg/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, by MG6 microglia following hypoxic exposure (1% O2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-κB (NF-κB) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1β, TNF-α, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammatory responses through inhibition of the NF-κB activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-κB activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation. PMID:23983903

  5. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    PubMed

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. PMID:25283246

  6. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

    PubMed Central

    Zhong, Leilei; Huang, Xiaobin; Karperien, Marcel; Post, Janine N.

    2015-01-01

    Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP)/Transforming growth factor-β (TGFβ), Parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), Fibroblast growth factor (FGF), Insulin like growth factor (IGF) and Hypoxia-inducible factor (HIF). This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC) repair, and improves understanding of the disease stages and cellular responses within an OA articular joint. PMID:26287176

  7. Hearts of Hypoxia-inducible Factor Prolyl 4-Hydroxylase-2 Hypomorphic Mice Show Protection against Acute Ischemia-Reperfusion Injury*

    PubMed Central

    Hyvärinen, Jaana; Hassinen, Ilmo E.; Sormunen, Raija; Mäki, Joni M.; Kivirikko, Kari I.; Koivunen, Peppi; Myllyharju, Johanna

    2010-01-01

    Hypoxia-inducible factor (HIF) has a pivotal role in oxygen homeostasis and cardioprotection mediated by ischemic preconditioning. Its stability is regulated by HIF prolyl 4-hydroxylases (HIF-P4Hs), the inhibition of which is regarded as a promising strategy for treating diseases such as anemia and ischemia. We generated a viable Hif-p4h-2 hypomorph mouse line (Hif-p4h-2gt/gt) that expresses decreased amounts of wild-type Hif-p4h-2 mRNA: 8% in the heart; 15% in the skeletal muscle; 34–47% in the kidney, spleen, lung, and bladder; 60% in the brain; and 85% in the liver. These mice have no polycythemia and show no signs of the dilated cardiomyopathy or hyperactive angiogenesis observed in mice with broad spectrum conditional Hif-p4h-2 inactivation. We focused here on the effects of chronic Hif-p4h-2 deficiency in the heart. Hif-1 and Hif-2 were stabilized, and the mRNA levels of glucose transporter-1, several enzymes of glycolysis, pyruvate dehydrogenase kinase 1, angiopoietin-2, and adrenomedullin were increased in the Hif-p4h-2gt/gt hearts. When isolated Hif-p4h-2gt/gt hearts were subjected to ischemia-reperfusion, the recovery of mechanical function and coronary flow rate was significantly better than in wild type, while cumulative release of lactate dehydrogenase reflecting the infarct size was reduced. The preischemic amount of lactate was increased, and the ischemic versus preischemic [CrP]/[Cr] and [ATP] remained at higher levels in Hif-p4h-2gt/gt hearts, indicating enhanced glycolysis and an improved cellular energy state. Our data suggest that chronic stabilization of Hif-1α and Hif-2α by genetic knockdown of Hif-p4h-2 promotes cardioprotection by induction of many genes involved in glucose metabolism, cardiac function, and blood pressure. PMID:20185832

  8. Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation☆

    PubMed Central

    Cui, Hong; Han, Weijuan; Yang, Lijun; Chang, Yanzhong

    2013-01-01

    Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor 1α, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage. There is little evidence of direct regulatory effects of hypoxia-inducible factor 1α on oligodendrocyte lineage gene-1. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxygen-glucose deprivation. Then, slices were transfected with hypoxia-inducible factor 1α or oligodendrocyte lineage gene-1. The expression levels of hypoxia-inducible factor 1α and oligodendrocyte lineage gene-1 were significantly up-regulated in rat brains prior to transfection, as detected by immunohistochemical staining. Eight hours after transfection of slices with hypoxia-inducible factor 1α, oligodendrocyte lineage gene-1 expression was upregulated, and reached a peak 24 hours after transfection. Oligodendrocyte lineage gene-1 transfection induced no significant differences in hypoxia-inducible factor 1α levels in rat brain tissues with oxygen-glucose deprivation. These experimental findings indicate that hypoxia-inducible factor 1α can regulate oligodendrocyte lineage gene-1 expression in hypoxic brain tissue, thus repairing the neural impairment. PMID:25206673

  9. Prolonged Hypoxia Increases Survival Even in Zebrafish (Danio rerio) Showing Cardiac Arrhythmia

    PubMed Central

    Kopp, Renate; Bauer, Ines; Ramalingam, Anil; Egg, Margit; Schwerte, Thorsten

    2014-01-01

    Tolerance towards hypoxia is highly pronounced in zebrafish. In this study even beneficial effects of hypoxia, specifically enhanced survival of zebrafish larvae, could be demonstrated. This effect was actually more pronounced in breakdance mutants, which phenotypically show cardiac arrhythmia. Breakdance mutants (bre) are characterized by chronically reduced cardiac output. Despite an about 50% heart rate reduction, they become adults, but survival rate significantly drops to 40%. Normoxic bre animals demonstrate increased hypoxia inducible factor 1 a (Hif-1α) expression, which indicates an activated hypoxic signaling pathway. Consequently, cardiovascular acclimation, like cardiac hypertrophy and increased erythrocyte concentration, occurs. Thus, it was hypothesized, that under hypoxic conditions survival might be even more reduced. When bre mutants were exposed to hypoxic conditions, they surprisingly showed higher survival rates than under normoxic conditions and even reached wildtype values. In hypoxic wildtype zebrafish, survival yet exceeded normoxic control values. To specify physiological acclimation, cardiovascular and metabolic parameters were measured before hypoxia started (3 dpf), when the first differences in survival rate occurred (7 dpf) and when survival rate plateaued (15 dpf). Hypoxic animals expectedly demonstrated Hif-1α accumulation and consequently enhanced convective oxygen carrying capacity. Moreover, bre animals showed a significantly enhanced heart rate under hypoxic conditions, which reached normoxic wildtype values. This improvement in convective oxygen transport ensured a sufficient oxygen and nutrient supply and was also reflected in the significantly higher mitochondrial activity. The highly optimized energy metabolism observed in hypoxic zebrafish larvae might be decisive for periods of higher energy demand due to organ development, growth and increased activity. However, hypoxia increased survival only during a short period of

  10. Benign masseter muscle hypertrophy.

    PubMed

    Rispoli, Daniel Zeni; Camargo, Paulo M; Pires, José L; Fonseca, Vinicius R; Mandelli, Karina K; Pereira, Marcela A C

    2008-01-01

    Idiopathic hypertrophy of the masseter muscle is a rare disorder of unknown cause. Some authors associate it with the habit of chewing gum, temporo-mandibular joint disorder, congenital and functional hypertrophies, and emotional disorders (stress and nervousness). Most patients complain of the cosmetic change caused by facial asymmetry, also called square face, however, symptoms such as trismus, protrusion and bruxism may also occur. The goals of the present investigation were: to report a case of idiopathic masseter hypertrophy, describe its symptoms and treatment. The patient reported bilateral bulging in the region of the mandible angle, of slow and progressive evolution. He did not complain of pain or discomfort, however there was bilateral otalgia, nighttime trismus and stress. In his physical exam we noticed bilateral masseter hypertrophy without local inflammatory alterations. We indicated surgical treatment with an extraoral approach. Complementary tests are indicated when there is diagnostic doubts. Treatment varies from conservative to surgical, and the later depends on surgeon skill and experience.

  11. Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases

    PubMed Central

    Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

    2016-01-01

    Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia. Hypoxia is linked to prominent epigenetic changes in chromatin landscape. Screening studies have indicated that the stabilization of HIF-1α increases the expression of distinct histone lysine demethylases (KDM). HIF-1α stimulates the expression of KDM3A, KDM4B, KDM4C, and KDM6B, which enhance gene transcription by demethylating H3K9 and H3K27 sites (repressive epigenetic marks). In addition, HIF-1α induces the expression of KDM2B and KDM5B, which repress transcription by demethylating H3K4me2,3 sites (activating marks). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites. These epigenetic marks have important role in the control of heterochromatin segments and 3D folding of chromosomes, as well as the genetic loci regulating cell type commitment, proliferation, and cellular senescence, e.g. the INK4 box. A chronic stimulation of HIF-1α can provoke tissue fibrosis and cellular senescence, which both are increasingly present with aging and age-related diseases. We will review the regulation of HIF-1α-dependent induction of KDMs and clarify their role in

  12. KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1{alpha} survival pathways

    SciTech Connect

    Oommen, Deepu; Prise, Kevin M.

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer KNK437, a benzylidene lactam compound, is a novel radiosensitizer. Black-Right-Pointing-Pointer KNK437 inhibits AKT signaling and abrogates the accumulation of HIF-1{alpha} under hypoxia. Black-Right-Pointing-Pointer KNK437 abrogates hypoxia induced resistance to radiation. -- Abstract: KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1{alpha} (HIF-1{alpha}). HIF-1{alpha} is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1{alpha}. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1{alpha} in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1{alpha} levels in KNK437-treated cells. This suggested that the absence of HIF-1{alpha} in hypoxic cells was not due to the enhanced protein degradation. HIF-1{alpha} is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1{alpha} mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1{alpha} levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

  13. Terpenoid tetrahydroisoquinoline alkaloids emetine, klugine, and isocephaeline inhibit the activation of hypoxia-inducible factor-1 in breast tumor cells.

    PubMed

    Zhou, Yu-Dong; Kim, Yong-Pil; Mohammed, Kaleem Asjad; Jones, Deborah K; Muhammad, Ilias; Dunbar, D Chuck; Nagle, Dale G

    2005-06-01

    Klugine (1), isocephaeline (2), and emetine (4) inhibited hypoxia-inducible factor-1 (HIF-1) activation by hypoxia in T47D breast tumor cells (IC(50) values 0.2, 1.1, and 0.11 muM, respectively). Compounds 1, 2, and 4 inhibited both hypoxia- and iron chelator-induced HIF-1 activation by blocking HIF-1alpha protein accumulation. PMID:15974627

  14. Folic Acid Represses Hypoxia-Induced Inflammation in THP-1 Cells through Inhibition of the PI3K/Akt/HIF-1α Pathway.

    PubMed

    Huang, Xiaoyan; He, Zhiying; Jiang, Xinwei; Hou, Mengjun; Tang, Zhihong; Zhen, Xiaozhou; Liang, Yuming; Ma, Jing

    2016-01-01

    Though hypoxia has been implicated as a cause of inflammation, the underlying mechanism is not well understood. Folic acid has been shown to provide protection against oxidative stress and inflammation in patients with cardiovascular disease and various models approximating insult to tissue via inflammation. It has been reported that hypoxia-induced inflammation is associated with oxidative stress, upregulation of hypoxia-inducible factor 1-alpha (HIF-1α), and production of pro-inflammatory molecules. Whether folic acid protects human monocytic cells (THP-1 cells) against hypoxia-induced damage, however, remains unknown. We used THP-1 cells to establish a hypoxia-induced cellular injury model. Pretreating THP-1 cells with folic acid attenuated hypoxia-induced inflammatory responses, including a decrease in protein and mRNA levels of interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), coupled with increased levels of IL-10. Folic acid also reduced hypoxia-induced Akt phosphorylation and decreased nuclear accumulation of HIF-1α protein. Both LY294002 (a selective inhibitor of phosphatidyl inositol-3 kinase, PI3K) and KC7F2 (a HIF-1α inhibitor) reduced levels of hypoxia-induced inflammatory cytokines. We also found that insulin (an Akt activator) and dimethyloxallyl glycine (DMOG, a HIF-1α activator) induced over-expression of inflammatory cytokines, which could be blocked by folic acid. Taken together, these findings demonstrate how folic acid attenuates the hypoxia-induced inflammatory responses of THP-1 cells through inhibition of the PI3K/Akt/HIF-1α pathway.

  15. Beat‐to‐Beat Spatiotemporal Variability in the T Vector Is Associated With Sudden Cardiac Death in Participants Without Left Ventricular Hypertrophy: The Atherosclerosis Risk in Communities (ARIC) Study

    PubMed Central

    Waks, Jonathan W.; Soliman, Elsayed Z.; Henrikson, Charles A.; Sotoodehnia, Nona; Han, Lichy; Agarwal, Sunil K.; Arking, Dan E.; Siscovick, David S.; Solomon, Scott D.; Post, Wendy S.; Josephson, Mark E.; Coresh, Josef; Tereshchenko, Larisa G.

    2015-01-01

    Background Despite advances in prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) remains a clinical challenge. Risk stratification in the general population is needed. Methods and Results Beat‐to‐beat spatiotemporal variability in the T vector was measured as the mean angle between consecutive T‐wave vectors (mean TT′ angle) on standard 12‐lead ECGs in 14 024 participants in the Atherosclerosis Risk in Communities (ARIC) study. Subjects with left ventricular hypertrophy, atrial arrhythmias, frequent ectopy, ventricular pacing, or QRS duration ≥120 ms were excluded. The mean spatial TT′ angle was 5.21±3.55°. During a median of 14 years of follow‐up, 235 SCDs occurred (1.24 per 1000 person‐years). After adjustment for demographics, coronary heart disease risk factors, and known ECG markers for SCD, mean TT′ angle was independently associated with SCD (hazard ratio 1.089; 95% CI 1.044 to 1.137; P<0.0001). A mean TT′ angle >90th percentile (>9.57°) was associated with a 2‐fold increase in the hazard for SCD (hazard ratio 2.01; 95% CI 1.28 to 3.16; P=0.002). In a subgroup of patients with T‐vector amplitude ≥0.2 mV, the association with SCD was almost twice as strong (hazard ratio 3.92; 95% CI 1.91 to 8.05; P<0.0001). A significant interaction between mean TT′ angle and age was found: TT′ angle was associated with SCD in participants aged <55 years (hazard ratio 1.096; 95% CI 0.043 to 1.152; P<0.0001) but not in participants aged ≥55 years (Pinteraction=0.009). Conclusions In a large, prospective, community‐based cohort of left ventricular hypertrophy–free participants, increased beat‐to‐beat spatiotemporal variability in the T vector, as assessed by increasing TT′ angle, was associated with SCD. PMID:25600143

  16. Hypoxia-induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway

    PubMed Central

    Wan, Gang; Xie, Weidong; Liu, Zhenyan; Xu, Wei; Lao, Yuanzhi; Huang, Nunu; Cui, Kai; Liao, Meijian; He, Jie; Jiang, Yuyang; Yang, Burton B; Xu, Hongxi; Xu, Naihan; Zhang, Yaou

    2014-01-01

    Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including cancer. Hypoxia induces upregulation of a specific set of microRNAs (miRNAs) in a variety of cell types. Here, we describe hypoxia-induced MIR155 as a potent inducer of autophagy. Enforced expression of MIR155 increases autophagic activity in human nasopharyngeal cancer and cervical cancer cells. Knocking down endogenous MIR155 inhibits hypoxia-induced autophagy. We demonstrated that MIR155 targets multiple players in MTOR signaling, including RHEB, RICTOR, and RPS6KB2. MIR155 suppresses target-gene expression by directly interacting with their 3′ untranslated regions (UTRs), mutations of the binding sites abolish their MIR155 responsiveness. Furthermore, by downregulating MTOR signaling, MIR155 also attenuates cell proliferation and induces G1/S cell cycle arrest. Collectively, these data present a new role for MIR155 as a key regulator of autophagy via dysregulation of MTOR pathway. PMID:24262949

  17. The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells.

    PubMed

    Guan, Guofeng; Zhang, Yinglong; Lu, Yao; Liu, Lijuan; Shi, Doufei; Wen, Yanhua; Yang, Lianjia; Ma, Qiong; Liu, Tao; Zhu, Xiaodong; Qiu, Xiuchun; Zhou, Yong

    2015-02-01

    HIF-1α mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF-1α/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1α and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1α inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF-1α/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics.

  18. The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells.

    PubMed

    Guan, Guofeng; Zhang, Yinglong; Lu, Yao; Liu, Lijuan; Shi, Doufei; Wen, Yanhua; Yang, Lianjia; Ma, Qiong; Liu, Tao; Zhu, Xiaodong; Qiu, Xiuchun; Zhou, Yong

    2015-02-01

    HIF-1α mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF-1α/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1α and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1α inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF-1α/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics. PMID:25444927

  19. Kamebakaurin inhibits the expression of hypoxia-inducible factor-1α and its target genes to confer antitumor activity.

    PubMed

    Wang, Ke Si; Ma, Juan; Mi, Chunliu; Li, Jing; Lee, Jung Joon; Jin, Xuejun

    2016-04-01

    Hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that mediates the adaptation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Kamebakaurin is a diterpenoid compound isolated from Isodon excia (Maxin.) Hara, which has been used for anti-inflammatory activities. However, its antitumor activity along with molecular mechanism has not been reported. Kamebakaurin showed potent inhibitory activity against HIF-1 activation induced by hypoxia or CoCl2 in various human cancer cell lines. This compound significantly decreased the hypoxia-induced accumulation of HIF-1α protein, whereas it did not affect the expression of topoisomerase-I (Topo-I). Further analysis revealed that kamebakaurin inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Furthermore, kamebakaurin prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin (EPO). However, kamebakaurin caused cell growth inhibition via cell cycle arrest at G1 phase in tumor cells. In vivo studies, we further confirmed the inhibitory effect of kamebakaurin on the expression of HIF-1α proteins, leading to growth inhibition of HCT116 cells in a xenograft tumor model. These results show that kamebakaurin is an effective inhibitor of HIF-1 and provide new perspectives into its anticancer activity. PMID:26781327

  20. Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis.

    PubMed

    Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

    2016-01-01

    Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

  1. Ets-1 as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells.

    PubMed

    Qiao, N; Xu, C; Zhu, Y-X; Cao, Y; Liu, D-C; Han, X

    2015-02-19

    Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic β-cell failure in type 2 diabetes. Pancreatic β-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to β-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of β-cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic β-cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period.

  2. Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis

    PubMed Central

    Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

    2016-01-01

    Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

  3. A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration

    PubMed Central

    Jang, Kusik; Kim, Inhyub; Kim, Bo-Kyung; Lee, Kyeong; Won, Misun

    2016-01-01

    We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacetylamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structure-based virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1α and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1α accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells. PMID:27611801

  4. Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

    PubMed Central

    Kalucka, Joanna; Ettinger, Andreas; Franke, Kristin; Mamlouk, Soulafa; Singh, Rashim Pal; Farhat, Katja; Muschter, Antje; Olbrich, Susanne; Breier, Georg; Katschinski, Dörthe M.; Huttner, Wieland; Weidemann, Alexander

    2013-01-01

    Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds. PMID:23798557

  5. The role of ion channels in the hypoxia-induced aggressiveness of glioblastoma

    PubMed Central

    Sforna, Luigi; Cenciarini, Marta; Belia, Silvia; D’Adamo, Maria Cristina; Pessia, Mauro; Franciolini, Fabio; Catacuzzeno, Luigi

    2015-01-01

    The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca2+ concentration, ultimately leading to cell proliferation, migration or death. In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors. PMID:25642170

  6. Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection.

    PubMed

    Shepardson, Kelly M; Jhingran, Anupam; Caffrey, Alayna; Obar, Joshua J; Suratt, Benjamin T; Berwin, Brent L; Hohl, Tobias M; Cramer, Robert A

    2014-09-01

    Hypoxia inducible factor 1α (HIF1α) is the mammalian transcriptional factor that controls metabolism, survival, and innate immunity in response to inflammation and low oxygen. Previous work established that generation of hypoxic microenvironments occurs within the lung during infection with the human fungal pathogen Aspergillus fumigatus. Here we demonstrate that A. fumigatus stabilizes HIF1α protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1α mice, we observed that HIF1α is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1α deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1α mice to A. fumigatus was in part due to decreased early production of the chemokine CXCL1 (KC) and increased neutrophil apoptosis at the site of infection, resulting in decreased neutrophil numbers in the lung. Addition of recombinant CXCL1 restored neutrophil survival and numbers, murine survival, and fungal clearance. These results suggest that there are unique HIF1α mediated mechanisms employed by the host for protection and defense against fungal pathogen growth and invasion in the lung. Additionally, this work supports the strategy of exploring HIF1α as a therapeutic target in specific immunosuppressed populations with fungal infections.

  7. Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1.

    PubMed

    Abán, C; Martinez, N; Carou, C; Albamonte, I; Toro, A; Seyahian, A; Franchi, A; Leguizamón, G; Trigubo, D; Damiano, A; Farina, M

    2016-10-01

    During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process.

  8. Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation.

    PubMed

    Yang, Ling; Zheng, Jianchao; Xu, Rui; Zhang, Yujie; Gu, Luo; Dong, Jing; Zhu, Yichao; Zhou, Ruijue; Zheng, Lu; Zhang, Xiaoying; Du, Jun

    2014-01-01

    Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation. PMID:25123138

  9. Mutant hypoxia inducible factor-1α improves angiogenesis and tissue perfusion in ischemic rabbit skeletal muscle.

    PubMed

    Li, Mingyan; Liu, Cheng; Bin, Jianping; Wang, Yuegang; Chen, Jianwei; Xiu, Jiancheng; Pei, Jingxian; Lai, Yanxian; Chen, Dongdong; Fan, Caixia; Xie, Jiajia; Tao, Yu; Wu, Pingsheng

    2011-01-01

    Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It regulates genes involved in angiogenesis, but is inactivated rapidly by normoxia. Ad-HIF-1α-Trip was constructed by transforming Pro402, Pro564, and Asn803 in HIF-1α to alanine in order to delay degradation and create a constitutive transcriptional activator. In this study, we investigated whether Ad-HIF-1α-Trip could induce functional mature angiogenesis and the possible mechanisms involved. We found that Ad-HIF-1α-Trip increased the expression of multiple angiogenic genes in cultured HMVEC-Ls, including VEGF, PLGF, PAI-1, and PDGF. In a rabbit model of acute hind limb ischemia, Ad-HIF-1α-Trip improved tissue perfusion and collateral vessels, as measured by contrast-enhanced ultrasound (CEU), CT angiography, and vascular casting. Ad-HIF-1α-Trip also produced more histologically identifiable capillaries, which were verified by immunostaining, compared with controls. Interestingly, inhibition of CBP/p300 by curcumin prevented HIF-1α from inducing the expression of several angiogenic genes. The present study suggests that Ad-HIF-1α-Trip can induce mature angiogenesis and improve tissue perfusion in ischemic rabbit skeletal muscle. CBP/p300, which interacts with the transactivation domains of HIF-1α, is important for HIF-1α-induced transcription of angiogenic genes. PMID:20937289

  10. Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition

    PubMed Central

    Tamama, Kenichi; Kawasaki, Haruhisa; Kerpedjieva, Svetoslava S.; Guan, Jianjun; Ganju, Ramesh K.; Sen, Chandan K.

    2014-01-01

    Cell therapy with bone marrow multipotential stromal cells (MSCs) represents a promising approach to promote wound healing and tissue regeneration. MSCs expanded in vitro lose early progenitors with differentiation and therapeutic potentials under normoxic condition, whereas hypoxic condition promotes MSC self-renewal through preserving colony forming early progenitors and maintaining undifferentiated phenotypes. Hypoxia inducible factor (HIF) pathway is a crucial signaling pathway activated in hypoxic condition. We evaluated the roles of HIFs in MSC differentiation, colony formation, and paracrine activity under hypoxic condition. Hypoxic condition reversibly decreased osteogenic and adipogenic differentiation. Decrease of osteogenic differentiation depended on HIF pathway; whereas decrease of adipogenic differentiation depended on the activation of unfolded protein response (UPR), but not HIFs. Hypoxia-mediated increase of MSC colony formation was not HIF-dependent also. Hypoxic exposure increased secretion of VEGF, HGF and basic FGF in a HIF-dependent manner. These findings suggest that HIF has a limited, but pivotal role in enhancing MSC self-renewal and growth factor secretions under hypoxic condition. PMID:21328454

  11. Hypoxia induces a novel signature of chromatin modifications and global repression of transcription.

    PubMed

    Johnson, Amber Buescher; Denko, Nicholas; Barton, Michelle Craig

    2008-04-01

    Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels,