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Sample records for aortic enos expression

  1. Reversal of SIN-1-induced eNOS dysfunction by the spin trap, DMPO, in bovine aortic endothelial cells via eNOS phosphorylation

    PubMed Central

    Das, Amlan; Gopalakrishnan, Bhavani; Druhan, Lawrence J; Wang, Tse-Yao; De Pascali, Francesco; Rockenbauer, Antal; Racoma, Ira; Varadharaj, Saradhadevi; Zweier, Jay L; Cardounel, Arturo J; Villamena, Frederick A

    2014-01-01

    Background and Purpose Nitric oxide (NO) derived from eNOS is mostly responsible for the maintenance of vascular homeostasis and its decreased bioavailability is characteristic of reactive oxygen species (ROS)-induced endothelial dysfunction (ED). Because 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), a commonly used spin trap, can control intracellular nitroso-redox balance by scavenging ROS and donating NO, it was employed as a cardioprotective agent against ED but the mechanism of its protection is still not clear. This study elucidated the mechanism of protection by DMPO against SIN-1-induced oxidative injury to bovine aortic endothelial cells (BAEC). Experimental Approach BAEC were treated with SIN-1, as a source of peroxynitrite anion (ONOO−), and then incubated with DMPO. Cytotoxicity following SIN-1 alone and cytoprotection by adding DMPO was assessed by MTT assay. Levels of ROS and NO generation from HEK293 cells transfected with wild-type and mutant eNOS cDNAs, tetrahydrobiopterin bioavailability, eNOS activity, eNOS and Akt kinase phosphorylation were measured. Key Results Post-treatment of cells with DMPO attenuated SIN-1-mediated cytotoxicity and ROS generation, restoration of NO levels via increased in eNOS activity and phospho-eNOS levels. Treatment with DMPO alone significantly increased NO levels and induced phosphorylation of eNOS Ser1179 via Akt kinase. Transfection studies with wild-type and mutant human eNOS confirmed the dual role of eNOS as a producer of superoxide anion (O2−) with SIN-1 treatment, and a producer of NO in the presence of DMPO. Conclusion and Implications Post-treatment with DMPO of oxidatively challenged cells reversed eNOS dysfunction and could have pharmacological implications in the treatment of cardiovascular diseases. PMID:24405159

  2. PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells.

    PubMed

    Haider, Dominik G; Bucek, Robert A; Giurgea, Aura G; Maurer, Gerald; Glogar, Helmut; Minar, Erich; Wolzt, Michael; Mehrabi, Mohammad R; Baghestanian, Mehrdad

    2005-11-01

    Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-alpha (HIF-1alpha) are important regulators of endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1 analog treatment in patients with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have investigated the effects of the PGE1 analog alprostadil on eNOS, VEGF, and HIF-1alpha expression in human umbilical vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition, we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF, treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA expression in HUVEC and decreases HIF-1alpha. Hypoxia potently increased eNOS, VEGF, and HIF-1alpha synthesis. The alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126. Consistently, the expression of eNOS and VEGF was increased, and HIF-1alpha was reduced in failing hearts treated with alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with HF where endothelial dysfunction is involved in the disease process.

  3. Molecular characterisation and expression profiling of the ENO1 gene in the ovarian follicle of the Sichuan white goose.

    PubMed

    Kang, Bo; Jiang, Dong Mei; Bai, Lin; He, Hui; Ma, Rong

    2014-01-01

    The ENO1 gene encodes a multifunctional enzyme that has been identified as a key component of the glycolytic pathway. Our previous studies demonstrated that ENO1 gene expression was higher in the ovaries of laying geese compared with prelaying geese. However, the molecular characterisation and expression profiling of the ENO1 gene in geese tissues and ovarian follicles remain to be determined. In this study, ENO1 cDNA (1,445 bp long) of the Sichuan white goose was cloned and characterised. The ORF of ENO1 cDNA is 1,305 bp in length and encodes a 434 amino acid protein with a molecular weight of 47.27 kDa. ENO1 expression in all of the examined tissues was the highest in spleen and the lowest in breast muscle. High expression of ENO1 appeared in the kidney, liver, adrenal gland, and retina. With increasing follicle growth, ENO1 gene expression began to decrease from the small white follicle to F5, which was followed by a sharp increase in expression in F4 and then a gradual decrease in expression from F3 to F1. Furthermore, in the postovulatory follicles (POF), the levels of ENO1 gene expression decreased gradually from POF1 to POF4. In conclusion, the ENO1 transcript was widely distributed in various tissues of the Sichuan white goose, but ENO1 expression was tissue-specific. Furthermore, the results of the ENO1 expression profiling of ovarian follicles suggest that ENO1 may play an important dual role in the progress of follicular development, where ENO1 acts as a glycolytic enzyme and also mediates apoptosis.

  4. Hindlimb unweighting decreases endothelium-dependent dilation and eNOS expression in soleus not gastrocnemius

    NASA Technical Reports Server (NTRS)

    Woodman, C. R.; Schrage, W. G.; Rush, J. W.; Ray, C. A.; Price, E. M.; Hasser, E. M.; Laughlin, M. H.

    2001-01-01

    We tested the hypothesis that hindlimb unweighting (HLU) decreases endothelium-dependent vasodilation and expression of endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) in arteries of skeletal muscle with reduced blood flow during HLU. Sprague-Dawley rats (300-350 g) were exposed to HLU (n = 15) or control (n = 15) conditions for 14 days. ACh-induced dilation was assessed in muscle with reduced [soleus (Sol)] or unchanged [gastrocnemius (Gast)] blood flow during HLU. eNOS and SOD-1 expression were measured in feed arteries (FA) and in first-order (1A), second-order (2A), and third-order (3A) arterioles. Dilation to infusion of ACh in vivo was blunted in Sol but not Gast. In arteries of Sol muscle, HLU decreased eNOS mRNA and protein content. eNOS mRNA content was significantly less in Sol FA (35%), 1A arterioles (25%) and 2A arterioles (18%). eNOS protein content was less in Sol FA (64%) and 1A arterioles (65%) from HLU rats. In arteries of Gast, HLU did not decrease eNOS mRNA or protein. SOD-1 mRNA expression was less in Sol 2A arterioles (31%) and 3A arterioles (29%) of HLU rats. SOD-1 protein content was less in Sol FA (67%) but not arterioles. SOD-1 mRNA and protein content were not decreased in arteries from Gast. These data indicate that HLU decreases endothelium-dependent vasodilation, eNOS expression, and SOD-1 expression primarily in arteries of Sol muscle where blood flow is reduced during HLU.

  5. PGC-1α dictates endothelial function through regulation of eNOS expression

    PubMed Central

    Craige, Siobhan M.; Kröller-Schön, Swenja; Li, Chunying; Kant, Shashi; Cai, Shenghe; Chen, Kai; Contractor, Mayur M.; Pei, Yongmei; Schulz, Eberhard; Keaney, John F.

    2016-01-01

    Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1α sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1α EC TG mice were protected. Mechanistically, PGC-1α promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1α expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor α (ERRα) is required to coordinate the PGC-1α -induced eNOS expression. In conclusion, endothelial PGC-1α expression protects from vascular dysfunction by promoting NO• bioactivity through ERRα induced expression of eNOS. PMID:27910955

  6. Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts.

    PubMed Central

    Akyürek, L. M.; Fellström, B. C.; Yan, Z. Q.; Hansson, G. K.; Funa, K.; Larsson, E.

    1996-01-01

    In the vascular system, distinct isoforms of nitric oxide synthase (NOS) generate nitric oxide (NO), which acts as a biological messenger. Its role in the development of transplant arteriosclerosis (TA) is still unclear. To investigate whether NO is involved in TA, we studied the expression of NOS isoforms, inducible NOS (iNOS) and endothelial NOS (eNOS), by immunohistochemistry and in situ hybridization during the first two post-transplantation months and their relation with cold ischemia (1 to 24 hours) and reperfusion injury using an aortic transplantation model in the rat. We found an increased iNOS expression in the intima and adventitia and a decreased expression in the media, whereas eNOS expression was not significantly altered during the development of TA. Co-localization studies suggested that iNOS-positive cells were vascular smooth muscle cells, monocyte-derived macrophages, and endothelial cells. Prolonged ischemic storage time resulted in an increase in eNOS expression in the neointima. In situ hybridization showed iNOS mRNA expression by vascular cells in the neointima and media. NO produced by iNOS and eNOS may be involved, at least in part, in the pathogenesis of TA in aortic grafts. Additional studies are needed to confirm the modulatory mechanism of NO during the development of TA. Images Figure 3 Figure 4 Figure 6 PMID:8952533

  7. Effect of Exercise Training on Enos Expression, NO Production and Oxygen Metabolism in Human Placenta

    PubMed Central

    Ramírez-Vélez, Robinson; Bustamante, Juanita; Czerniczyniec, Analia; Aguilar de Plata, Ana C.; Lores-Arnaiz, Silvia

    2013-01-01

    Objective To determine the effects of combined aerobic and resistance exercise training during the second half of pregnancy on endothelial NOS expression (eNOS), nitric oxide (NO) production and oxygen metabolism in human placenta. Methods The study included 20 nulliparous in gestational week 16–20, attending prenatal care at three tertiary hospitals in Colombia who were randomly assigned into one of two groups: The exercise group (n = 10) took part in an exercise session three times a week for 12 weeks which consisted of: aerobic exercise at an intensity of 55–75% of their maximum heart rate for 60 min and 25 mins. Resistance exercise included 5 exercise groups circuit training (50 repetitions of each) using barbells (1–3 kg/exercise) and low-to-medium resistance bands. The control group (n = 10) undertook their usual physical activity. Mitochondrial and cytosol fractions were isolated from human placental tissue by differential centrifugation. A spectrophotometric assay was used to measure NO production in cytosolic samples from placental tissue and Western Blot technique to determine eNOS expression. Mitochondrial superoxide levels and hydrogen peroxide were measured to determine oxygen metabolism. Results Combined aerobic and resistance exercise training during pregnancy leads to a 2-fold increase in eNOS expression and 4-fold increase in NO production in placental cytosol (p = 0.05). Mitochondrial superoxide levels and hydrogen peroxide production rate were decreased by 8% and 37% respectively in the placental mitochondria of exercising women (p = 0.05). Conclusion Regular exercise training during the second half of pregnancy increases eNOS expression and NO production and decreases reactive oxygen species generation in human placenta. Collectively, these data demonstrate that chronic exercise increases eNOS/NO production, presumably by increasing endothelial shear stress. This adaptation may contribute to the beneficial effects of

  8. miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1.

    PubMed

    Evangelista, Alicia M; Deschamps, Anne M; Liu, Delong; Raghavachari, Nalini; Murphy, Elizabeth

    2013-06-17

    It is well recognized that there is sex-dimorphic expression of mRNA and protein in the heart; however, the underlying mechanism is poorly understood. Endothelial nitric oxide synthase (eNOS) is an important regulator of cardiac function, and the expression levels of eNOS differ between male and female hearts. The aim of this study was to examine whether expression of specific microRNA (miRNA, miR) in males and females contributes to changes in the expression of eNOS. miRNA was extracted from the myocardium of male and female C57BL/6 mice and subjected to an Affymetrix miRNA array. Decreased expression of miR-222 was discovered in females and confirmed by qRT-PCR from whole heart or isolated cardiomyocytes. The transcription factor V-ets erythroblastosis virus E26 oncogene homolog-1 (ets-1) was identified as a potential target of miR-222 using TargetScan, and fivefold increased ets-1 protein expression in females was confirmed by Western blot. Targeting of ets-1 by miR-222 was determined in HEK293 cells overexpressing luciferase under regulation of either the ets-1 3'-UTR, a null 3'-UTR control, or a scrambled ets-1 3'-UTR and treated with a small molecule miR-222 mimic or inhibitor. Additionally qRT-PCR confirmed that mRNA levels of the ets-1 transcriptional target, eNOS, were 25% higher in females. Compared with untreated myocyte controls, 50% inhibition of eNOS expression was achieved by treatment with a miR-222 mimic, compared with a 25% increase due to miR-222 inhibitor. Our findings indicate that sex-dependent miR-222 regulation alters the expression of the cardiac regulatory protein eNOS.

  9. Histone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia-induced cell growth.

    PubMed

    Tan, Xiaoling; Feng, Lan; Huang, Xiaoyong; Yang, Yidong; Yang, Chengzhong; Gao, Yuqi

    2017-03-07

    Hypoxia stimulates excessive growth of vascular smooth muscle cells (VSMCs) contributing to vascular remodelling. Recent studies have shown that histone deacetylase inhibitors (HDIs) suppress VSMC proliferation and activate eNOS expression. However, the effects of HDI on hypoxia-induced VSMC growth and the role of activated eNOS in VSMCs are unclear. Using an EdU incorporation assay and flow cytometry analysis, we found that the HDIs, butyrate (Bur) and suberoylanilide hydroxamic acid (SAHA) significantly suppressed the proliferation of hypoxic VSMC lines and induced apoptosis. Remarkable induction of cleaved caspase 3, p21 expression and reduction of PCNA expression were also observed. Increased eNOS expression and enhanced NO secretion by hypoxic VSMC lines were detected using Bur or SAHA treatment. Knockdown of eNOS by siRNA transfection or exposure of hypoxic VSMCs to NO scavengers weakened the effects of Bur and SAHA on the growth of hypoxic VSMCs. In animal experiments, administration of Bur to Wistar rats exposed to hypobaric hypoxia for 28 days ameliorated the thickness and collagen deposition in pulmonary artery walls. Although the mean pulmonary arterial pressure (mPAP) was not obviously decreased with Bur in hypoxic rats, right ventricle hypertrophy index (RVHI) was decreased and the oxygen partial pressure of arterial blood was elevated. Furthermore, cell viability was decreased and eNOS and cleaved caspase 3 were induced in HDI-treated rat pulmonary arterial SMCs. These findings imply that HDIs prevent hypoxia-induced VSMC growth, in correlation with activated eNOS expression and activity in hypoxic VSMCs.

  10. The effect of high protein diet and exercise on irisin, eNOS, and iNOS expressions in kidney.

    PubMed

    Tastekin, Ebru; Palabiyik, Orkide; Ulucam, Enis; Uzgur, Selda; Karaca, Aziz; Vardar, Selma Arzu; Yilmaz, Ali; Aydogdu, Nurettin

    2016-08-01

    Long-term effects of high protein diets (HPDs) on kidneys are still not sufficiently studied. Irisin which increases oxygen consumption and thermogenesis in white fat cells was shown in skeletal muscles and many tissues. Nitric oxide synthases (NOS) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. We aimed to investigate the effects of HPD, irisin and NO expression in kidney and relation of them with exercise and among themselves. Animals were grouped as control, exercise, HPD and exercise combined with HPD (exercise-HPD). Rats were kept on a HPD for 5 weeks and an exercise program was given them as 5 exercise and 2 rest days per week exercising on a treadmill with increasing speed and angle. In our study, while HPD group had similar total antioxidant capacity (TAC) levels with control group, exercise and exercise-HPD groups had lower levels (p < 0.05). Kidneys of exercising rats had no change in irisin or eNOS expression but their iNOS expression had increased (p < 0.001). HPD-E group has not been observed to cause kidney damage and not have a significant effect on rat kidney irisin, eNOS, or iNOS expression. Localization of irisin, eNOS, and iNOS staining in kidney is highly selective and quite clear in this study. Effects of exercise and HPD on kidney should be evaluated with different exercise protocols and contents of the diet. İrisin, eNOS, and iNOS staining localizations should be supported with various research studies.

  11. Resveratrol Prevented Lipopolysaccharide-Induced Endothelial Dysfunction in Rat Thoracic Aorta Through Increased eNOS Expression

    PubMed Central

    Uğurel, Seda Sultan; Kuşçu, Nilay; Özenci, Çiler Çelik; Dalaklıoğlu, Selvinaz; Taşatargil, Arda

    2016-01-01

    Background: The cardiovascular benefits of Resveratrol (RVT) have been well established by previous experimental and clinical studies. Aims: The goal of this study was to test the effectiveness of RVT administration on the impaired endothelial function induced by lipopolysaccharide (LPS), and to elucidate the role of endothelial nitric oxide synthase (eNOS)/Sirtuin 1 (SIRT1) pathway. Study Design: Animal experiment. Methods: Endotoxemia was induced by intraperitoneal injection of 10 mg/kg LPS, and the thoracic aorta was isolated six hours later. RVT was injected intraperitoneally 15 minutes before LPS administration. Six hours after LPS injection, potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP) were used to examine to vascular reactivity and endothelial function. eNOS, phospho-eNOS (p-eNOS) (Ser 1177), and SIRT1 expressions in thoracic aorta were evaluated by Western blot. Results: LPS administration significantly inhibited the relaxation response induced by ACh, while the relaxation to SNP was not significantly altered. Phe- and KCl-induced contractile responses in the thoracic aorta significantly decreased in LPS-injected group. eNOS and p-eNOS expression decreased significantly in arteries obtained from LPS group rats. The impaired vasoreactivity as well as decreased expressions of eNOS, p-eNOS, and SIRT1 in vessels from LPS-injected rats were improved by RVT treatment. Conclusion: The endothelium-dependent vasodilatation of the thoracic aorta was significantly inhibited by LPS administration, and RVT treatment may improve vascular endothelial function. The protective effect of RVT might be associated with increased eNOS expression and activity. PMID:27403381

  12. Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS.

    PubMed

    Wang, Weiye; Ha, Chang Hoon; Jhun, Bong Sook; Wong, Chelsea; Jain, Mukesh K; Jin, Zheng-Gen

    2010-04-08

    Fluid shear stress generated by steady laminar blood flow protects vessels from atherosclerosis. Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) are fluid shear stress-responsive genes and key mediators in flow anti-inflammatory and antiatherosclerotic actions. However, the molecular mechanisms underlying flow induction of KLF2 and eNOS remain largely unknown. Here, we show a novel role of histone deacetylase 5 (HDAC5) in flow-mediated KLF2 and eNOS expression. We found for the first time that fluid shear stress stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a calcium/calmodulin-dependent pathway. Consequently, flow induced the dissociation of HDAC5 and myocyte enhancer factor-2 (MEF2) and enhanced MEF2 transcriptional activity, which leads to expression of KLF2 and eNOS. Adenoviral overexpression of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 were replaced by Ala259/Ala498, HDAC5-S/A), which shows resistance to flow-induced nuclear export, suppressed flow-mediated MEF2 transcriptional activity and expression of KLF2 and eNOS. Importantly, HDAC5-S/A attenuated the flow-inhibitory effect on monocyte adhesion to endothelial cells. Taken together, our results reveal that phosphorylation-dependent derepression of HDAC5 mediates flow-induced KLF2 and eNOS expression as well as flow anti-inflammation, and suggest that HDAC5 could be a potential therapeutic target for the prevention of atherosclerosis.

  13. Chronic aerobic exercise associated to dietary modification improve endothelial function and eNOS expression in high fat fed hamsters.

    PubMed

    Boa, Beatriz C S; Souza, Maria das Graças C; Leite, Richard D; da Silva, Simone V; Barja-Fidalgo, Thereza Christina; Kraemer-Aguiar, Luiz Guilherme; Bouskela, Eliete

    2014-01-01

    Obesity is epidemic in the western world and central adipose tissue deposition points to increased cardiovascular morbidity and mortality, independently of any association between obesity and other cardiovascular risk factors. Physical exercise has been used as non-pharmacological treatment to significantly reverse/attenuate obesity comorbidities. In this study we have investigated effects of exercise and/or dietary modification on microcirculatory function, body composition, serum glucose, iNOS and eNOS expression on 120 male hamsters treated for 12 weeks with high fat chow (HF, n = 30) starting on the 21st day of birth. From week 12 to 20, animals were randomly separated in HF (no treatment change), return to standard chow (HFSC, n = 30), high fat chow associated to an aerobic exercise training program (AET) (HFEX, n = 30) and return to standard chow+AET (HFSCEX, n = 30). Microvascular reactivity in response to acetylcholine and sodium nitroprusside and macromolecular permeability increase induced by 30 minutes ischemia followed by reperfusion were assessed on the cheek pouch preparation. Total body fat and aorta eNOS and iNOS expression by immunoblotting assay were evaluated on the experimental day. Compared to HFSC and HFSCEX groups, HF and HFEX ones presented increased visceral fat [(mean±SEM) (HF)4.9±1.5 g and (HFEX)4.7±0.9 g vs. (HFSC)*3.0±0.7 g and (HFSCEX)*1.9±0.4 g/100 g BW]; impaired endothelial-dependent vasodilatation [Ach 10(-8) M (HF)87.9±2.7%; (HFSC)*116.7±5.9%; (HFEX)*109.1±4.6%; (HFSCEX)*105±2.8%; Ach10(-6) M (HF)95.3±3.1%; (HFSC)*126±6.2%; (HFEX)*122.5±2.8%; (HFSCEX)*118.1±4.3% and Ach10(-4) M (HF)109.5±4.8%; (HFSC)*149.6±6.6%; (HFEX)*143.5±5.4% and (HFSCEX)*139.4±5.2%], macromolecular permeability increase after ischemia/reperfusion [(HF)40.5±4.2; (HFSC)*19.0±1.6; (HFEX)*18.6±2.1 and (HFSCEX)* 21.5±3.7 leaks/cm2), decreased eNOS expression, increased leptin and glycaemic levels. Endothelial

  14. Alteration in cardiac uncoupling proteins and eNOS gene expression following high-intensity interval training in favor of increasing mechanical efficiency

    PubMed Central

    Fallahi, Ali Asghar; Shekarfroush, Shahnaz; Rahimi, Mostafa; Jalali, Amirhossain; Khoshbaten, Ali

    2016-01-01

    Objective(s): High-intensity interval training (HIIT) increases energy expenditure and mechanical energy efficiency. Although both uncoupling proteins (UCPs) and endothelial nitric oxide synthase (eNOS) affect the mechanical efficiency and antioxidant capacity, their effects are inverse. The aim of this study was to determine whether the alterations of cardiac UCP2, UCP3, and eNOS mRNA expression following HIIT are in favor of increased mechanical efficiency or decreased oxidative stress. Materials and Methods: Wistar rats were divided into five groups: control group (n=12), HIIT for an acute bout (AT1), short term HIIT for 3 and 5 sessions (ST3 and ST5), long-term training for 8 weeks (LT) (6 in each group). The rats of the training groups were made to run on a treadmill for 60 min in three stages: 6 min running for warm-up, 7 intervals of 7 min running on treadmill with a slope of 5° to 20° (4 min with an intensity of 80-110% VO2max and 3 min at 50-60% VO2max), and 5-min running for cool-down. The control group did not participate in any exercise program. Rats were sacrificed and the hearts were extracted to analyze the levels of UCP2, UCP3 and eNOS mRNA by RT-PCR. Results: UCP3 expression was increased significantly following an acute training bout. Repeated HIIT for 8 weeks resulted in a significant decrease in UCPs mRNA and a significant increase in eNOS expression in cardiac muscle. Conclusion: This study indicates that Long term HIIT through decreasing UCPs mRNA and increasing eNOS mRNA expression may enhance energy efficiency and physical performance. PMID:27114795

  15. Antenatal Maternally-Administered Phosphodiesterase Type 5 Inhibitors Normalize eNOS Expression in the Fetal Lamb Model of Congenital Diaphragmatic Hernia

    PubMed Central

    Shue, Eveline H; Schecter, Samuel C.; Gong, Wenhui; Etemadi, Mozziyar; Johengen, Michael; Iqbal, Corey; Derderian, S. Christopher; Oishi, Peter; Fineman, Jeffrey R.; Miniati, Doug

    2013-01-01

    Purpose Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. Methods CDH were created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. Results Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82±12% in Normal-Placebo, 61±5% in CDH-Placebo, 116±6% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105±15% in Normal-Placebo, 82±3% in CDH-Placebo, 158±16% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p = 0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p = 0.0002). Conclusions PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH. PMID:24439578

  16. Clinical Implication of Aortic Wall Biopsy in Aortic Valve Disease with Bicuspid Valve Pathology

    PubMed Central

    Kim, Yong Han; Kim, Ji Seong; Choi, Jae-Woong; Chang, Hyoung Woo; Na, Kwon Joong; Kim, Jun Sung; Kim, Kyung-Hwan

    2016-01-01

    Background Although unique aortic pathology related to bicuspid aortic valve (BAV) has been previously reported, clinical implications of BAV to aortopathy risk have yet to be investigated. We looked for potential differences in matrix protein expressions in the aortic wall in BAV patients. Methods Aorta specimens were obtained from 31 patients: BAV group (n=27), tricuspid aortic valve (TAV) group (n=4). The BAV group was categorized into three subgroups: left coronary sinus-right coronary sinus (R+L group; n=13, 42%), right coronary sinus-non-coronary sinus (R+N group; n=8, 26%), and anteroposterior (AP group; n=6, 19%). We analyzed the expression of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase (MMP)-9, and tissue inhibitor of matrix metalloproteinase (TIMP)-2. Results Based on the mean value of the control group, BAV group showed decreased expression of eNOS in 72.7% of patients, increased MMP-9 in 82.3%, and decreased TIMP in 79.2%. There was a higher tendency for aortopathy in the BAV group: eNOS (BAV:TAV)= 53%±7%:57%±11%, MMP-9 (BAV:TAV)=48%±10%:38%±1%. The AP group showed lower expression of eNOS than the fusion (R+L, R+N) group did; 48%±5% vs. 55%±7% (p=0.081). Conclusion Not all patients with BAV had expression of aortopathy; however, for patients who had a suspicious form of bicuspid valve, aortic wall biopsy could be valuable to signify the presence of aortopathy. PMID:27965921

  17. Role of reactive oxygen species in the signalling cascade of cyclosporine A-mediated up-regulation of eNOS in vascular endothelial cells

    PubMed Central

    López-Ongil, S; Hernández-Perera, O; Navarro-Antolín, J; Pérez de Lema, G; Rodríguez-Puyol, M; Lamas, S; Rodríguez-Puyol, D

    1998-01-01

    Cyclosporine A (CsA) increases eNOS mRNA expression in bovine cultured aortic endothelial cells (BAEC). As some effects of CsA may be mediated by reactive oxygen species (ROS), present experiments were devoted to test the hypothesis that the CsA-induced eNOS up-regulation could be dependent on an increased synthesis of ROS.CsA induced a dose-dependent increase of ROS synthesis, with the two fluorescent probes used, DHR123 (CsA 1 μM: 305±7% over control) and H2DCFDA (CsA 1 μM: 178±6% over control).Two ROS generating systems, xanthine plus xanthine oxidase (XXO) and glucose oxidase (GO), increased the expression of eNOS mRNA in BAEC, an effect which was maximal after 8 h of incubation (XXO: 168±21% of control values. GO: 208±18% of control values). The ROS-dependent increased eNOS mRNA expression was followed by an increase in eNOS activity.The effect of CsA on eNOS mRNA expression was abrogated by catalase, and superoxide dismutase (SOD). In contrast, the antioxidant PDTC augmented eNOS mRNA expression, both in basal conditions and in the presence of CsA.The potential participation of the transcription factor AP-1 was explored. Electrophoretic mobility shift assays were consistent with an increase in AP-1 DNA-binding activity in BAEC treated with CsA or glucose oxidase.The present results support a role for ROS, particularly superoxide anion and hydrogen peroxide, as mediators of the CsA-induced eNOS mRNA up-regulation. Furthermore, they situate ROS as potential regulators of gene expression in endothelial cells, both in physiological and pathophysiological situations. PMID:9647467

  18. Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression

    PubMed Central

    Azuma, Junya; Wong, Ronald J.; Morisawa, Takeshi; Hsu, Mark; Maegdefessel, Lars; Zhao, Hui; Kalish, Flora; Kayama, Yosuke; Wallenstein, Matthew B.; Deng, Alicia C.; Spin, Joshua M.; Stevenson, David K.; Dalman, Ronald L.; Tsao, Philip S.

    2016-01-01

    Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease. PMID:26894432

  19. Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

    PubMed

    Azuma, Junya; Wong, Ronald J; Morisawa, Takeshi; Hsu, Mark; Maegdefessel, Lars; Zhao, Hui; Kalish, Flora; Kayama, Yosuke; Wallenstein, Matthew B; Deng, Alicia C; Spin, Joshua M; Stevenson, David K; Dalman, Ronald L; Tsao, Philip S

    2016-01-01

    Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

  20. Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism

    NASA Technical Reports Server (NTRS)

    Boo, Yong Chool; Hwang, Jinah; Sykes, Michelle; Michell, Belinda J.; Kemp, Bruce E.; Lum, Hazel; Jo, Hanjoong

    2002-01-01

    Shear stress stimulates nitric oxide (NO) production by phosphorylating endothelial NO synthase (eNOS) at Ser(1179) in a phosphoinositide-3-kinase (PI3K)- and protein kinase A (PKA)-dependent manner. The eNOS has additional potential phosphorylation sites, including Ser(116), Thr(497), and Ser(635). Here, we studied these potential phosphorylation sites in response to shear, vascular endothelial growth factor (VEGF), and 8-bromocAMP (8-BRcAMP) in bovine aortic endothelial cells (BAEC). All three stimuli induced phosphorylation of eNOS at Ser(635), which was consistently slower than that at Ser(1179). Thr(497) was rapidly dephosphorylated by 8-BRcAMP but not by shear and VEGF. None of the stimuli phosphorylated Ser(116). Whereas shear-stimulated Ser(635) phosphorylation was not affected by phosphoinositide-3-kinase inhibitors wortmannin and LY-294002, it was blocked by either treating the cells with a PKA inhibitor H89 or infecting them with a recombinant adenovirus-expressing PKA inhibitor. These results suggest that shear stress stimulates eNOS by two different mechanisms: 1) PKA- and PI3K-dependent and 2) PKA-dependent but PI3K-independent pathways. Phosphorylation of Ser(635) may play an important role in chronic regulation of eNOS in response to mechanical and humoral stimuli.

  1. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in L-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT₁R Expression.

    PubMed

    Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

    2016-02-29

    This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N(ω)-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS.

  2. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression

    PubMed Central

    Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

    2016-01-01

    This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in Nω-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID:26938552

  3. MicroRNA Expression Signature in Degenerative Aortic Stenosis

    PubMed Central

    2016-01-01

    Degenerative aortic stenosis, characterized by narrowing of the exit of the left ventricle of the heart, has become the most common valvular heart disease in the elderly. The aim of this study was to investigate the microRNA (miRNA) signature in degenerative AS. Through microarray analysis, we identified the miRNA expression signature in the tissue samples from healthy individuals (n = 4) and patients with degenerative AS (n = 4). Six miRNAs (hsa-miR-193a-3p, hsa-miR-29b-1-5p, hsa-miR-505-5p, hsa-miR-194-5p, hsa-miR-99b-3p, and hsa-miR-200b-3p) were overexpressed and 14 (hsa-miR-3663-3p, hsa-miR-513a-5p, hsa-miR-146b-5p, hsa-miR-1972, hsa-miR-718, hsa-miR-3138, hsa-miR-21-5p, hsa-miR-630, hsa-miR-575, hsa-miR-301a-3p, hsa-miR-636, hsa-miR-34a-3p, hsa-miR-21-3p, and hsa-miR-516a-5p) were downregulated in aortic tissue from AS patients. GeneSpring 13.1 was used to identify potential human miRNA target genes by comparing a 3-way comparison of predictions from TargetScan, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify potential pathways and functional annotations associated with AS. Twenty miRNAs were significantly differentially expressed between patients with AS samples and normal controls and identified potential miRNA targets and molecular pathways associated with this morbidity. This study describes the miRNA expression signature in degenerative AS and provides an improved understanding of the molecular pathobiology of this disease. PMID:27579316

  4. MicroRNA Expression Signature in Degenerative Aortic Stenosis.

    PubMed

    Shi, Jing; Liu, Hui; Wang, Hui; Kong, Xiangqing

    2016-01-01

    Degenerative aortic stenosis, characterized by narrowing of the exit of the left ventricle of the heart, has become the most common valvular heart disease in the elderly. The aim of this study was to investigate the microRNA (miRNA) signature in degenerative AS. Through microarray analysis, we identified the miRNA expression signature in the tissue samples from healthy individuals (n = 4) and patients with degenerative AS (n = 4). Six miRNAs (hsa-miR-193a-3p, hsa-miR-29b-1-5p, hsa-miR-505-5p, hsa-miR-194-5p, hsa-miR-99b-3p, and hsa-miR-200b-3p) were overexpressed and 14 (hsa-miR-3663-3p, hsa-miR-513a-5p, hsa-miR-146b-5p, hsa-miR-1972, hsa-miR-718, hsa-miR-3138, hsa-miR-21-5p, hsa-miR-630, hsa-miR-575, hsa-miR-301a-3p, hsa-miR-636, hsa-miR-34a-3p, hsa-miR-21-3p, and hsa-miR-516a-5p) were downregulated in aortic tissue from AS patients. GeneSpring 13.1 was used to identify potential human miRNA target genes by comparing a 3-way comparison of predictions from TargetScan, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify potential pathways and functional annotations associated with AS. Twenty miRNAs were significantly differentially expressed between patients with AS samples and normal controls and identified potential miRNA targets and molecular pathways associated with this morbidity. This study describes the miRNA expression signature in degenerative AS and provides an improved understanding of the molecular pathobiology of this disease.

  5. Resveratrol Ameliorates High Glucose and High-Fat/Sucrose Diet-Induced Vascular Hyperpermeability Involving Cav-1/eNOS Regulation

    PubMed Central

    Peng, Xiao lin; Qu, Wei; Wang, Lin zhi; Huang, Bin qing; Ying, Chen jiang; Sun, Xiu fa; Hao, Li ping

    2014-01-01

    Vascular endothelial hyperpermeability is one of the manifestations of endothelial dysfunction. Resveratrol (Res) is considered to be beneficial in protecting endothelial function. However, currently, the exact protective effect and involved mechanisms of Res on endothelial dysfunction-hyperpermeability have not been completely clarified. The aim of present study is to investigate the effects of Res on amelioration of endothelial hyperpermeability and the role of caveolin-1 (Cav-1)/endothelial nitric oxide synthase (eNOS) pathway. Adult male Wistar rats were treated with a normal or high-fat/sucrose diet (HFS) with or without Res for 13 weeks. HFS and in vitro treatment with high glucose increased hyperpermeability in rat aorta, heart, liver and kidney and cultured bovine aortic endothelial cells (BAECs), respectively, which was attenuated by Res treatment. Application of Res reversed the changes in eNOS and Cav-1 expressions in aorta and heart of rats fed HFS and in BAECs incubated with high glucose. Res stimulated the formation of NO inhibited by high glucose in BAECs. Beta-Cyclodextrin (β-CD), caveolae inhibitor, showed the better beneficial effect than Res alone to up-regulate eNOS phosphorylative levels, while NG-Nitro-77 L-arginine methyl ester (L-NAME), eNOS inhibitor, had no effect on Cav-1 expression. Our studies suggested that HFS and in vitro treatment with high glucose caused endothelial hyperpermeability, which were ameliorated by Res at least involving Cav-1/eNOS regulation. PMID:25419974

  6. Resveratrol ameliorates high glucose and high-fat/sucrose diet-induced vascular hyperpermeability involving Cav-1/eNOS regulation.

    PubMed

    Peng, Xiao Lin; Qu, Wei; Wang, Lin Zhi; Huang, Bin Qing; Ying, Chen Jiang; Sun, Xiu Fa; Hao, Li Ping

    2014-01-01

    Vascular endothelial hyperpermeability is one of the manifestations of endothelial dysfunction. Resveratrol (Res) is considered to be beneficial in protecting endothelial function. However, currently, the exact protective effect and involved mechanisms of Res on endothelial dysfunction-hyperpermeability have not been completely clarified. The aim of present study is to investigate the effects of Res on amelioration of endothelial hyperpermeability and the role of caveolin-1 (Cav-1)/endothelial nitric oxide synthase (eNOS) pathway. Adult male Wistar rats were treated with a normal or high-fat/sucrose diet (HFS) with or without Res for 13 weeks. HFS and in vitro treatment with high glucose increased hyperpermeability in rat aorta, heart, liver and kidney and cultured bovine aortic endothelial cells (BAECs), respectively, which was attenuated by Res treatment. Application of Res reversed the changes in eNOS and Cav-1 expressions in aorta and heart of rats fed HFS and in BAECs incubated with high glucose. Res stimulated the formation of NO inhibited by high glucose in BAECs. Beta-Cyclodextrin (β-CD), caveolae inhibitor, showed the better beneficial effect than Res alone to up-regulate eNOS phosphorylative levels, while NG-Nitro-77 L-arginine methyl ester (L-NAME), eNOS inhibitor, had no effect on Cav-1 expression. Our studies suggested that HFS and in vitro treatment with high glucose caused endothelial hyperpermeability, which were ameliorated by Res at least involving Cav-1/eNOS regulation.

  7. Endothelial function does not improve with high-intensity continuous exercise training in SHR: implications of eNOS uncoupling.

    PubMed

    Battault, Sylvain; Singh, François; Gayrard, Sandrine; Zoll, Joffrey; Reboul, Cyril; Meyer, Grégory

    2016-02-01

    Exercise training is a well-recognized way to improve vascular endothelial function by increasing nitric oxide (NO) bioavailability. However, in hypertensive subjects, unlike low- and moderate-intensity exercise training, the beneficial effects of continuous high-intensity exercise on endothelial function are not clear, and the underlying mechanisms remain unknown. The aim of this study was to investigate the impact of high-intensity exercise on vascular function, especially on the NO pathway, in spontaneous hypertensive rats (SHR). These effects were studied on WKY, sedentary SHR and SHR that exercised at moderate (SHR-MOD) and high intensity (SHR-HI) on a treadmill (1 h per day; 5 days per week for 6 weeks at 55% and 80% of their maximal aerobic velocity, respectively). Endothelial function and specific NO contributions to acetylcholine-mediated relaxation were evaluated by measuring the aortic ring isometric forces. Endothelial nitric oxide synthase (eNOS) expression and phosphorylation (ser1177) were evaluated by western blotting. The total aortic and eNOS-dependent reactive oxygen species (ROS) production was assessed using electron paramagnetic resonance in aortic tissue. Although the aortas of SHR-HI had increased eNOS levels without alteration of eNOS phosphorylation, high-intensity exercise had no beneficial effect on endothelium-dependent vasorelaxation, unlike moderate exercise. This result was associated with increased eNOS-dependent ROS production in the aortas of SHR-HI. Notably, the use of the recoupling agent BH4 or a thiol-reducing agent blunted eNOS-dependent ROS production in the aortas of SHR-HI. In conclusion, the lack of a positive effect of high-intensity exercise on endothelial function in SHR was mainly explained by redox-dependent eNOS uncoupling, resulting in a switch from NO to O2(-) generation.

  8. Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth

    PubMed Central

    Soto, Manuel Sarmiento; O'Brien, Emma R.; Andreou, Kleopatra; Scrace, Simon F.; Zakaria, Rasheed; Jenkinson, Michael D.; O'Neill, Eric; Sibson, Nicola R.

    2016-01-01

    Over 20% of cancer patients will suffer metastatic spread to the brain, and prognosis remains poor. Communication between tumour cells and host tissue is essential during metastasis, yet little is known of the processes underlying such interactions in the brain. Here we test the hypothesis that cross-talk between tumour cells and host brain cells, through tumour cell leukocyte function associated protein-1 (LFA-1), is critical in metastasis development. Temporal expression of LFA-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1) was determined in two different mouse models of brain metastasis. Marked upregulation of both proteins was found, co-localising with astrocytes, microglia and tumour cells themselves. Silencing of LFA-1 expression in MDA231Br-GFP cells prior to intracerebral injection resulted in > 70% reduction in tumour burden compared to control MDA231Br-GFP cells (p < 0.005, n = 5). Subsequent qRT-PCR analysis of brain tissue revealed significant reductions in COX-2, VEGF and eNOS from host brain tissue, but not tumour cells, in mice injected with LFA-1 knockdown cells (p < 0.0001, n = 5). Finally, expression of both LFA-1 and ICAM-1 was demonstrated in human brain metastasis samples. The results of this study suggest LFA-1 as a new target in brain metastasis therapy and highlight the potential synergy with current anti-COX-2 and anti-NOS therapies. PMID:27447568

  9. Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus.

    PubMed

    Youn, Ji-Youn; Zhou, Jun; Cai, Hua

    2015-08-01

    We have recently shown that angiotensin II-mediated uncoupling of endothelial nitric oxide synthase (eNOS) contributes to endothelial dysfunction in streptozotocin-induced type 1 diabetes mellitus. However, it has remained unclear whether and how eNOS uncoupling occurs in type 2 diabetes mellitus (T2DM) and the consequences of such in regulating vascular function. Here we investigated a role of bone morphogenic protein (BMP)-4 in mediating eNOS uncoupling, endothelial dysfunction, and inflammation in db/db mice. Circulating levels of BMP4 were markedly elevated in db/db mice but not in mice with type 1 diabetes mellitus, in which angiotensin II levels were significantly increased. Infusion of BMP4 antagonist noggin into db/db mice (15 μg/kg/day, 4 weeks) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin (H(4)B) bioavailability. The impaired endothelium-dependent vasorelaxation in db/db aortas was significantly improved by noggin infusion. Exposure of aortic endothelial cells to BMP4 (50 ng/mL, 24 hours) resulted in eNOS uncoupling, which was attenuated by H(4)B precursor sepiapterin or small interfering RNA silencing nicotinamide adenine dinucleotide phosphate oxidase isoform 1 (NOX1). Interestingly, BMP4-dependent NOX1 up-regulation was abrogated by sepiapterin, implicating a NOX1-uncoupled eNOS-NOX1 feed-forward loop. BMP4 induction of cyclooxygenase 2 (COX2) expression and vascular cell adhesion protein 1 was found in db/db mice. Consistently, COX2 was up-regulated by BMP4 in endothelial cells, which was attenuated by sepiapterin, implicating an upstream role of eNOS uncoupling in COX2-mediated inflammatory activation. Taken together, our data for the first time reveal a novel role of BMP4 in inducing NOX1-dependent eNOS uncoupling in T2DM, which may promote development of novel therapeutics restoring endothelial function in T2DM.

  10. Aortic angiography

    MedlinePlus

    ... to: Abdominal aortic aneurysm Aortic dissection Aortic regurgitation Aortic stenosis Congenital (present from birth) problems Double aortic arch ... Aortic aneurysm repair - endovascular Aortic dissection Aortic insufficiency Aortic stenosis Magnetic resonance ... Patient Instructions Abdominal ...

  11. RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing.

    PubMed

    Guauque-Olarte, Sandra; Droit, Arnaud; Tremblay-Marchand, Joël; Gaudreault, Nathalie; Kalavrouziotis, Dimitri; Dagenais, Francois; Seidman, Jonathan G; Body, Simon C; Pibarot, Philippe; Mathieu, Patrick; Bossé, Yohan

    2016-10-01

    The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves.

  12. Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome.

    PubMed

    Busnadiego, O; Gorbenko Del Blanco, D; González-Santamaría, J; Habashi, J P; Calderon, J F; Sandoval, P; Bedja, D; Guinea-Viniegra, J; Lopez-Cabrera, M; Rosell-Garcia, T; Snabel, J M; Hanemaaijer, R; Forteza, A; Dietz, H C; Egea, G; Rodriguez-Pascual, F

    2015-08-01

    Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transforming growth factor-β (TGF-β)- and angiotensin II-dependent pathways, alterations in the vascular extracellular matrix (ECM) may also play a role in the onset and progression of the aortic disease. Lysyl oxidases (LOX) are extracellular enzymes, which initiates the formation of covalent cross-linking of collagens and elastin, thereby contributing to the maturation of the ECM. Here we have explored the role of LOX in the formation of aortic aneurysms in MFS. We show that aortic tissue from MFS patients and MFS mouse model (Fbn1(C1039G/+)) displayed enhanced expression of the members of the LOX family, LOX and LOX-like 1 (LOXL1), and this is associated with the formation of mature collagen fibers. Administration of a LOX inhibitor for 8weeks blocked collagen accumulation and aggravated elastic fiber impairment, and these effects correlated with the induction of a strong and rapidly progressing aortic dilatation, and with premature death in the more severe MFS mouse model, Fbn1(mgR/mgR), without any significant effect on wild type animals. This detrimental effect occurred preferentially in the ascending portion of the aorta, with little or no involvement of the aortic root, and was associated to an overactivation of both canonical and non-canonical TGF-β signaling pathways. The blockade of angiotensin II type I receptor with losartan restored TGF-β signaling activation, normalized elastic fiber impairment and prevented the aortic dilatation induced by LOX inhibition in Fbn1(C1039G/+) mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS.

  13. Genistein, a soy phytoestrogen, upregulates the expression of human endothelial nitric oxide synthase and lowers blood pressure in spontaneously hypertensive rats.

    PubMed

    Si, Hongwei; Liu, Dongmin

    2008-02-01

    Genistein, a soy phytoestrogen, may improve vascular function, but the mechanism of this effect is unclear. Endothelial-derived nitric oxide (NO) is a key regulator of vascular tone and atherogenesis. Previous studies have established that estrogen can act directly on vascular endothelial cells (EC) to enhance NO synthesis through genomic stimulation of endothelial NO synthase (eNOS) expression. However, it is unknown whether genistein has a similar effect. We therefore investigated whether genistein directly regulates NO synthesis in primary human aortic EC (HAEC) and human umbilical vein EC (HUVEC). Genistein, at physiologically achievable concentrations in individuals consuming soy products, enhanced the expression of eNOS and subsequently elevated NO synthesis in both HAEC and HUVEC, with 1-10 micromol/L genistein inducing the maximal effects. However, the effects of genistein on eNOS and NO were not mediated by activation of estrogen signaling or inhibition of tyrosine kinases, 2 known biological actions of genistein. Genistein (1-10 micromol/L) increased eNOS gene expression (1.8- to 2.6-fold of control) and significantly increased eNOS promoter activity of the human eNOS gene in HAEC and HUVEC, suggesting that genistein activates eNOS transcription. Dietary supplementation of genistein to spontaneously hypertensive rats restored aortic eNOS levels, improved aortic wall thickness, and alleviated hypertension, confirming the biological relevance of the in vitro findings. Our data suggest that genistein has direct genomic effects on the vascular wall that are unrelated to its known actions, leading to increased eNOS expression and NO synthesis, thereby improving hypertension.

  14. Expression of alphaVbeta3 integrin in the chick embryo aortic endothelium.

    PubMed

    Corbel, Catherine

    2002-09-01

    The integrin chain alphaV, expressed in association with beta3, by cells of the megakaryocytic/thrombocytic and endothelial lineages is thought to play an important role in angiogenesis. alphaVbeta3 expression by endothelial cells is not constitutive but induced by various stimuli in avian and human models. Here the developmental pattern of alphaVbeta3 expression was analysed in the chick embryo by immunocytochemistry, using a specific monoclonal antibody. On day 2 of development alphaVbeta3 expression was restricted to rare cells in the blood stream, in the embryo proper and in the yolk sac blood islands. AlphaVbeta3 expression by endothelial cells became detectable on day 3 and was restricted to the dorsal aorta. Interestingly it was absent from the intra-aortic hemopoietic clusters (E3.5) which, as we have showed previously, express the alphaIIbbeta3 integrin and display progenitor potentialities. However the endothelium underlying intra-embryonic hemopoietic clusters expressed this integrin. In contrast E6-7 para-aortic hemopoietic foci contained numerous alphaVbeta3 positive cells. Both alphaVbeta3 and alphaIIbbeta3 were expressed in these latter hemopoietic sites, while alphaVbeta3 was still selectively expressed by the aortic endothelium until E6. Thereafter, at E7 the pulmonary artery also expressed it. Since alphaIIbbeta3 is expressed by avian and murine multilineage hemopoietic progenitors, we then studied the hemopoietic potentialities of alphaVbeta3/alphaIIbeta3 double positive cells from embryonic bone marrow differentiating in vitro in erythro-myeloid conditions. Thrombocytic, erythroid and myeloid progenitor potentialities were found within the cell population expressing both beta3 integrins.

  15. Diesel Particulate Exposed Macrophages Alter Endothelial Cell Expression of eNOS, iNOS, MCP1, and Glutathione Synthesis Genes

    PubMed Central

    Weldy, Chad S.; Wilkerson, Hui-Wen; Larson, Timothy V.; Stewart, James A.; Kavanagh, Terrance J.

    2011-01-01

    There is considerable debate regarding inhaled diesel exhaust particulate (DEP) causing impairments in vascular reactivity. Although there is evidence that inhaled particles can translocate from the lung into the systemic circulation, it has been suggested that inflammatory factors produced in the lung following macrophage particle engulfment also pass into the circulation. To investigate these differing hypotheses, we used in vitro systems to model each exposure. By using a direct exposure system and a macrophage-endothelial cell co-culture model, we compared the effects of direct DEP exposure and exposure to inflammatory factors produced by DEP-treated macrophages, on endothelial cell mRNA levels for eNOS, iNOS, endothelin-1, and endothelin-converting-enzyme-1. As markers of oxidative stress, we measured the effects of DEP treatment on glutathione (GSH) synthesis genes and on total GSH. In addition, we analyzed the effect of DEP treatment on monocyte chemo-attractant protein-1. Direct DEP exposure increased endothelial GCLC and GCLM as well as total GSH in addition to increased eNOS, iNOS and Mcp1 mRNA. Alternatively, inflammatory factors released from DEP-exposed macrophages markedly up-regulated endothelial iNOS and Mcp1 while modestly down-regulating eNOS. These data support both direct exposure to DEP and the release of inflammatory cytokines as explanations for DEP-induced impairments in vascular reactivity. PMID:21920430

  16. p38 mitogen-activated protein kinase activates eNOS in endothelial cells by an estrogen receptor alpha-dependent pathway in response to black tea polyphenols.

    PubMed

    Anter, Elad; Chen, Kai; Shapira, Oz M; Karas, Richard H; Keaney, John F

    2005-05-27

    Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERalpha on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERalpha on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38alpha MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERalpha phosphorylation and downstream activation of Akt, and eNOS. The key role of ERalpha Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERalpha subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERalpha with p38 MAPK as ERalpha with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERalpha and these data uncover a new mechanism of ERalpha activation that has broad implications for NO bioactivity and endothelial cell phenotype.

  17. Silicic acid in drinking water prevents age-related alterations in the endothelium-dependent vascular relaxation modulating eNOS and AQP1 expression in experimental mice: an immunohistochemical study.

    PubMed

    Buffoli, Barbara; Foglio, Eleonora; Borsani, Elisa; Exley, Christopher; Rezzani, Rita; Rodella, Luigi Fabrizio

    2013-06-01

    The maintenance of endothelial integrity is of great importance in coping with age-related vascular alterations. Endothelium-derived nitric oxide is one of the various vasoactive substances able to regulate vascular tone and homeostasis, and whose decrease is known to be related with senescence in endothelial cells. There are reports on the efficacy of silicon, especially as silicic acid, in protecting vascular integrity during age-related vascular diseases. The aim of this study was to evaluate the ability of supplementation of silicic acid in drinking water in the maintenance of vascular health in a mouse model of early physiological aging. In particular, we evaluated the relationship between Si supplementation and endothelial nitric oxide synthase (eNOS) expression, taking into account also the aquaporin-1 (AQP-1) isoform that, as recently reported, seems to be involved in nitric oxide transport across cell membranes. Our results showed that silicic acid supplementation increased both eNOS and AQP-1 expression, suggesting that silicic acid modulation of endothelial nitric oxide synthase and aquaporin-1 could represent a potential strategy against age-related vascular senescence.

  18. NOX isoforms in the development of abdominal aortic aneurysm.

    PubMed

    Siu, Kin Lung; Li, Qiang; Zhang, Yixuan; Guo, Jun; Youn, Ji Youn; Du, Jie; Cai, Hua

    2017-04-01

    Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling.

  19. [Effect of captopril on expression of PTEN in aorta of aortic-induced hypertensive rats].

    PubMed

    Yan, Zhiqiang; Hu, Ya'e; Liu, Bo; Jiang, Zonglai

    2004-12-01

    This study inquired about the role of tumor suppressor PTEN in the arterial remodeling of Ang II induced hypertension. The expression of PTEN of aorta was examined in the aortic-constricted hypertensive rats (hypertension group), in the aortic-constricted hypertensive rats treated with captopril(hypertension and captopril group), and in the rats having undergone sham operation (control group). At day 28 after surgery, the aortas were collected from the groups. The expression of PTEN mRNA was detected by RT-PCR. The expression and location of PTEN protein were determined by immunohistochemistry. The results showed that the expression of PTEN in aorta of the hypertension group was significantly lower than that of the hypertension and captopril group, and similarly lower than that of the control group. The intensity of PTEN-positive immunohistochemical production in aorta of the hypertension group was weaker than that of the hypertension and captopril group, and likewise, it was weaker than the control. PTEN-positive immunohistochemical production was located in VSMC of aorta. The findings indicated that the expression of PTEN is reduced in hypertensive aorta, that the reduced PTEN experession can be reversed by captopril treatment, that AngII and the increased mechanical strain may participate in regulating expression of PTEN, and that PTEN may play a role in the arterial remodeling induced by hypertension.

  20. Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus

    PubMed Central

    Youn, Ji-Youn; Zhou, Jun

    2015-01-01

    We have recently shown that angiotensin II-mediated uncoupling of endothelial nitric oxide synthase (eNOS) contributes to endothelial dysfunction in streptozotocin-induced type 1 diabetes mellitus. However, it has remained unclear whether and how eNOS uncoupling occurs in type 2 diabetes mellitus (T2DM) and the consequences of such in regulating vascular function. Here we investigated a role of bone morphogenic protein (BMP)-4 in mediating eNOS uncoupling, endothelial dysfunction, and inflammation in db/db mice. Circulating levels of BMP4 were markedly elevated in db/db mice but not in mice with type 1 diabetes mellitus, in which angiotensin II levels were significantly increased. Infusion of BMP4 antagonist noggin into db/db mice (15 μg/kg/day, 4 weeks) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin (H4B) bioavailability. The impaired endothelium-dependent vasorelaxation in db/db aortas was significantly improved by noggin infusion. Exposure of aortic endothelial cells to BMP4 (50 ng/mL, 24 hours) resulted in eNOS uncoupling, which was attenuated by H4B precursor sepiapterin or small interfering RNA silencing nicotinamide adenine dinucleotide phosphate oxidase isoform 1 (NOX1). Interestingly, BMP4-dependent NOX1 up-regulation was abrogated by sepiapterin, implicating a NOX1-uncoupled eNOS-NOX1 feed-forward loop. BMP4 induction of cyclooxygenase 2 (COX2) expression and vascular cell adhesion protein 1 was found in db/db mice. Consistently, COX2 was up-regulated by BMP4 in endothelial cells, which was attenuated by sepiapterin, implicating an upstream role of eNOS uncoupling in COX2-mediated inflammatory activation. Taken together, our data for the first time reveal a novel role of BMP4 in inducing NOX1-dependent eNOS uncoupling in T2DM, which may promote development of novel therapeutics restoring endothelial function in T2DM. PMID:26121233

  1. Flavonoids from artichoke (Cynara scolymus L.) up-regulate endothelial-type nitric-oxide synthase gene expression in human endothelial cells.

    PubMed

    Li, Huige; Xia, Ning; Brausch, Isolde; Yao, Ying; Förstermann, Ulrich

    2004-09-01

    Nitric oxide (NO) produced by endothelial nitric-oxide synthase (eNOS) represents an antithrombotic and anti-atherosclerotic principle in the vasculature. Hence, an enhanced expression of eNOS in response to pharmacological interventions could provide protection against cardiovascular diseases. In EA.hy 926 cells, a cell line derived from human umbilical vein endothelial cells (HUVECs), an artichoke leaf extract (ALE) increased the activity of the human eNOS promoter (determined by luciferase reporter gene assay). An organic subfraction from ALE was more potent in this respect than the crude extract, whereas an aqueous subfraction of ALE was without effect. ALE and the organic subfraction thereof also increased eNOS mRNA expression (measured by an RNase protection assay) and eNOS protein expression (determined by Western blot) both in EA.hy 926 cells and in native HUVECs. NO production (measured by NO-ozone chemiluminescence) was increased by both extracts. In organ chamber experiments, ex vivo incubation (18 h) of rat aortic rings with the organic subfraction of ALE enhanced the NO-mediated vasodilator response to acetylcholine, indicating that the up-regulated eNOS remained functional. Caffeoylquinic acids and flavonoids are two major groups of constituents of ALE. Interestingly, the flavonoids luteolin and cynaroside increased eNOS promoter activity and eNOS mRNA expression, whereas the caffeoylquinic acids cynarin and chlorogenic acid were without effect. Thus, in addition to the lipid-lowering and antioxidant properties of artichoke, an increase in eNOS gene transcription may also contribute to its beneficial cardiovascular profile. Artichoke flavonoids are likely to represent the active ingredients mediating eNOS up-regulation.

  2. Activation of Endothelial Nitric Oxide (eNOS) Occurs through Different Membrane Domains in Endothelial Cells

    PubMed Central

    Tran, Jason; Magenau, Astrid; Rodriguez, Macarena; Rentero, Carles; Royo, Teresa; Enrich, Carlos; Thomas, Shane R.; Grewal, Thomas; Gaus, Katharina

    2016-01-01

    Endothelial cells respond to a large range of stimuli including circulating lipoproteins, growth factors and changes in haemodynamic mechanical forces to regulate the activity of endothelial nitric oxide synthase (eNOS) and maintain blood pressure. While many signalling pathways have been mapped, the identities of membrane domains through which these signals are transmitted are less well characterized. Here, we manipulated bovine aortic endothelial cells (BAEC) with cholesterol and the oxysterol 7-ketocholesterol (7KC). Using a range of microscopy techniques including confocal, 2-photon, super-resolution and electron microscopy, we found that sterol enrichment had differential effects on eNOS and caveolin-1 (Cav1) colocalisation, membrane order of the plasma membrane, caveolae numbers and Cav1 clustering. We found a correlation between cholesterol-induced condensation of the plasma membrane and enhanced high density lipoprotein (HDL)-induced eNOS activity and phosphorylation suggesting that cholesterol domains, but not individual caveolae, mediate HDL stimulation of eNOS. Vascular endothelial growth factor (VEGF)-induced and shear stress-induced eNOS activity was relatively independent of membrane order and may be predominantly controlled by the number of caveolae on the cell surface. Taken together, our data suggest that signals that activate and phosphorylate eNOS are transmitted through distinct membrane domains in endothelial cells. PMID:26977592

  3. Activation of Endothelial Nitric Oxide (eNOS) Occurs through Different Membrane Domains in Endothelial Cells.

    PubMed

    Tran, Jason; Magenau, Astrid; Rodriguez, Macarena; Rentero, Carles; Royo, Teresa; Enrich, Carlos; Thomas, Shane R; Grewal, Thomas; Gaus, Katharina

    2016-01-01

    Endothelial cells respond to a large range of stimuli including circulating lipoproteins, growth factors and changes in haemodynamic mechanical forces to regulate the activity of endothelial nitric oxide synthase (eNOS) and maintain blood pressure. While many signalling pathways have been mapped, the identities of membrane domains through which these signals are transmitted are less well characterized. Here, we manipulated bovine aortic endothelial cells (BAEC) with cholesterol and the oxysterol 7-ketocholesterol (7KC). Using a range of microscopy techniques including confocal, 2-photon, super-resolution and electron microscopy, we found that sterol enrichment had differential effects on eNOS and caveolin-1 (Cav1) colocalisation, membrane order of the plasma membrane, caveolae numbers and Cav1 clustering. We found a correlation between cholesterol-induced condensation of the plasma membrane and enhanced high density lipoprotein (HDL)-induced eNOS activity and phosphorylation suggesting that cholesterol domains, but not individual caveolae, mediate HDL stimulation of eNOS. Vascular endothelial growth factor (VEGF)-induced and shear stress-induced eNOS activity was relatively independent of membrane order and may be predominantly controlled by the number of caveolae on the cell surface. Taken together, our data suggest that signals that activate and phosphorylate eNOS are transmitted through distinct membrane domains in endothelial cells.

  4. Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats.

    PubMed

    Dai, Zen-Kong; Tan, Mian-Shin; Chai, Chee-Yin; Chou, Shah-Hwa; Lin, Pei-Chin; Yeh, Jwu-Lai; Jeng, Arco Y; Chang, Chung-I; Chen, Ing-Jun; Wu, Jiunn-Ren

    2006-06-01

    Sildenafil, an oral phosphodiesterase Type 5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism. We previously showed that aortic banding could result in left ventricular overloading and pulmonary hypertension (PH). In this study, we investigated whether early administration of sildenafil, either immediately after or 2 weeks after aortic banding, could ameliorate the development of PH and alter gene expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS), and alter the levels of cGMP in rats undergoing an ascending aortic banding. Rats (n = 32) were divided into sham-operated and banding groups with or without treatment. The banded rats were further divided into three groups: (i) receiving saline on Days 1-28 (AOB28; n = 8), (ii) receiving saline on Days 1-14 followed by treatment with 50 mg/kg/day sildenafil on Days 15-28 (AOB28/Sil(15-28); n = 8), and (iii) receiving 50 mg/kg/day sildenafil on days 1-28 (AOB28/Sil(1-28); n = 8). The sham-operated rats were administrated saline on Days 1-28 (n = 8). Four weeks after banding, there was a significant development of PH with pulmonary vascular remodeling. Although both sildenafil-treatment groups had significant increases in cGMP and had reductions in the thickening in the medial layer of pulmonary arteriole, notable attenuation of PH occurred only in the AOB28/Sil(1-28) group. PreproET-1 and eNOS messenger RNA (mRNA) expressions were measured by competitive reverse transcription polymerase chain reaction, and eNOS protein was determined by Western blotting. Sildenafil did not alter the elevated ET-1 or preproET-1 mRNA in banded rats. Interestingly, pulmonary eNOS increased in the AOB28/Sil(1-28) group. In conclusion, early treatment with sildenafil inhibited the rise in pulmonary arterial pressure and pulmonary vascular remodeling in PH secondary to heart failure, and cGMP, but not ET-1, might be involved. Clinically, early repeated administration of sildenafil may offer an

  5. Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves.

    PubMed

    Wirrig, Elaine E; Hinton, Robert B; Yutzey, Katherine E

    2011-03-01

    Approximately 5 million people are affected with aortic valve disease (AoVD) in the United States. The most common treatment is aortic valve (AoV) replacement surgery, however, replacement valves are susceptible to failure, necessitating additional surgeries. The molecular mechanisms underlying disease progression and late AoV calcification are not well understood. Recent studies suggest that genes involved in bone and cartilage development play an active role in osteogenic-like calcification in human calcific AoVD (CAVD). In an effort to define the molecular pathways involved in AoVD progression and calcification, expression of markers of valve mesenchymal progenitors, chondrogenic precursors, and osteogenic differentiation was compared in pediatric non-calcified and adult calcified AoV specimens. Valvular interstitial cell (VIC) activation, extracellular matrix (ECM) disorganization, and markers of valve mesenchymal and skeletal chondrogenic progenitor cells were observed in both pediatric and adult AoVD. However, activated BMP signaling, increased expression of cartilage and bone-type collagens, and increased expression of the osteogenic marker Runx2 are observed in adult diseased AoVs. They are not observed in the majority of pediatric diseased valves, representing a marked distinction in the molecular profile between pediatric and adult diseased AoVs. The combined evidence suggests that an actively regulated osteochondrogenic disease process underlies the pathological changes affecting AoVD progression, ultimately resulting in stenotic AoVD. Both pediatric and adult diseased AoVs express protein markers of valve mesenchymal and chondrogenic progenitor cells while adult diseased AoVs also express proteins involved in osteogenic calcification. These findings provide specific molecular indicators of AoVD progression, which may lead to identification of early disease markers and the development of potential therapeutics.

  6. X-ray Structure of Engineered Human Aortic Preferentially Expressed Protein-1 (APEG-1)

    SciTech Connect

    Manjasetty,B.; Niesen, F.; Scheich, C.; Roske, Y.; Goetz, F.; Behlke, J.; Sievert, V.; Heinemann, U.; Buessow, K.

    2005-01-01

    Arterial smooth muscle cells (SMC) are essential for the formation and function of the cardiovascular system. Abnormalities in their growth can cause a wide range of human disorders such as atherosclerosis, the principal cause for heart failure, thus the leading cause for deaths in the western world. The molecular mechanisms that regulate SMC growth and differentiation are unclear partly due to the lack of specific markers and defined in vitro differentiation systems. The recently discovered Aortic Preferentially Expressed Protein-1 (APEG-1) may serve as a sensitive marker for vascular SMC differentiation. APEG-1 is expressed in differentiated vascular SMC in vivo and was found to be down-regulated rapidly in de-differentiated vascular SMC in vitro and in injured arteries in vivo.

  7. 3-Methylcholanthrene/Aryl-Hydrocarbon Receptor-Mediated Hypertension Through eNOS Inactivation.

    PubMed

    Chang, Chih-Cheng; Hsu, Yung-Ho; Chou, Hsiu-Chu; Lee, Yuan-Chii G; Juan, Shu-Hui

    2017-05-01

    Endothelial nitric oxide synthase (eNOS) modulates vascular blood pressure and is predominantly expressed in endothelial cells and activated through the protein kinase B (Akt/PKB)-dependent pathway. We previously reported that 3-methylcholanthrene (3MC) activates the aryl hydrocarbon receptor (AhR) and reduces PI3K/Akt phosphorylation. This study investigated the mechanism underlying the downregulatory effects of 3-MC on nitric oxide (NO) production occurring through the AhR/RhoA/Akt-mediated mechanism. The mechanism underlying the effects of 3-MC on eNOS activity and blood pressure was examined in vitro and in vivo through genetic and pharmacological approaches. Results indicated that 3-MC modified heat shock protein 90 (HSP90), caveolin-1, dynein, and eNOS mRNA and protein expression through the AhR/RhoA-dependent mechanism in mouse cerebral vascular endothelial cells (MCVECs) and that 3-MC reduced eNOS phosphorylation through the AhR/RhoA-mediated inactivation of Akt1. The upregulation of dynein expression was associated with decreased eNOS dimer formation (eNOS dimer; an activated form of the enzyme). Coimmunoprecipitation assay results indicated that 3-MC significantly reduced the interaction between eNOS and its regulatory proteins, including Akt1 and HSP90, but increased the interaction between eNOS and caveolin-1. Immunofluorescence and Western blot analysis revealed that 3-MC reduced the amount of membrane-bound activated eNOS, and a modified Griess assay revealed that 3-MC concomitantly reduced NO production. However, simvastatin reduced 3-MC-mediated murine hypertension. Our study results indicate that AhR, RhoA, and eNOS have major roles in blood pressure regulation. Statin intervention might provide a potential therapeutic approach for reducing hypertension caused by 3-MC. J. Cell. Physiol. 232: 1020-1029, 2017. © 2016 Wiley Periodicals, Inc.

  8. Activation of eNOS in endothelial cells exposed to ionizing radiation involves components of the DNA damage response pathway

    SciTech Connect

    Nagane, Masaki; Yasui, Hironobu; Sakai, Yuri; Yamamori, Tohru; Niwa, Koichi; Hattori, Yuichi; Kondo, Takashi; Inanami, Osamu

    2015-01-02

    Highlights: • eNOS activity is increased in BAECs exposed to X-rays. • ATM is involved in this increased eNOS activity. • HSP90 modulates the radiation-induced activation of ATM and eNOS. - Abstract: In this study, the involvement of ataxia telangiectasia mutated (ATM) kinase and heat shock protein 90 (HSP90) in endothelial nitric oxide synthase (eNOS) activation was investigated in X-irradiated bovine aortic endothelial cells. The activity of nitric oxide synthase (NOS) and the phosphorylation of serine 1179 of eNOS (eNOS-Ser1179) were significantly increased in irradiated cells. The radiation-induced increases in NOS activity and eNOS-Ser1179 phosphorylation levels were significantly reduced by treatment with either an ATM inhibitor (Ku-60019) or an HSP90 inhibitor (geldanamycin). Geldanamycin was furthermore found to suppress the radiation-induced phosphorylation of ATM-Ser1181. Our results indicate that the radiation-induced eNOS activation in bovine aortic endothelial cells is regulated by ATM and HSP90.

  9. ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in Non-Hodgkin's Lymphomas

    SciTech Connect

    Zhu, Xinghua; Miao, Xiaobing; Wu, Yaxun; Li, Chunsun; Guo, Yan; Liu, Yushan; Chen, Yali; Lu, Xiaoyun; Wang, Yuchan; He, Song

    2015-07-15

    Enolases are glycolytic enzymes responsible for the ATP-generated conversion of 2-phosphoglycerate to phosphoenolpyruvate. In addition to the glycolytic function, Enolase 1 (ENO1) has been reported up-regulation in several tumor tissues. In this study, we investigated the expression and biologic function of ENO1 in Non-Hodgkin's Lymphomas (NHLs). Clinically, by western blot analysis we observed that ENO1 expression was apparently higher in diffuse large B-cell lymphoma than in the reactive lymphoid tissues. Subsequently, immunohistochemical staining of 144 NHLs suggested that the expression of ENO1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas. Further, we identified ENO1 as an independent prognostic factor, and it was significantly correlated with overall survival of NHL patients. In addition, we found that ENO1 could promote cell proliferation, regulate cell cycle associated gene and PI3K/AKT signaling pathway in NHLs. Finally, we verified that ENO1 participated in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to FN or HS5 cells significantly protected OCI-Ly8 and Daudi cells from cytotoxicity compared with those cultured in suspension, and these effects were attenuated when transfected with ENO1-siRNA. Based on the study, we propose that inhibition of ENO1 expression may be a novel strategy for therapy for NHLs patients, and it may be a target for drug resistance. - Highlights: • ENO1 expression is reversely correlated with clinical outcomes of patients with NHLs. • ENO1 promotes the proliferation of NHL cells. • ENO1 regulates cell adhesion mediated drug resistance.

  10. A three-dimensional co-culture model of the aortic valve using magnetic levitation.

    PubMed

    Tseng, Hubert; Balaoing, Liezl R; Grigoryan, Bagrat; Raphael, Robert M; Killian, T C; Souza, Glauco R; Grande-Allen, K Jane

    2014-01-01

    The aortic valve consists of valvular interstitial cells (VICs) and endothelial cells (VECs). While these cells are understood to work synergistically to maintain leaflet structure and valvular function, few co-culture models of these cell types exist. In this study, aortic valve co-cultures (AVCCs) were assembled using magnetic levitation and cultured for 3 days. Immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction were used to assess the maintenance of cellular phenotype and function, and the formation of extracellular matrix. AVCCs stained positive for CD31 and α-smooth muscle actin (αSMA), demonstrating that the phenotype was maintained. Functional markers endothelial nitric oxide synthase (eNOS), von Willebrand factor (VWF) and prolyl-4-hydroxylase were present. Extracellular matrix components collagen type I, laminin and fibronectin also stained positive, with reduced gene expression of these proteins in three dimensions compared to two dimensions. Genes for collagen type I, lysyl oxidase and αSMA were expressed less in AVCCs than in 2-D cultures, indicating that VICs are quiescent. Co-localization of CD31 and αSMA in the AVCCs suggests that endothelial-mesenchymal transdifferentiation might be occurring. Differences in VWF and eNOS in VECs cultured in two and three dimensions also suggests that the AVCCs possibly have anti-thrombotic potential. Overall, a co-culture model of the aortic valve was designed, and serves as a basis for future experiments to understand heart valve biology.

  11. MDP up-regulates the gene expression of type I interferons in human aortic endothelial cells.

    PubMed

    Lv, Qingshan; Yang, Mei; Liu, Xueting; Zhou, Lina; Xiao, Zhilin; Chen, Xiaobin; Chen, Meifang; Xie, Xiumei; Hu, Jinyue

    2012-03-23

    Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2). Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs) with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF) 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  12. Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

    PubMed

    LaDisa, John F; Bozdag, Serdar; Olson, Jessica; Ramchandran, Ramani; Kersten, Judy R; Eddinger, Thomas J

    2015-01-01

    Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with >6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

  13. Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

    PubMed Central

    LaDisa, John F.; Bozdag, Serdar; Olson, Jessica; Ramchandran, Ramani; Kersten, Judy R.; Eddinger, Thomas J.

    2015-01-01

    Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with >6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID’s for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA. PMID:26207811

  14. Vitamin D Receptor Deficiency and Low Vitamin D Diet Stimulate Aortic Calcification and Osteogenic Key Factor Expression in Mice

    PubMed Central

    Schmidt, Nadine; Brandsch, Corinna; Kühne, Hagen; Thiele, Alexandra; Hirche, Frank; Stangl, Gabriele I.

    2012-01-01

    Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR−/−) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01). Data from LDL receptor knockout (LDLR−/−) mice that were fed western diet with either low (50 IU/kg), recommended (1,000 IU/kg), or high (10,000 IU/kg) amounts of vitamin D3 over 16 weeks revealed increasing plasma concentrations of 25(OH)D (P<0.001) with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001). Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas. PMID:22536373

  15. High-fat, cholesterol-rich diet affects leptin expression in the aortic layers.

    PubMed

    Krawczynska, Agata; Olczak, Elzbieta; Rembiszewska, Alina; Gromadzka-Ostrowska, Joanna

    2013-01-01

    Leptin is stated to be an important mediator between obesity and cardiovascular disease. However, whether leptin location in the aorta is dependent on diet and its atherogenic character is still unknown. This study examined the relationship between a high-fat diet with or without cholesterol and the expression of leptin in aortic layers. Forty male rats were fed a high-fat diet with fish or grape seed oil as a dietary fat source, with or without cholesterol, to enhance the atherogenic character of their diet. The experiments lasted for three and six weeks, respectively. Plasma lipid profile, plasma leptin concentration and leptin expression in the endothelium (E), myometrium (M) and adventitia (A) were examined. The length of feeding was a key factor which influenced both the lipid profile and leptin expression in the aorta. Leptin concentration positively correlated with body weight and plasma triglycerides only in the three-week experiment, which suggests that the physiological actions of leptin can be disturbed by prolonged consumption of a high-fat diet. Short-term intake of a high-fat diet with fish oil, increasing high density lipoprotein cholesterol (HDL) level and decreasing total cholesterol (TC)/HDL ratio, enhanced leptin expression in E in comparison to the group fed grape seed oil. However, in the group with the highest diet intake, leptin expression in each layer was lowest. Generally, leptin expression was most common in E; however, an extension of the period of feeding in groups fed a diet with grape seed oil with or without additional cholesterol increased leptin presence in M and A in comparison to the group fed fish oil. Significantly higher values of TC and HDL in the same groups may suggest that leptin changes in the aorta and the atherogenic impact of grape seed oil can be connected when the consumption of a high-fat diet is excessive.

  16. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor 2

    PubMed Central

    Song, Rui; Zeng, Qingchun; Ao, Lihua; Yu, Jessica A.; Cleveland, Joseph C.; Zhao, Ke-seng; Fullerton, David A.; Meng, Xianzhong

    2012-01-01

    Background While biglycan and oxidized low-density lipoprotein (oxLDL) accumulation has been observed in calcific, stenotic aortic valves, their role in the pathogenesis of calcific aortic valve disease is poorly understood. We hypothesized that soluble biglycan induces the osteogenic response in human aortic valve interstitial cells (AVICs) via Toll-like receptor (TLR) 2 and TLR4, and mediates the pro-osteogenic effect of oxLDL. Methods and Results AVICs of stenotic valves express higher levels of biglycan. Stimulation of cells from normal valves with biglycan increased the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) among the chondrogenic/osterogenic markers examined, and caused accumulation of calcium deposits. TLR2 silencing, but not TLR4 silencing, reduced BMP-2 and ALP levels following biglycan stimulation although co-immunoprecipitation revealed that biglycan intercts with both TLR2 and TLR4. Biglycan induced the phosphorylation of ERK1/2, p38 MAPK and NF-κB. Inhibition of ERK1/2 markedly reduced the up-regulation of BMP-2 and ALP expression by biglycan while inhibition of p38 MAPK or NF-κB had a moderate effect. Stimulation of AVICs with oxLDL up-regulated biglycan expression and release. Knockdown neutralization of biglycan reduced the effect of oxLDL on BMP-2 and ALP expression. Conclusion Extracellular soluble biglycan induces the expression of BMP-2 and ALP in human AVICs primarily via TLR2 and contributes to the the pro-osteogenic effect of oxLDL. These findings highlight the potential role of soluble biglycan and oxLDL in the development of calcific aortic valve disease. PMID:22982459

  17. Cyclic strain is a weak inducer of prostacyclin synthase expression in bovine aortic endothelial cells

    NASA Technical Reports Server (NTRS)

    Segurola, R. J. Jr; Oluwole, B.; Mills, I.; Yokoyama, C.; Tanabe, T.; Kito, H.; Nakajima, N.; Sumpio, B. E.

    1997-01-01

    Recent studies indicate that hemodynamic forces such as cyclic strain and shear stress can increase prostacyclin (PGI2) secretion by endothelial cells (EC) but the effect of these forces on prostacyclin synthase (PGIS) gene expression remains unclear and is the focus of this study. Bovine aortic EC were seeded onto type I collagen coated flexible membranes and grown to confluence. The membranes and attached EC were subjected to 10% average strain at 60 cpm (0.5 sec deformation alternating with 0.5 sec relaxation) for up to 5 days. PGIS gene expression was determined by Northern blot analysis and protein level by Western blot analysis. The effect of cyclic strain on the PGIS promoter was determined by the transfection of a 1-kb human PGIS gene promoter construct coupled to a luciferase reporter gene into EC, followed by determination of luciferase activity. PGIS gene expression increased 1.7-fold in EC subjected to cyclic strain for 24 hr. Likewise, EC transfected with a pGL3B-PGIS (-1070/-10) construct showed an approximate 1.3-fold elevation in luciferase activity in EC subjected to cyclic strain for 3, 4, 8, and 12 hr. The weak stimulation of PGIS gene expression by cyclic strain was reflected in an inability to detect alterations in PGIS protein levels in EC subjected to cyclic strain for as long as 5 days. These data suggest that strain-induced stimulation of PGIS gene expression plays only a minor role in the ability of cyclic strain to stimulate PGI2 release in EC. These findings coupled with our earlier demonstration of a requisite addition of exogenous arachidonate in order to observe strain-induced PGI2 release, implicates a mechanism that more likely involves strain-induced stimulation of PGIS activity.

  18. Increased Expression of Lamin A/C Correlate with Regions of High Wall Stress in Abdominal Aortic Aneurysms

    PubMed Central

    Malkawi, Amir; Pirianov, Grisha; Torsney, Evelyn; Chetter, Ian; Sakalihasan, Natzi; Loftus, Ian M.; Nordon, Ian; Huggins, Christopher; Charolidi, Nicoletta; Thompson, Matt; Xu, Xie Yun; Cockerill, Gillian W.

    2015-01-01

    Background Since aortic diameter is the most ­significant risk factor for rupture, we sought to identify stress-dependent changes in gene expression to illuminate novel molecular processes in aneurysm rupture. Materials and Methods We constructed finite element maps of abdominal computerized tomography scans (CTs) of seven abdominal aortic aneurysm (AAA) patients to map wall stress. Paired biopsies from high- and low-stress areas were collected at surgery using vascular landmarks as coordinates. Differential gene expression was evaluated by Illumina Array analysis, using the whole genome DNA-mediated, annealing, selection, extension, and ligation (DASL) gene chip (n = 3 paired samples). Results The sole significant candidate from this analysis, Lamin A/C, was validated at the protein level, using western blotting. Lamin A/C expression in the inferior mesenteric vein (IMV) of AAA patients was compared to a control group and in aortic smooth muscle cells in culture in response to physiological pulsatile stretch. ­Areas of high wall stress (n = 7) correlate to those ­regions which have the thinnest walls [778 µm (585–1120 µm)] in comparison to areas of lowest wall stress [1620 µm (962–2919 µm)]. Induced expression of Lamin A/C ­correlated with areas of high wall stress from AAAs but was not significantly induced in the IMV from AAA patients compared to controls (n = 16). Stress-induced expression of Lamin A/C was mimicked by exposing aortic smooth muscle cells to prolonged pulsatile stretch. Conclusion Lamin A/C protein is specifically increased in areas of high wall stress in AAA from patients, but is not increased on other vascular beds of aneurysm patients, suggesting that its elevation may be a compensatory response to the pathobiology leading to aneurysms. PMID:27175366

  19. Eno-Osher schemes for Euler equations

    NASA Technical Reports Server (NTRS)

    Vandervegt, Jacobus J.

    1992-01-01

    The combination of the Osher approximate Riemann solver for the Euler equations and various ENO schemes is discussed for one-dimensional flow. The three basic approaches, viz. the ENO scheme using primitive variable reconstruction, either with Cauchy-Kowalewski procedure for time integration or the TVD Runge-Kutta scheme, and the flux-ENO method are tested on different shock tube cases. The shock tube cases were chosen to present a serious challenge to the ENO schemes in order to test their ability to capture flow discontinuities, such as shocks. Also the effect of the ordering of the eigen values, viz. natural or reversed ordering, in the Osher scheme is investigated. The ENO schemes are tested up to fifth order accuracy in space and time. The ENO-Osher scheme using the Cauchy-Kowalewski procedure for time integration is found to be the most accurate and robust compared with the other methods and is also computationally efficient. The tests showed that the ENO schemes perform reasonably well, but have problems in cases where two discontinuities are close together. In that case there are not enough points in the smooth part of the flow to create a non-oscillatory interpolation.

  20. Circulating Blood eNOS Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis

    PubMed Central

    Wood, Katherine C.; Cortese-Krott, Miriam M.; Kovacic, Jason C.; Noguchi, Audrey; Liu, Virginia B.; Wang, Xunde; Raghavachari, Nalini; Boehm, Manfred; Kato, Gregory J.; Kelm, Malte; Gladwin, Mark T.

    2013-01-01

    Objective Mice genetically deficient in endothelial nitric oxide synthase (eNOS−/−) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. While the current paradigm holds that this bioactivity derives specifically from expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed. Approach and Results To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted WT and eNOS−/− mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NAME and repristinated by the NOS substrate L-Arginine, and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert 14C-Arginine into 14C-Citrulline in a NOS-dependent fashion. Conclusions These are the first studies to definitively establish a role for a blood borne eNOS, using cross transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect. PMID:23702660

  1. Insights into the arginine paradox: evidence against the importance of subcellular location of arginase and eNOS.

    PubMed

    Elms, Shawn; Chen, Feng; Wang, Yusi; Qian, Jin; Askari, Bardia; Yu, Yanfang; Pandey, Deepesh; Iddings, Jennifer; Caldwell, Ruth B; Fulton, David J R

    2013-09-01

    Reduced production of nitric oxide (NO) is one of the first indications of endothelial dysfunction and precedes overt cardiovascular disease. Increased expression of Arginase has been proposed as a mechanism to account for diminished NO production. Arginases consume l-arginine, the substrate for endothelial nitric oxide synthase (eNOS), and l-arginine depletion is thought to competitively reduce eNOS-derived NO. However, this simple relationship is complicated by the paradox that l-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. One mechanism proposed to explain this is compartmentalization of intracellular l-arginine into distinct, poorly interchangeable pools. In the current study, we investigated this concept by targeting eNOS and Arginase to different intracellular locations within COS-7 cells and also BAEC. We found that supplemental l-arginine and l-citrulline dose-dependently increased NO production in a manner independent of the intracellular location of eNOS. Cytosolic arginase I and mitochondrial arginase II reduced eNOS activity equally regardless of where in the cell eNOS was expressed. Similarly, targeting arginase I to disparate regions of the cell did not differentially modify eNOS activity. Arginase-dependent suppression of eNOS activity was reversed by pharmacological inhibitors and absent in a catalytically inactive mutant. Arginase did not directly interact with eNOS, and the metabolic products of arginase or downstream enzymes did not contribute to eNOS inhibition. Cells expressing arginase had significantly lower levels of intracellular l-arginine and higher levels of ornithine. These results suggest that arginases inhibit eNOS activity by depletion of substrate and that the compartmentalization of l-arginine does not play a major role.

  2. Expression of a functional extracellular calcium-sensing receptor in human aortic endothelial cells

    SciTech Connect

    Ziegelstein, Roy C.; Xiong Yali; He Chaoxia; Hu Qinghua . E-mail: qinghuaa@jhmi.edu

    2006-03-31

    Extracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub o}) regulates the functions of many cell types through a G protein-coupled [Ca{sup 2+}]{sub o}-sensing receptor (CaR). Whether the receptor is functionally expressed in vascular endothelial cells is largely unknown. In cultured human aortic endothelial cells (HAEC), RT-PCR yielded the expected 555-bp product corresponding to the CaR, and CaR protein was demonstrated by fluorescence immunostaining and Western blot. RT-PCR also demonstrated the expression in HAEC of alternatively spliced variants of the CaR lacking exon 5. Although stimulation of fura 2-loaded HAEC by several CaR agonists (high [Ca{sup 2+}]{sub o}, neomycin, and gadolinium) failed to increase intracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub i}), the CaR agonist spermine stimulated an increase in [Ca{sup 2+}]{sub i} that was diminished in buffer without Ca{sup 2+} and was abolished after depletion of an intracellular Ca{sup 2+} pool with thapsigargin or after blocking IP{sub 3}- and ryanodine receptor-mediated Ca{sup 2+} release with xestospongin C and with high concentration ryanodine, respectively. Spermine stimulated an increase in DAF-FM fluorescence in HAEC, consistent with NO production. Both the increase in [Ca{sup 2+}]{sub i} and in NO production were reduced or absent in HAEC transfected with siRNA specifically targeted to the CaR. HAEC express a functional CaR that responds to the endogenous polyamine spermine with an increase in [Ca{sup 2+}]{sub i}, primarily due to release of IP{sub 3}- and ryanodine-sensitive intracellular Ca{sup 2+} stores, leading to the production of NO. Expression of alternatively spliced variants of the CaR may result in the absence of a functional response to other known CaR agonists in HAEC.

  3. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells.

    PubMed

    Nishinaga, M; Ozawa, T; Shimada, K

    1993-09-01

    Previous studies showed that homocysteine, a thrombo-atherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of porcine aortic endothelial cell cultures with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. The inhibitory effect was observed at a homocysteine concentration as low as 0.1 mM, and the maximal suppression occurred at 1 mM of homocysteine after 24 h. In contrast with a marked reduction in the maximal antithrombin III binding capacity (approximately 30% of control), the radioactivity of [35S]sulfate incorporated into heparan sulfate on the cell surface was minimally (< 15%) reduced. The cells remained viable after homocysteine treatment. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with 1 mM homocysteine, cysteine, or 2-mercaptoethanol; no reduction in binding activity was observed after preincubation with the same concentration of methionine, alanine, or valine. This sulfhydryl effect may be caused by generation of hydrogen peroxide, as incubation of catalase, but not superoxide dismutase, with homocysteine-treated endothelial cells prevented this reduction, whereas copper augmented the inhibitory effects of the metabolite. Thus, our data suggest that the inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the

  4. Numerical experiments on the accuracy of ENO and modified ENO schemes

    NASA Technical Reports Server (NTRS)

    Shu, Chi-Wang

    1990-01-01

    Further numerical experiments are made assessing an accuracy degeneracy phenomena. A modified essentially non-oscillatory (ENO) scheme is proposed, which recovers the correct order of accuracy for all the test problems with smooth initial conditions and gives comparable results with the original ENO schemes for discontinuous problems.

  5. Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

    PubMed Central

    Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K. Craig

    2016-01-01

    Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB–mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms. PMID:26483397

  6. Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.

    PubMed

    Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K Craig; Liu, Bo

    2016-01-01

    Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB-mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms.

  7. Angiotensin II induces an increase in MMP-2 expression in idiopathic ascending aortic aneurysm via AT1 receptor and JNK pathway.

    PubMed

    Wang, Chunmao; Chang, Qian; Qian, Xiangyang; Tian, Chuan; Sun, Xiaogang

    2015-07-01

    The cellular and molecular mechanisms responsible for human idiopathic ascending aortic aneurysm (IAAA) remain unknown. Matrix metalloproteinase-2 (MMP-2) is a key enzyme for the degradation of extracellular matrix in aneurysmal walls. The aim of this study was to elucidate the role of the angiotensin II (Ang II) pathway in MMP-2 induction in IAAA aortic walls. Quantitative polymerase chain reaction and western blot analysis were used to compare the MMP-2 mRNA and protein levels in ascending aortic specimens with those in IAAA patients (n = 10) and heart transplant donors (n = 5) without any aortopathy. It was found that MMP-2 expression was significantly increased, which was associated with elastic lamellae disruption in IAAA walls. Additionally, the expression levels of angiotensinogen (AGT) and Ang II in the ascending aortic tissues from individuals with and without IAAAs were detected by western blot analysis and radioimmunoassay, respectively. The results demonstrated that the expressions of AGT and Ang II protein were significantly increased in the ascending aortic tissues of IAAA patients. Furthermore, whether Ang II induces MMP-2 expression was investigated using human IAAA walls ex vivo culture. It was found that exogenous Ang II increased the MMP-2 expression in a dose-dependent manner, which was completely inhibited by the Ang II type 1 receptor (AT1R) inhibitor candesartan and was mediated by c-Jun N-terminal kinase (JNK) activation. Taken together, these results indicate that Ang II can induce an increase of MMP-2 expression via AT1R and JNK in ex vivo cultured IAAA aortic walls, and suggest that angiotensin receptor blocker (ARB) drugs and JNK inhibitors have the potential in the prevention or treatment of IAAAs.

  8. Space chimp Enos returns to Patrick Air Force Base

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Enos the chimpanzee that orbited the earth twice in a Mercury spacecraft arrives back at Patrick Air Force Base. Enos landed some 220 nautical miles south of Bermuda and was picked up up by the U.S.S. Stormes.

  9. Adenoviral expression of 15-lipoxygenase-1 in rabbit aortic endothelium: role in arachidonic acid-induced relaxation.

    PubMed

    Aggarwal, Nitin T; Holmes, Blythe B; Cui, Lijie; Viita, Helena; Yla-Herttuala, Seppo; Campbell, William B

    2007-02-01

    Endothelium-dependent vasorelaxation of the rabbit aorta is mediated by either nitric oxide (NO) or arachidonic acid (AA) metabolites from cyclooxygenase (COX) and 15-lipoxygenase (15-LO) pathways. 15-LO-1 metabolites of AA, 11,12,15-trihydroxyeicosatrienoic acid (THETA), and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) cause concentration-dependent relaxation. We tested the hypothesis that in the 15-LO pathway of AA metabolism, 15-LO-1 is sufficient and is the rate-limiting step in inducing relaxations in rabbit aorta. Aorta and rabbit aortic endothelial cells were treated with adenoviruses containing human 15-LO-1 cDNA (Ad-15-LO-1) or beta-galactosidase (Ad-beta-Gal). Ad-15-LO-1-transduction increased the expression of a 75-kDa protein corresponding to 15-LO-1, detected by immunoblotting with an anti-human15-LO-1 antibody, and increased the production of HEETA and THETA from [(14)C]AA. Immunohistochemical studies on Ad-15-LO-1-transduced rabbit aorta showed the presence of 15-LO-1 in endothelial cells. Ad-15-LO-1-treated aortic rings showed enhanced relaxation to AA (max 31.7 +/- 3.2%) compared with Ad-beta-Gal-treated (max 12.7 +/- 3.2%) or control nontreated rings (max 13.1 +/- 1.6%) (P < 0.01). The relaxations in Ad-15-LO-1-treated aorta were blocked by the 15-LO inhibitor cinnamyl-3,4-dihydroxy-a-cyanocinnamate. Overexpression of 15-LO-1 in the rabbit aortic endothelium is sufficient to increase the production of the vasodilatory HEETA and THETA and enhance the relaxations to AA. This confirms the role of HEETA and THETA as endothelium-derived relaxing factors.

  10. TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells

    SciTech Connect

    Patel, Devang N.; Bailey, Steven R.; Gresham, John K.; Schuchman, David B.; Shelhamer, James H.; Goldstein, Barry J.; Foxwell, Brian M.; Stemerman, Michael B.; Maranchie, Jodi K.; Valente, Anthony J.; Mummidi, Srinivas; Chandrasekar, Bysani . E-mail: chandraseka@uthscsa.edu

    2006-09-08

    CXCL16 is a transmembrane non-ELR CXC chemokine that signals via CXCR6 to induce aortic smooth muscle cell (ASMC) proliferation. While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known. Here, we demonstrate that LPS upregulates CXCR6 mRNA, protein, and surface expression in human ASMC. Inhibition of TLR4 with neutralizing antibodies or specific siRNA interference blocked LPS-mediated CXCR6 expression. LPS stimulated both AP-1 (c-Fos, c-Jun) and NF-{kappa}B (p50 and p65) activation, but only inhibition of AP-1 attenuated LPS-induced CXCR6 expression. Using dominant negative expression vectors and siRNA interference, we demonstrate that LPS induces AP-1 activation via MyD88, TRAF6, ERK1/2, and JNK signaling pathways. Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA. Finally, CXCR6 knockdown inhibited CXCL16-induced ASMC proliferation. These results demonstrate that LPS-TLR4-NOX4-AP-1 signaling can induce CXCR6 expression in ASMC, and suggest that the CXCL16-CXCR6 axis may be an important proinflammatory pathway in the pathogenesis of atherosclerosis.

  11. Mechanical Strain Induced Expression of Matrix Metalloproteinase-9 via Stretch-Activated Channels in Rat Abdominal Aortic Dissection

    PubMed Central

    Qiu, ZhiHuang; Chen, LiangWan; Cao, Hua; Chen, Qiang; Peng, Hua

    2017-01-01

    Background The aim of the study was to investigate the expression of matrix metalloproteinase-9 (MMP-9) in rat abdominal aortic dissection (AD) induced by mechanical strain, so as to offer a better understanding of the possible mechanisms of AD. Material/Methods Experimental AD in rats was achieved by the injection of porcine pancreatic elastase. At days 0, 1, 3, 5, 7, 14, 21, and 30 after the establishment of AD model, serum MMP-9 levels were measured by enzyme-linked immunosorbent assay (ELISA). Four groups of vascular rings were stretched in vitro with a mechanical strength of 0 g, 1 g, 3 g, or 5 g for 30 min. Another four groups were pretreated with GdCl3, streptomycin, SN50, and SN50M, followed by stretching with 3 g for 30 min. The messenger RNA and the protein of MMP-9 were analyzed by real-time RT-PCR and Western blotting, and NF-κB p65 was detected by ELISA. Results After the establishment of rat abdominal AD model, the serum MMP-9 levels of AD groups increased significantly. The results showed increased expression of MMP-9 in rat AD vessels stretched with mechanical strength of 1 g, 3 g, and 5 g, but this effect was mostly blocked by Gd Cl3 and streptomycin. The NF-κB activity in aortic rings was activated by stretching with a mechanical strength of 3 g and was blocked by SN50, but not by SN50M. Conclusions The expression of MMP-9 in serum was increased significantly after rat abdominal AD formation. Mechanical strain induced MMP-9 expression in AD vessels, which was mediated through the activation of the stretch-activated channel-induced NF-κB pathway. PMID:28286334

  12. Defining the Role of Fluid Shear Stress in the Expression of Early Signaling Markers for Calcific Aortic Valve Disease

    PubMed Central

    Sun, Ling; Rajamannan, Nalini M.; Sucosky, Philippe

    2013-01-01

    Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between cardiovascular risk factors, molecular signaling networks and hemodynamic cues. While earlier studies demonstrated that alterations in fluid shear stress (FSS) on the fibrosa could trigger inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. This knowledge could be critical to the elucidation of key CAVD risk factors such as congenital valve defects, aging and hypertension, which are known to generate FSS disturbances. The objective of this study was to characterize ex vivo the contribution of isolated and combined abnormalities in FSS magnitude and frequency to early valvular pathogenesis. The ventricularis and fibrosa of porcine aortic valve leaflets were exposed simultaneously to different combinations of sub-physiologic/physiologic/supra-physiologic levels of FSS magnitude and frequency for 24, 48 and 72 hours in a double cone-and-plate device. Endothelial activation and paracrine signaling were investigated by measuring cell-adhesion molecule (ICAM-1, VCAM-1) and cytokine (BMP-4, TGF-β1) expressions, respectively. Extracellular matrix (ECM) degradation was characterized by measuring the expression and activity of the proteases MMP-2, MMP-9, cathepsin L and cathepsin S. The effect of the FSS treatment yielding the most significant pathological response was examined over a 72-hour period to characterize the time-dependence of FSS mechano-transduction. While cytokine expression was stimulated under elevated FSS magnitude at normal frequency, ECM degradation was stimulated under both elevated FSS magnitude at normal frequency and physiologic FSS magnitude at abnormal frequency. In contrast, combined FSS magnitude and frequency abnormalities essentially maintained valvular homeostasis. The pathological response under supra-physiologic FSS magnitude peaked at 48 hours but was then maintained until the

  13. Increased Expression and Activation of Absent in Melanoma 2 Inflammasome Components in Lymphocytic Infiltrates of Abdominal Aortic Aneurysms

    PubMed Central

    Dihlmann, Susanne; Erhart, Philipp; Mehrabi, Arianeb; Nickkholgh, Arash; Lasitschka, Felix; Böckler, Dittmar; Hakimi, Maani

    2014-01-01

    Chronic vascular inflammation is a key hallmark in the pathogenesis of abdominal aortic aneurysm (AAA). Recent investigations have suggested that the inflammasome, a cytosolic multiprotein complex that recognizes pathogen-associated molecular patterns, plays a role in atherosclerosis. However, its role in AAA inflammation has not yet been investigated. This pilot study analyzed inflammasome activation and its intramural localization in 24 biopsy samples from 11 patients with asymptomatic AAA versus 12 aortic samples from apparently healthy controls. Using a histological inflammation scale, we identified grade 2/3 inflammatory changes with lymphoid aggregates/tertiary lymphoid organs in 21 out of 24 AAA samples, whereas only 7 of the 12 control samples exhibited local grade 1 inflammatory changes. Strong expression levels of “apoptosis-associated speck-like protein with a caspase recruitment domain” (ASC), caspase-1, caspase-5 and “absent in melanoma 2” (AIM2) were detected by immunohistochemistry in both sporadic infiltrating lymphoid cells and lymphoid aggregates located in the outer media and adventitia of AAA samples. In contrast, inflammasome-positive cells were restricted to cholesterol plaque–associated areas and to single infiltrating cells in control aortas. Analysis of gene expression using real-time polymerase chain reaction (PCR) revealed significantly increased median mRNA levels of the inflammasome core components PYCARD (ASC), CASP1 (Caspase-1) and IL1B (IL-1β) in AAA tissue compared with normal aorta. Moreover, significantly increased median amounts of AIM2 protein and mature caspase-5 (p20) were found in samples associated with high rupture risk compared with paired low rupture risk samples of the same AAA patient. We conclude from our data that AAA-associated lymphoid cells are capable of inflammasome signaling, suggesting that inflammasome activation is involved in the chronic inflammatory process driving AAA progression. PMID:24618883

  14. Regulation of proliferation and gene expression in cultured human aortic smooth muscle cells by resveratrol and standardized grape extracts

    SciTech Connect

    Wang Zhirong; Chen Yan; Labinskyy, Nazar; Hsieh Tzechen; Ungvari, Zoltan; Wu, Joseph M. . E-mail: Joseph_Wu@nymc.edu

    2006-07-21

    Epidemiologic studies suggest that low to moderate consumption of red wine is inversely associated with the risk of coronary heart disease; the protection is in part attributed to grape-derived polyphenols, notably trans-resveratrol, present in red wine. It is not clear whether the cardioprotective effects of resveratrol can be reproduced by standardized grape extracts (SGE). In the present studies, we determined, using cultured human aortic smooth muscle cells (HASMC), growth and specific gene responses to resveratrol and SGE provided by the California Table Grape Commission. Suppression of HASMC proliferation by resveratrol was accompanied by a dose-dependent increase in the expression of tumor suppressor gene p53 and heat shock protein HSP27. Using resveratrol affinity chromatography and biochemical fractionation procedures, we showed by immunoblot analysis that treatment of HASMC with resveratrol increased the expression of quinone reductase I and II, and also altered their subcellular distribution. Growth of HASMC was significantly inhibited by 70% ethanolic SGE; however, gene expression patterns in various cellular compartments elicited in response to SGE were substantially different from those observed in resveratrol-treated cells. Further, SGE also differed from resveratrol in not being able to induce relaxation of rat carotid arterial rings. These results indicate that distinct mechanisms are involved in the regulation of HASMC growth and gene expression by SGE and resveratrol.

  15. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?

    PubMed

    Balakumar, Pitchai; Kathuria, Sonam; Taneja, Gaurav; Kalra, Sanjeev; Mahadevan, Nanjaian

    2012-01-01

    Statins are widely used in the treatment of dyslipidemia and associated cardiovascular abnormalities including atherosclerosis, hypertension and coronary heart disease. Needless to mention, statins have cholesterol-lowering effects by means of inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis. Besides cholesterol-lowering effects, statins possess pleiotropic anti-inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties, which may additionally play imperative roles in statins-mediated cardiovascular protection. However, the precise mechanisms involved in the cardiovascular defensive potential of statins have not completely been elucidated. Intriguingly, a considerable number of studies demonstrated the potential modulatory role of statins on endothelial nitric oxide synthase (eNOS), a key enzyme involved in the regulation of cardiovascular function by generating endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy of note is that vascular generation of nitric oxide has beneficial anti-inflammatory, anti-platelet and vasodilatory actions. The upregulation of eNOS by statins is mediated through inhibition of synthesis of isoprenoids and subsequent prevention of isoprenylation of small GTPase Rho, whereas statin-induced activation of eNOS is mediated through activation of phosphotidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) signals. Additionally, statins enhance eNOS activation by abrogating caveolin-1 expression in vascular endothelium. In light of this view-point, we suggest in this review that eNOS upregulation and activation, in part, could play a fundamental role in the cardiovascular defensive potential of statins. The eNOS modulatory role of statins may have an imperative influence on the functional regulation of cardiovascular system and may offer new perspectives for the better use of statins in ameliorating cardiovascular disorders.

  16. Aortic Valve Disease

    MedlinePlus

    ... Ventricle Normal Heart Select Disease To Learn More Aortic Stenosis Aortic Insufficiency Aorta The aorta is the main ... the rest of your body. Aortic Valve In aortic stenosis, the aortic valve becomes narrowed and does not ...

  17. Binding Sites for Ets Family of Transcription Factors Dominate the Promoter Regions of Differentially Expressed Genes in Abdominal Aortic Aneurysms

    PubMed Central

    Nischan, Jennifer; Gatalica, Zoran; Curtis, Mindee; Lenk, Guy M.; Tromp, Gerard; Kuivaniemi, Helena

    2011-01-01

    Background Previously, we identified 3,274 distinct differentially expressed genes in abdominal aortic aneurysm (AAA) tissue compared to non-aneurysmal controls. As transcriptional control is responsible for these expression changes, we sought to find common transcriptional elements in the promoter regions of the differentially expressed genes. Methods and Results We analyzed the up- and downregulated gene sets with Whole Genome rVISTA to determine the transcription factor binding sites (TFBSs) overrepresented in the 5 kb promoter regions of the 3,274 genes. The downregulated gene set yielded 144 TFBSs that were overrepresented in the subset when compared to the entire genome. In contrast, the upregulated gene set yielded only 13 distinct overrepresented TFBSs. Interestingly, as classified by TRANSFAC®, 8 of the 13 transcription factors (TFs) binding to these regions belong to the ETS family. Additionally, NFKB and its subunits p50 and p65 showed enrichment. Immunohistochemical analyses in 10 of the TFs from the upregulated analysis showed 9 to be present in AAA tissue. Based on Gene Ontology analysis of biological process categories of the upregulated target genes of enriched TFs, 10 TFs had enrichment in immune system process among their target genes. Conclusions Our genome-wide analysis provides further evidence of ETS and NFKB involvement in AAA. Additionally, our results provide novel insight for future studies aiming to dissect the pathogenesis of AAA and have uncovered potential therapeutic targets for AAA prevention. PMID:20031636

  18. Oral administration of bisphenol A induces high blood pressure through angiotensin II/CaMKII-dependent uncoupling of eNOS.

    PubMed

    Saura, Marta; Marquez, Susana; Reventun, Paula; Olea-Herrero, Nuria; Arenas, María Isabel; Moreno-Gómez-Toledano, Rafael; Gómez-Parrizas, Mónica; Muñóz-Moreno, Carmen; González-Santander, Marta; Zaragoza, Carlos; Bosch, Ricardo J

    2014-11-01

    Bisphenol A (BPA) is found in human urine and fat tissue. Higher urinary BPA concentrations are associated with arterial hypertension. To shed light on the underlying mechanism, we orally administered BPA (4 nM to 400 μM in drinking water) to 8-wk-old CD11 mice over 30 d. Mice developed dosage-dependent high blood pressure (systolic 130 ± 12 vs. 170 ± 12 mmHg; EC50 0.4 μM), impairment of acetylcholine (AcH)-induced carotid relaxation (0.66 ± 0.08 vs. 0.44 ± 0.1 mm), a 1.7-fold increase in arterial angiotensin II (AngII), an 8.7-fold increase in eNOS mRNA and protein, and significant eNOS-dependent superoxide and peroxynitrite accumulation. AngII inhibition with 0.5 mg/ml losartan reduced oxidative stress and normalized blood pressure and endothelium-dependent relaxation, which suggests that AngII uncouples eNOS and contributes to the BPA-induced endothelial dysfunction by promoting oxidative and nitrosative stress. Microarray analysis of mouse aortic endothelial cells revealed a 2.5-fold increase in expression of calcium/calmodulin-dependent protein kinase II-α (CaMKII-α) in response to 10 nM BPA, with increased expression of phosphorylated-CaMKII-α in carotid rings of BPA-exposed mice, whereas CaMKII-α inhibition with 100 nM autocamptide-2-related inhibitor peptide (AIP) reduced BPA-mediated increase of superoxide. Administration of CaMKII-α inhibitor KN 93 reduced BPA-induced blood pressure and carotid blood velocity in mice, and reverted BPA-mediated carotid constriction in response to treatment with AcH. Given that CaMKII-α inhibition prevents BPA-mediated high blood pressure, our data suggest that BPA regulates blood pressure by inducing AngII/CaMKII-α uncoupling of eNOS.

  19. Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells.

    PubMed Central

    Natarajan, R; Gu, J L; Rossi, J; Gonzales, N; Lanting, L; Xu, L; Nadler, J

    1993-01-01

    The lipoxygenase (LO) pathway of arachidonate metabolism has been suggested to play a key role in atherosclerosis and in mediating several actions of angiotensin II (AII). However, the relationship between LO activation and factors linked to accelerated diabetic vascular disease such as hyperglycemia and AII is not known. We have investigated the effect of high glucose (HG; 25 mM) and AII on LO activity as well as LO protein and mRNA expression in porcine aortic vascular smooth muscle cells (PVSMCs). We observed that cells cultured in HG had significantly higher levels of the cell-associated LO products 12- and 15-hydroxyeicosatetraenoic acids (HETEs). AII added to cells grown in HG specifically further increased only cell-associated 12-HETE levels. Using immunoblot analysis and reverse transcriptase PCRs, we demonstrated the presence in PVSMCs of porcine leukocyte-type 12-LO protein and mRNA, respectively. Furthermore, the levels of both were markedly upregulated by AII as well as by HG. These studies suggest that enhanced 12-LO activity and expression are mechanisms for accelerated vascular disease produced by HG and AII in diabetes mellitus. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:8506339

  20. Cyclic strain inhibits acute pro-inflammatory gene expression in aortic valve interstitial cells.

    PubMed

    Smith, Kathryn E; Metzler, Scott A; Warnock, James N

    2010-02-01

    Mechanical in vitro preconditioning of tissue engineered heart valves is viewed as an essential process for tissue development prior to in vivo implantation. However, a number of pro-inflammatory genes are mechanosensitive and their elaboration could elicit an adverse response in the host. We hypothesized that the application of normal physiological levels of strain to isolated valve interstitial cells would inhibit the expression of pro-inflammatory genes. Cells were subjected to 0, 5, 10, 15 and 20% strain. Expression of VCAM-1, MCP-1, GM-CSF and OPN was then measured using qRT-PCR. With the exception of OPN, all genes were significantly up regulated when no strain was applied. MCP-1 expression was significantly lower in the presence of strain, although strain magnitude did not affect the expression level. VCAM-1 and GM-CSF had the lowest expression levels at 15% strain, which represent normal physiological conditions. These findings were confirmed using confocal microscopy. Additionally, pSMAD 2/3 and IkappaBalpha expression were imaged to elucidate potential mechanisms of gene expression. Data showed that 15% strain increased pSMAD 2/3 expression and prevented phosphorylation of IkappaBalpha. In conclusion, cyclic strain reduces expression of pro-inflammatory genes, which may be beneficial for the in vitro pre-conditioning of tissue engineered heart valves.

  1. Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile

    PubMed Central

    CHEN, XUDONG; ZHENG, CHENGFEI; HE, YUNJUN; TIAN, LU; LI, JIANHUI; LI, DONGLIN; JIN, WEI; LI, MING; ZHENG, SHUSEN

    2015-01-01

    The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein-protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co-repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4α (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies. PMID:26498477

  2. Polychlorinated biphenyl-induced VCAM-1 expression is attenuated in aortic endothelial cells isolated from caveolin-1 deficient mice

    SciTech Connect

    Han, Sung Gu; Eum, Sung Yong; Toborek, Michal; Smart, Eric; Hennig, Bernhard

    2010-07-15

    Exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of cardiovascular diseases such as atherosclerosis. Vascular cell adhesion molecule-1 (VCAM-1) is a critical mediator for adhesion and uptake of monocytes across the endothelium in the early stages of atherosclerosis development. The upregulation of VCAM-1 by PCBs may be dependent on functional membrane domains called caveolae. Caveolae are particularly abundant in endothelial cell membranes and involved in trafficking and signal transduction. The objective of this study was to investigate the role of caveolae in PCB-induced endothelial cell dysfunction. Primary mouse aortic endothelial cells (MAECs) isolated from caveolin-1-deficient mice and background C57BL/6 mice were treated with coplanar PCBs, such as PCB77 and PCB126. In addition, siRNA gene silencing technique was used to knockdown caveolin-1 in porcine vascular endothelial cells. In MAECs with functional caveolae, VCAM-1 protein levels were increased after exposure to both coplanar PCBs, whereas expression levels of VCAM-1 were not significantly altered in cells deficient of caveolin-1. Furthermore, PCB-induced monocyte adhesion was attenuated in caveolin-1-deficient MAECs. Similarly, siRNA silencing of caveolin-1 in porcine endothelial cells confirmed the caveolin-1-dependent VCAM-1 expression. Treatment of cells with PCB77 and PCB126 resulted in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), and pharmacological inhibition of ERK1/2 diminished the observed PCB-induced increase in monocyte adhesion. These findings suggest that coplanar PCBs induce adhesion molecule expression, such as VCAM-1, in endothelial cells, and that this response is regulated by caveolin-1 and functional caveolae. Our data demonstrate a critical role of functional caveolae in the activation and dysfunction of endothelial cells by coplanar PCBs.

  3. Serum Amyloid A Promotes E-Selectin Expression via Toll-Like Receptor 2 in Human Aortic Endothelial Cells

    PubMed Central

    2016-01-01

    Periodontitis is a chronic inflammatory disease that affects the periodontium. Recent studies suggest an association between periodontal and cardiovascular diseases. However, the detailed molecular mechanism is unknown. A previous study has demonstrated that experimental periodontitis induces serum amyloid A (SAA) in the liver and peripheral blood of ApoE-deficient mice as an atherosclerosis model. SAA is an acute-phase protein that affects systemic inflammation. The aim of this study is to investigate the atherosclerosis-onset mechanism using human aortic endothelial cells (HAECs) stimulated by SAA in vitro. Atherosclerosis PCR array and qPCR analyses showed upregulation of adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in HAECs upon SAA stimulation. In addition, the results demonstrated that Toll-like receptor, TLR2, could serve as an important receptor of SAA in HAECs. Furthermore, small interfering RNA (siRNA) against TLR2 inhibited the upregulation of adhesion molecules in HAECs stimulated by SAA. Our results suggest that SAA stimulates the expression of adhesion molecules via TLR2. SAA could be an important molecule for atherosclerosis induced by periodontal disease. PMID:27799725

  4. Nelfinavir Suppresses Insulin Signaling and Nitric Oxide Production by Human Aortic Endothelial Cells: Protective Effects of Thiazolidinediones

    PubMed Central

    Mondal, Debasis; Liu, Kai; Hamblin, Milton; Lasky, Joseph A.; Agrawal, Krishna C.

    2013-01-01

    ABSTRACT Background In human immunodeficiency virus 1 (HIV-1)–infected individuals, exposure to a protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimen increases cardiovascular disease and endothelial dysfunction. However, the mechanisms of PI-induced effects on endothelial cells (ECs) are not known. Furthermore, strategies to suppress these deleterious outcomes of PIs need to be developed. Insulin-induced PI3K/Akt signaling and endothelial nitric oxide (NO)-synthase (eNOS) phosphorylation regulates NO production by ECs that maintain vascular homeostasis. We evaluated whether nelfinavir (NEL), a potent HIV-1 PI that suppresses Akt phosphorylation, can alter insulin-induced NO production in human aortic endothelial cells (HAECs) and whether insulin sensitization of HAECs via the peroxisome proliferator-activated receptor-gamma agonists, thiazolidinediones, can ameliorate these side effects. Methods Real-time NO production in HAECs was monitored by fluorimetric dyes DAF-FM DA and DAF-2 DA. Immunodetection studies were used to determine the phosphorylation of Akt, eNOS, insulin receptor-β (IR-β), insulin receptor substrate-1 (IRS-1), and PI3K/p85α. Expression of eNOS messenger RNA was measured by reverse transcription polymerase chain reaction. Results In vitro exposure (72 hours) of HAECs to NEL (0.25-2 μg/mL) decreased both basal (2.5-fold) and insulin-induced NO production (4- to 5-fold). NEL suppressed insulin-induced phosphorylation of both Akt and eNOS at serine residues 473 and 1177, respectively. NEL decreased tyrosine phosphorylation of IR-β, IRS-1, and PI3K. Coexposure to troglitazone (TRO; 250 nM) ameliorated the suppressive effects of NEL on insulin signaling and NO production. Coexposure to TRO also increased eNOS expression in NEL-treated HAECs. Conclusion Our findings indicate that treatment with potent insulin sensitizers may protect against PI-mediated endothelial dysfunction during long-term HAART. PMID:23533049

  5. Disruption of cytoskeletal structures mediates shear stress-induced endothelin-1 gene expression in cultured porcine aortic endothelial cells.

    PubMed Central

    Morita, T; Kurihara, H; Maemura, K; Yoshizumi, M; Yazaki, Y

    1993-01-01

    Hemodynamic shear stress alters the architecture and functions of vascular endothelial cells. We have previously shown that the synthesis of endothelin-1 (ET-1) in endothelial cells is increased by exposure to shear stress. Here we examined whether shear stress-induced alterations in cytoskeletal structures are responsible for increases in ET-1 synthesis in cultured porcine aortic endothelial cells. Exposure of endothelial cells to 5 dyn/cm2 of low shear stress rapidly increased monomeric G-actin contents within 5 min without changing total actin contents. The ratio of G- to total actin, 54 +/- 0.8% in quiescent endothelial cells, increased to 87 +/- 4.2% at 6 h and then decreased. Following the disruption of filamentous (F)-actin into G-actin, ET-1 mRNA levels in endothelial cells also increased within 30 min and reached a peak at 6 h. The F-actin stabilizer, phalloidin, abolished shear stress-induced increases in ET-1 mRNA; however, it failed to inhibit increases in ET-1 mRNA secondary to other stimulants. This indicates that shear stress-induced increases in ET-1 mRNA levels may be mediated by the disruption of actin fibers. Furthermore, increases in ET-1 gene expression can be induced by actin-disrupting agents, cytochalasin B and D. Another cytoskeleton-disrupting agent, colchicine, which inhibits dimerization of tubulin, did not affect the basal level of ET-1 mRNA. However, colchicine completely inhibited shear stress- and cytochalasin B-induced increases in ET-1 mRNA levels. These results suggest that shear stress-induced ET-1 gene expression in endothelial cells is mediated by the disruption of actin cytoskeleton and this induction is dependent on the integrity of microtubules. Images PMID:8408624

  6. Gene silencing of endothelial von Willebrand Factor attenuates angiotensin II-induced endothelin-1 expression in porcine aortic endothelial cells

    PubMed Central

    Dushpanova, Anar; Agostini, Silvia; Ciofini, Enrica; Cabiati, Manuela; Casieri, Valentina; Matteucci, Marco; Del Ry, Silvia; Clerico, Aldo; Berti, Sergio; Lionetti, Vincenzo

    2016-01-01

    Expression of endothelin (ET)-1 is increased in endothelial cells exposed to angiotensin II (Ang II), leading to endothelial dysfunction and cardiovascular disorders. Since von Willebrand Factor (vWF) blockade improves endothelial function in coronary patients, we hypothesized that targeting endothelial vWF with short interference RNA (siRNA) prevents Ang II-induced ET-1 upregulation. Nearly 65 ± 2% silencing of vWF in porcine aortic endothelial cells (PAOECs) was achieved with vWF-specific siRNA without affecting cell viability and growth. While showing ET-1 similar to wild type cells at rest, vWF-silenced cells did not present ET-1 upregulation during exposure to Ang II (100 nM/24 h), preserving levels of endothelial nitric oxide synthase activity similar to wild type. vWF silencing prevented AngII-induced increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity and superoxide anion (O2−) levels, known triggers of ET-1 expression. Moreover, no increase in O2− or ET-1 levels was found in silenced cells treated with AngII or NOX-agonist phorbol ester (PMA 5 nM/48 h). Finally, vWF was required for overexpression of NOX4 and NOX2 in response to AngII and PMA. In conclusion, endothelial vWF knockdown prevented Ang II-induced ET-1 upregulation through attenuation of NOX-mediated O2− production. Our findings reveal a new role of vWF in preventing of Ang II-induced endothelial dysfunction. PMID:27443965

  7. Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells

    SciTech Connect

    Majesky, M.W.; Benditt, E.P.; Schwartz, S.M.

    1988-03-01

    Cultured arterial smooth muscle cells (SMC) can produce platelet-derived growth factor (PDGF)-like molecules. This property raises the possibility that SMC-derived PDGFs function as autocrine/paracrine regulators in the formation and maintenance of the artery wall. In this study the authors have asked if levels of mRNAs directing synthesis of PDFG are modulated in aortic SMC during postnatal development. The authors report here that genes encoding PDGF A- and B-chain precursors are expressed at similar low levels in intact aortas from newborn and adult rats. Marked differences in regulation of transcript abundance of these genes were revealed when aortic SMC were grown in cell culture. PDGF B-chain transcripts accumulated in passaged newborn rat SMC but not adult rat SMC, whereas PDGF A-chain RNA was found in comparable amounts in SMC from both age groups. Similarly, SMC from newborn rats secreted at least 60-fold more PDGF-like activity into conditioned medium than did adult rat SMC. These results show that PDGF A- and B-chain genes are transcribed in the normal rat aorta and provide evidence for age-related change in the control of PDGF B-chain gene expression in aortic SMC. Independent regulation of transcript levels in cultured SMC leaves open the possibility that PDGFs of different composition (AA, AB, BB) play different roles in normal function of the artery wall.

  8. Aortic Aneurysm

    MedlinePlus

    ... these occur in the part of the aorta running through the chest Abdominal aortic aneurysms (AAA) - these occur in the part of the aorta running through the abdomen Most aneurysms are found during ...

  9. Buckling Reduces eNOS Production and Stimulates Extracellular Matrix Remodeling in Arteries in Organ Culture.

    PubMed

    Xiao, Yangming; Liu, Qin; Han, Hai-Chao

    2016-09-01

    Artery buckling alters the fluid shear stress and wall stress in the artery but its temporal effect on vascular wall remodeling is poorly understood. The purpose of this study was to investigate the early effect of artery buckling on endothelial nitric oxide synthase (eNOS) expression and extracellular matrix remodeling. Bilateral porcine carotid arteries were maintained in an ex vivo organ culture system with and without buckling while under the same physiological pressure and flow rate for 3-7 days. Matrix metalloproteinase-2 (MMP-2), MMP-9, fibronectin, elastin, collagen I, III and IV, tissue inhibitor of metalloproteinase-2 (TIMP-2), and eNOS were determined using Western blotting and immunohistochemistry. Our results showed that MMP-2 expression level was significantly higher in buckled arteries than in the controls and higher at the inner curve than at the outer curve of buckled arteries, while collagen IV content showed an opposite trend, suggesting that artery buckling increased MMP-2 expression and collagen IV degradation in a site-specific fashion. However, no differences for MMP-9, fibronectin, elastin, collagen I, III, and TIMP-2 were observed among the outer and inner curve sides of buckled arteries and straight controls. Additionally, eNOS expression was significantly decreased in buckled arteries. These results suggest that artery buckling triggers uneven wall remodeling that could lead to development of tortuous arteries.

  10. Aortic Valve Stenosis

    MedlinePlus

    ... By Mayo Clinic Staff Aortic valve stenosis — or aortic stenosis — occurs when the heart's aortic valve narrows. This ... pressure may prevent or slow the development of aortic stenosis. Ask your doctor if you need to lower ...

  11. Multi-resolution analysis for ENO schemes

    NASA Technical Reports Server (NTRS)

    Harten, Ami

    1991-01-01

    Given an function, u(x), which is represented by its cell-averages in cells which are formed by some unstructured grid, we show how to decompose the function into various scales of variation. This is done by considering a set of nested grids in which the given grid is the finest, and identifying in each locality the coarsest grid in the set from which u(x) can be recovered to a prescribed accuracy. This multi-resolution analysis was applied to essentially non-oscillatory (ENO) schemes in order to advance the solution by one time-step. This is accomplished by decomposing the numerical solution at the beginning of each time-step into levels of resolution, and performing the computation in each locality at the appropriate coarser grid. An efficient algorithm for implementing this program in the 1-D case is presented; this algorithm can be extended to the multi-dimensional case with Cartesian grids.

  12. Efficient implementation of weighted ENO schemes

    NASA Technical Reports Server (NTRS)

    Jiang, Guang-Shan; Shu, Chi-Wang

    1995-01-01

    In this paper, we further analyze, test, modify and improve the high order WENO (weighted essentially non-oscillatory) finite difference schemes of Liu, Osher and Chan. It was shown by Liu et al. that WENO schemes constructed from the r-th order (in L1 norm) ENO schemes are (r+1)-th order accurate. We propose a new way of measuring the smoothness of a numerical solution, emulating the idea of minimizing the total variation of the approximation, which results in a 5-th order WENO scheme for the case r = 3, instead of the 4-th order with the original smoothness measurement by Liu et al. This 5-th order WENO scheme is as fast as the 4-th order WENO scheme of Liu et al., and both schemes are about twice as fast as the 4-th order ENO schemes on vector supercomputers and as fast on serial and parallel computers. For Euler systems of gas dynamics, we suggest computing the weights from pressure and entropy instead of the characteristic values to simplify the costly characteristic procedure. The resulting WENO schemes are about twice as fast as the WENO schemes using the characteristic decompositions to compute weights, and work well for problems which do not contain strong shocks or strong reflected waves. We also prove that, for conservation laws with smooth solutions, all WENO schemes are convergent. Many numerical tests, including the 1D steady state nozzle flow problem and 2D shock entropy wave interaction problem, are presented to demonstrate the remarkable capability of the WENO schemes, especially the WENO scheme using the new smoothness measurement, in resolving complicated shock and flow structures. We have also applied Yang's artificial compression method to the WENO schemes to sharpen contact discontinuities.

  13. Phenylephrine activates eNOS Ser 1177 phosphorylation and nitric oxide signaling in renal hypertensive rat aorta.

    PubMed

    Silva, Bruno R; Pernomian, Laena; Grando, Marcella D; Bendhack, Lusiane M

    2014-09-05

    The endothelial nitric oxide synthase (eNOS) plays an important role in the control of the vascular tone. This work aimed to evaluate the role of an α1-adrenoceptor agonist phenylephrine (PE) on eNOS activity and downstream signaling pathway activation in normotensive (2K) and renal hypertensive (2K-1C) intact-endothelium rat aortas. Concentration-effect curves were performed for PE in intact-endothelium aortas from 2K and 2K-1C rats, in the absence of or in the presence of NOS or soluble guanylyl cyclase (sGC) inhibitor. Intact endothelium aortas were stimulated with PE in organ chambers and eNOS Ser(1177)/Thr(495) phosphorylation expression was evaluated by western blot. Nitric Oxide (NO) production was evaluated in isolated endothelial cells from 2K and 2K-1C rat aortas by flow-cytometry using NO selective fluorescent probe, DAF-2DA. The sGC activity/expression was also evaluated. PE-induced contractile response is lower in 2K-1C than in 2K intact-endothelium rat aorta. This is due to higher eNOS Ser(1177) phosphorylation in 2K-1C, which induces the eNOS overactivation. It was abolished by NOS or sGC inhibition. Phenylephrine reduces NO production in 2K as compared to the basal level, but it is not modified in 2K-1C. In PE-stimulated endothelial cells, the NO production is higher in 2K-1C than in 2K. Phenylephrine induces higher cGMP production in 2K-1C than in 2K, despite the lower expression of sGC in 2K-1C. Our results suggest that alpha1-adrenoceptor activation contributes to the increased activity of the enzyme eNOS by Ser(1177) phosphorylation in 2K-1C intact-endothelium aorta, which consequently decreases PE-induced contractile response.

  14. Regulation of eNOS enzyme activity by posttranslational modification.

    PubMed

    Heiss, Elke H; Dirsch, Verena M

    2014-01-01

    The regulation of endothelial NO synthase (eNOS) employs multiple different cellular control mechanisms impinging on level and activity of the enzyme. This review aims at summarizing the current knowledge on the posttranslational modifications of eNOS, including acylation, nitrosylation, phosphorylation, acetylation, glycosylation and glutathionylation. Sites, mediators and impact on enzyme localization and activity of the single modifications will be discussed. Moreover, interdependence, cooperativity and competition between the different posttranslational modifications will be elaborated with special emphasis on the susceptibility of eNOS to metabolic cues.

  15. Sildenafil Promotes eNOS Activation and Inhibits NADPH Oxidase in the Transgenic Sickle Cell Mouse Penis

    PubMed Central

    Musicki, Biljana; Bivalacqua, Trinity J.; Champion, Hunter C.; Burnett, Arthur L.

    2014-01-01

    Introduction Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. Aims We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. Methods SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Main Outcome Measures Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Results Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters. Conclusion Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. PMID:24251665

  16. [Aortic dissection].

    PubMed

    Ogino, Hitoshi

    2011-07-01

    Acute aortic dissection suddenly occurrs and results in a variety of catastrophic sequelae including cardiac tamponade, rupture, and organ malperfusion. In acute stage (< 2 weeks), according to the classifications on the region of aortic dissection, the condition of the false channel and the onset, appropriate medical, surgical, or endovascular treatments including endovascular aneurysm repair followed by the rapid and accurate diagnosis of aortic dissection using computed tomography and ultrasound should be performed without delay. In the chronic stage (> 2 weeks), the behavior of the chronic dissection or residual distal dissection after the initial treatment should be followed-up carefully with best medical treatment at the regular intervals. If necessary, appropriate surgical and endovascular treatment should be carried out in the proper timing before rupture.

  17. autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function.

    PubMed

    Vo, Phuong A; Lad, Bhavini; Tomlinson, James A P; Francis, Stephanie; Ahluwalia, Amrita

    2005-02-25

    Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is responsible for sepsis-induced hypotension and plays a major contributory role in the ensuing multiorgan failure. The present study aimed to elucidate the role of endothelial NO in lipopolysaccharide (LPS)-induced iNOS expression, in isolated rat aortic rings. Exposure to LPS (1 mug/ml, 5 h) resulted in a reversal of phenylephrine precontracted tone in aortic rings (70.7 +/- 3.2%). This relaxation was associated with iNOS expression and NF-kappaB activation. Positive immunoreactivity for iNOS protein was localized in medial and adventitial layers of LPS-treated aortic rings. Removal of the endothelium rendered aortic rings resistant to LPS-induced relaxation (8.9 +/- 4.5%). Western blotting of these rings demonstrated an absence of iNOS expression. However, treatment of endothelium-denuded rings with the NO donor, diethylamine-NONOate (0.1 mum), restored LPS-induced relaxation (61.6 +/- 6.6%) and iNOS expression to levels comparable with arteries with intact endothelium. Blockade of endothelial NOS (eNOS) activation using geldanamycin and radicicol, inhibitors of heat shock protein 90, in endothelium-intact arteries suppressed both LPS-induced relaxation and LPS-induced iNOS expression (9.0 +/- 8.0% and 2.0 +/- 6.2%, respectively). Moreover, LPS treatment (12.5 mg/kg, intravenous, 15 h) of wild-type mice resulted in profound elevation of plasma [NO(x)] measurements that were reduced by approximately 50% in eNOS knock-out animals. Furthermore, LPS-induced changes in vascular reactivity and iNOS expression evident in wild-type tissues were profoundly suppressed in tissues taken from eNOS knockout animals. Together, these data suggest that eNOS-derived NO, in part via activation of NF-kappaB, regulates iNOS-induction by LPS. This study provides the first demonstration of a proinflammatory role of vascular eNOS in sepsis.

  18. Bicuspid Aortic Valve

    DTIC Science & Technology

    2006-08-01

    severe aortic stenosis . Figure 1F. Oblique axial cine bright blood imaging through the valve plane of the aorta, demonstrates the aortic valve to...the ascending aorta. This moderate to large jet is consistent with moderate to severe aortic stenosis . No diastolic jet to suggest aortic ...conditions. Functional impairment of the aortic valve—namely aortic stenosis and aortic regurgitation—is the most common complication (in up to 68-85% of

  19. Obesity, Inflammation, and Exercise Training: Relative Contribution of iNOS and eNOS in the Modulation of Vascular Function in the Mouse Aorta

    PubMed Central

    Silva, Josiane F.; Correa, Izabella C.; Diniz, Thiago F.; Lima, Paulo M.; Santos, Roger L.; Cortes, Steyner F.; Coimbra, Cândido C.; Lemos, Virginia S.

    2016-01-01

    Background: The understanding of obsesity-related vascular dysfunction remains controversial mainly because of the diseases associated with vascular injury. Exercise training is known to prevent vascular dysfunction. Using an obesity model without comorbidities, we aimed at investigating the underlying mechanism of vascular dysfunction and how exercise interferes with this process. Methods: High-sugar diet was used to induce obesity in mice. Exercise training was performed 5 days/week. Body weight, energy intake, and adipose tissues were assessed; blood metabolic and hormonal parameters were determined; and serum TNFα was measured. Blood pressure and heart rate were assessed by plethysmography. Changes in aortic isometric tension were recorded on myograph. Western blot was used to analyze protein expression. Nitric oxide (NO) was evaluated using fluorescence microscopy. Antisense oligodeoxynucleotides were used for inducible nitric oxide synthase isoform (iNOS) knockdown. Results: Body weight, fat mass, total cholesterol, low-density lipoprotein cholesterol fraction, insulin, and leptin were higher in the sedentary obese group (SD) than in the sedentary control animals (SS). Exercise training prevented these changes. No difference in glucose tolerance, insulin sensitivity, blood pressure, and heart rate was found. Decreased vascular relaxation and reduced endothelial nitric oxide synthase (eNOS) functioning in the SD group were prevented by exercise. Contractile response to phenylephrine was decreased in the aortas of the wild SD mice, compared with that of the SS group; however, no alteration was noted in the SD iNOS−/− animals. The decreased contractility was endothelium-dependent, and was reverted by iNOS inhibition or iNOS silencing. The aortas from the SD group showed increased basal NO production, serum TNFα, TNF receptor-1, and phospho-IκB. Exercise training attenuated iNOS-dependent reduction in contractile response in high-sugar diet–fed animals

  20. Multi-resolution analysis for ENO schemes

    NASA Technical Reports Server (NTRS)

    Harten, Ami

    1993-01-01

    Given a function u(x) which is represented by its cell-averages in cells which are formed by some unstructured grid, we show how to decompose the function into various scales of variation. This is done by considering a set of nested grids in which the given grid is the finest, and identifying in each locality the coarsest grid in the set from which u(x) can be recovered to a prescribed accuracy. We apply this multi-resolution analysis to Essentially Non-oscillatory Schemes (ENO) schemes in order to reduce the number of numerical flux computations which is needed in order to advance the solution by one time-step. This is accomplished by decomposing the numerical solution at the beginning of each time-step into levels of resolution, and performing the computation in each locality at the appropriate coarser grid. We present an efficient algorithm for implementing this program in the one-dimensional case; this algorithm can be extended to the multi-dimensional case with cartesian grids.

  1. Vascular nitric oxide: Beyond eNOS.

    PubMed

    Zhao, Yingzi; Vanhoutte, Paul M; Leung, Susan W S

    2015-10-01

    As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.

  2. Regulation of Endothelial Glutathione by ICAM-1 governs VEGF-A mediated eNOS Activity and Angiogenesis

    PubMed Central

    Langston, Will; Chidlow, John H.; Booth, Blake A.; Barlow, Shayne C.; Lefer, David J.; Patel, Rakesh P.; Kevil, Christopher G.

    2007-01-01

    Previous studies suggest that inflammatory cell adhesion molecules may modulate endothelial cell migration and angiogenesis through unknown mechanisms. Using a combination of in vitro and in vivo approaches, herein we reveal a novel redox sensitive mechanism by which ICAM-1 modulates endothelial GSH that controls VEGF-A induced eNOS activity, endothelial chemotaxis, and angiogenesis. In vivo disk angiogenesis assays showed attenuated VEGF-A mediated angiogenesis in ICAM-1−/− mice. Moreover, VEGF-A dependent chemotaxis, eNOS phosphorylation, and nitric oxide (NO) production were impaired in ICAM-1−/− MAEC compared to WT MAEC. Decreasing intracellular GSH in ICAM-1−/− MAEC to levels observed in WT MAEC with 150 μM buthionine sulfoximine (BSO) restored VEGF-A responses. Conversely, GSH supplementation of WT MAEC with 5 mM glutathione ethyl ester (GEE) mimicked defects observed in ICAM-1−/− cells. Deficient angiogenic responses in ICAM-1−/− cells were associated with increased expression of the lipid phosphatase, PTEN, consistent with antagonism of signaling pathways leading to eNOS activation. PTEN expression was also sensitive to GSH status, decreasing or increasing in proportion to intracellular GSH concentrations. These data suggest a novel role for ICAM-1 in modulating VEGF-A induced angiogenesis and eNOS activity through regulation of PTEN expression via modulation of intracellular GSH status. PMID:17291995

  3. 17-β-oestradiol-induced vasorelaxation in vitro is mediated by eNOS through hsp90 and akt/pkb dependent mechanism

    PubMed Central

    Bucci, Mariarosaria; Roviezzo, Fiorentina; Cicala, Carla; Pinto, Aldo; Cirino, Giuseppe

    2002-01-01

    The L-arginine-NO pathway has been implicated in the vasorelaxant effect of 17-β-oestradiol. Here we have addressed the involvement of two distinct activation steps of endothelial nitric oxide synthase (eNOS) in the 17-β-oestradiol-induced vasorelaxant effect on rat aortic rings. Rat aortic rings contracted with phenylephrine (PE) 1 μM relaxed in a concentration related fashion to 17-β-oestradiol water soluble cyclodextrin-encapsulated (E2) only when endothelium was present. The pure anti-oestrogen of E2 receptor ICI 182,780 (20 μM) significantly inhibited E2-induced vasorelaxation. Geldanamycin (10 μM), a specific inhibitor of heat shock protein 90 (hsp90) and Nω-nitro-L-arginine-methyl ester (L-NAME, 100 μM), a nitric oxide synthase inhibitor, significantly inhibited E2-induced vasorelaxation. Incubation of rat aortic rings up to 6 h with LY 294002 (25 μM), a specific inhibitor of PI(3)K akt/pkb pathway reduced E2-induced vasorelaxation. Incubation of rat isolated aorta with E2, induced prostacyclin (PGI2) release. PGI2 levels, measured as 6-keto PGF1α, were abolished by ibuprofen (10 μM), both L-NAME and GA did not influence basal or E2-stimulated PGI2 confirming the specificity of these two compounds on eNOS pathway. In conclusion, we demonstrate that E2 interaction with its receptor is followed by a vasorelaxant effect in rat aortic rings mediated by eNOS activation through both hsp90 and akt/pkb dependent mechanisms. PMID:11934809

  4. Docosahexaenoic acid attenuates VCAM-1 expression and NF-κB activation in TNF-α-treated human aortic endothelial cells.

    PubMed

    Wang, Tzu-Ming; Chen, Chun-Jung; Lee, Tzong-Shyuan; Chao, Han-Yi; Wu, Wen-Huey; Hsieh, Shu-Chen; Sheu, Huey-Herng; Chiang, An-Na

    2011-02-01

    This study was conducted to test the hypothesis that n-3 polyunsaturated fatty acids are able to down-regulate expression of adhesion molecules and nuclear factor-κB (NF-κB) activation in vascular endothelial cells, in addition to reducing atherosclerotic lesions in vivo. We report here that docosahexaenoic acid (DHA) reduces atherosclerotic lesions in the aortic arteries of apolipoprotein E knockout (apoE(-/-)) mice. Consistent with the observation in animal study, DHA inhibited THP-1 cell adhesion to tumor necrosis factor α (TNF-α)-activated human aortic endothelial cells (HAECs). Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) on the cell surface of HAECs was determined by cell-surface enzyme-linked immunosorbent assay. DHA and eicosapentaenoic acid decreased VCAM-1 expression in a dose-dependent manner in TNF-α treated HAECs, while cis-linoleic acid and arachidonic acid did not have any significant effect on either VCAM-1 or ICAM-1 expression. Moreover, DHA significantly reduced VCAM-1 protein expression in the cell lysates of TNF-α-treated HAECs, as determined by Western blot analysis. In line with NF-κB signaling pathway, DHA suppressed the TNF-α-activated IκBα phosphorylation and degradation as well as IκB kinase-β phosphorylation. Subsequently, translocation of the NF-κB (p50/p65) and AP-1 (c-Fos/c-Jun) subunits was down-regulated by DHA in the nucleus of HAECs. These results suggest that DHA negatively regulates TNF-α-induced VCAM-1 expression through attenuation of NF-κB signaling pathway and AP-1 activation. This study provides evidence that DHA may contribute to the prevention of atherosclerosis and inflammatory diseases in vivo.

  5. Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells

    SciTech Connect

    Hossain, Ekhtear; Ota, Akinobu; Karnan, Sivasundaram; Damdindorj, Lkhagvasuren; Takahashi, Miyuki; Konishi, Yuko; Konishi, Hiroyuki; Hosokawa, Yoshitaka

    2013-12-15

    Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis. - Highlights: • Sodium arsenite (SA) increases LOX-1 expression in mouse aortic endothelial cells. • SA enhances cellular uptake of oxidized LDL in dose-dependent manner. • SA-induced ROS generation enhances phosphorylation of NF-κB. • SA upregulates LOX-1 expression through ROS-activated NF-κB signaling pathway.

  6. Acute Aortic Syndromes and Thoracic Aortic Aneurysm

    PubMed Central

    Ramanath, Vijay S.; Oh, Jae K.; Sundt, Thoralf M.; Eagle, Kim A.

    2009-01-01

    Acute and chronic aortic diseases have been diagnosed and studied by physicians for centuries. Both the diagnosis and treatment of aortic diseases have been steadily improving over time, largely because of increased physician awareness and improvements in diagnostic modalities. This comprehensive review discusses the pathophysiology and risk factors, classification schemes, epidemiology, clinical presentations, diagnostic modalities, management options, and outcomes of various aortic conditions, including acute aortic dissection (and its variants intramural hematoma and penetrating aortic ulcers) and thoracic aortic aneurysms. Literature searches of the PubMed database were conducted using the following keywords: aortic dissection, intramural hematoma, aortic ulcer, and thoracic aortic aneurysm. Retrospective and prospective studies performed within the past 20 years were included in the review; however, most data are from the past 15 years. PMID:19411444

  7. Thoracic aortic aneurysm

    MedlinePlus

    ... common cause of a thoracic aortic aneurysm is hardening of the arteries . This condition is more common ... aortic aneurysm repair - open Aortic aneurysm repair - endovascular Hardening of the arteries High blood pressure Marfan syndrome ...

  8. Aortic Valve Regurgitation

    MedlinePlus

    ... valve. Also, a narrowing of the aortic valve (aortic stenosis) can be associated with leaking. High blood pressure (hypertension). High blood pressure may stretch the root of the aorta where the aortic valve sits. The valve flaps ( ...

  9. DIETARY FLAVONOID QUERCETIN STIMULATES VASORELAXATION IN AORTIC VESSELS

    PubMed Central

    Khoo, Nicholas K.H.; White, C. Roger; Pozzo-Miller, Lucas; Zhou, Fen; Constance, Chad; Inoue, Takafumi; Patel, Rakesh P.; Parks, Dale A.

    2010-01-01

    Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30 min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100 μM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca2+ concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function. PMID:20423726

  10. Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels.

    PubMed

    Khoo, Nicholas K H; White, C Roger; Pozzo-Miller, Lucas; Zhou, Fen; Constance, Chad; Inoue, Takafumi; Patel, Rakesh P; Parks, Dale A

    2010-08-01

    Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100muM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca(2+) concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function.

  11. Aortic Stenosis.

    PubMed

    Bakaeen, Faisal G; Rosengart, Todd K; Carabello, Blase A

    2017-01-03

    This issue provides a clinical overview of aortic stenosis, focusing on screening, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.

  12. A wound-like inflammatory aortic response in chronic portal hypertensive rats.

    PubMed

    de Las Heras, Natalia; Aller, María-Angeles; Martín-Fernández, Beatriz; Miana, María; Ballesteros, Sandra; Regadera, Javier; Cachofeiro, Victoria; Arias, Jaime; Lahera, Vicente

    2012-06-01

    Long-term prehepatic portal hypertension in the rat produces a low-grade splanchnic inflammation with liver steatosis and dyslipidemia. It has been suggested that in this experimental model these inflammatory alterations could represent a risk factor of vascular disease. Therefore, our aim was to investigate whether long-term prehepatic portal hypertension (PH) induces vascular pathology, fundamentally inflammatory aortopathy. Male Wistar sham-operated (SO) rats and rats with triple partial portal vein ligation in the very long-term (22 months) of postoperative evolution were used. Serum lipid profile, pro- and anti- inflammatory cytokines and ACTH and corticosterone were assayed by spectrophotometric and ELISA techniques. Aorta mRNA expression of oxidative and nitrosative stress enzymes, NFκB e IκB, immune-related cytokine production and vascular fibrosis parameters, were evaluated by real time RT-PCR. In addition, aortic p22phox subunit immunostaining, morphometry and vascular fibrosis in aorta were analyzed. PH rats have increased serum cholesterol, triglyceride, low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), while high-density lipoproteins (HDL) were lower than in SO rats. Serum ACTH and corticosterone decreased in PH rats. Also, serum TNF-α, IL-1β and IL-6 were significantly higher in PH-rats. Portal hypertensive-rats showed aortic oxidative stress with increased mRNA expressions of NAD(P)H oxidase p22phox, XDh, SOD and eNOS; higher aortic levels of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6; remodeling markers, like collagen I, CTGF and MMP-9; and finally, higher protein production of p22phox and collagen and extracellular matrix density were significantly higher in rats with PH. The results from the current study suggest that very long-term prehepatic portal hypertension in rats induces an abdominal aortic inflammatory and fibrotic response. Therefore, it could be considered that portal hypertension aggravates

  13. Sesamin attenuates intercellular cell adhesion molecule-1 expression in vitro in TNF-alpha-treated human aortic endothelial cells and in vivo in apolipoprotein-E-deficient mice.

    PubMed

    Wu, Wen-Huey; Wang, Shu-Huei; Kuan, I-I; Kao, Ya-Shi; Wu, Pei-Jhen; Liang, Chan-Jung; Chien, Hsiung-Fei; Kao, Chiu-Hua; Huang, Ching-Jang; Chen, Yuh-Lien

    2010-09-01

    Sesame lignans have antioxidative and anti-inflammatory properties. We focused on the effects of the lignans sesamin and sesamol on the expression of endothelial-leukocyte adhesion molecules in tumor necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs). When HAECs were pretreated with sesamin (10 or 100 microM), the TNF-alpha-induced expression of intercellular cell adhesion molecule-1 (ICAM-1) was significantly reduced (35 or 70% decrease, respectively) by Western blotting. Sesamol was less effective at inhibiting ICAM-1 expression (30% decrease at 100 microM). Sesamin and sesamol reduced the marked TNF-alpha-induced increase in human antigen R (HuR) translocation and the interaction between HuR and the 3'UTR of ICAM-1 mRNA. Both significantly reduced the binding of monocytes to TNF-alpha-stimulated HAECs. Sesamin significantly attenuated TNF-alpha-induced ICAM-1 expression and cell adhesion by downregulation of extracellular signal-regulated kinase 1/2 and p38. Furthermore, in vivo, sesamin attenuated intimal thickening and ICAM-1 expression seen in aortas of apolipoprotein-E-deficient mice. Taken together, these data suggest that sesamin inhibits TNF-alpha-induced extracellular signal-regulated kinase/p38 phosphorylation, nuclear translocation of NF-kappaB p65, cytoplasmic translocalization of HuR and thereby suppresses ICAM-1 expression, resulting in reduced adhesion of leukocytes. These results also suggest that sesamin may prevent the development of atherosclerosis and inflammatory responses.

  14. Chronic Exercise Training Improved Aortic Endothelial and Mitochondrial Function via an AMPKα2-Dependent Manner

    PubMed Central

    Chen, Xiaohui; An, Xiangbo; Chen, Dongrui; Ye, Maoqing; Shen, Weili; Han, Weiqing; Zhang, Youyi; Gao, Pingjin

    2016-01-01

    Chronic exercise training is known to protect the vasculature; however, the underlying mechanisms remain obscure. The present study hypothesized that exercise may improve aortic endothelial and mitochondrial function through an adenosine monophosphate-activated protein kinase α2 (AMPKα2)-dependent manner. Ten-week-old AMPKα2 knockout (AMPKα2−/−) mice and age-matched wild-type (WT) mice were subjected to daily treadmill running for 6 weeks, and the thoracic aorta from these mice were used for further examination. Our results showed that exercise significantly promoted vasodilatation and increased expression and phosphorylation of endothelial nitric oxide synthase (eNOS), concomitant with increased AMPKα2 expression in WT mice. These effects were not observed in AMPKα2−/− mice. Furthermore, exercise training increased thoracic aortic mitochondrial content as indicated by increased Complex I and mitochondrial DNA (mtDNA) in WT mice but not in AMPKα2−/− mice. This may be caused by decreased mitochondrial autophagy since the expression of BH3 domain-containing BCL2 family members BNIP3-like (BNIP3L) and LC3B were decreased in WT mice with exercise. And these changes were absent with AMPKα2 deletion in mice. Importantly, exercise increased the expression of manganous superoxide dismutase (MnSOD) and catalase, suggesting that mitochondrial antioxidative capacity was increased. Notably, the improved antioxidative capacity was lost in AMPKα2−/− mice with exercise. In conclusion, this study illustrated that AMPKα2 plays a critical role in exercise-related vascular protection via increasing endothelial and mitochondrial function in the artery. PMID:28066264

  15. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179

    PubMed Central

    Thebault, Stéphanie; González, Carmen; García, Celina; Zamarripa, David Arredondo; Nava, Gabriel; Vaca, Luis; López-Casillas, Fernando; de la Escalera, Gonzalo Martínez; Clapp, Carmen

    2011-01-01

    Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS), as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca2+ levels ([Ca2+]i) upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca2+ from intracellular stores. The [Ca2+]i rise evoked by BK also involves the influx of extracellular Ca2+ via canonical transient receptor potential (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca2+ entry since La3+, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser1179, a post-translational modification that facilitates Ca2+-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca2+]i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis.

  16. PECAM-1 Isoforms, eNOS, and Endoglin Axis in Regulation of Angiogenesis

    PubMed Central

    Park, SunYoung; Sorenson, Christine M.; Sheibani, Nader

    2016-01-01

    Vascular development and maintenance of proper vascular function through various regulatory mechanisms are critical to our wellbeing. Delineating the regulatory processes involved in development of vascular system and function is one of the most important topics in human physiology and pathophysiology. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), a cell adhesion molecule with proangiogenic and proinflammatory activity, has been subject of numerous studies. Here we will review the important roles PECAM-1 and its isoforms play during angiogenesis, and its molecular mechanisms of action in the endothelium. In the endothelium, PECAM-1 not only plays a role as an adhesion molecule but also participates in intracellular signaling pathways which impact various cell adhesive mechanisms and endothelial nitric oxide (eNOS) expression and activity. In addition, recent studies from our laboratory have revealed an important relationship between PECAM-1 and endoglin expression. Endoglin is an essential molecule during angiogenesis, vascular development and integrity whose expression and activity are compromised in the absence of PECAM-1. Here we will discuss the roles PECAM-1 isoforms may play in modulation of endothelial cell adhesive mechanisms, eNOS and endoglin expression and activity, and angiogenesis. PMID:25976664

  17. Protective effect of eNOS overexpression against ischemia/reperfusion injury in small-for-size liver transplantation

    PubMed Central

    Zhang, Bo; Liu, Qiu-Hua; Zhou, Cui-Jie; Hu, Ming-Zheng; Qian, Hai-Xin

    2016-01-01

    Ischemia/reperfusion (I/R) injury can occur during small-for-size liver transplantation, resulting in delayed graft function and decreased long-term graft survival. The aim of the present study was to evaluate the effects of genetic overexpression of endothelial nitric oxide synthase (eNOS) in protecting hepatocytes against I/R injury in a rat model of small-for-size liver transplantation. L02 liver cells were transfected with the eNOS gene using an adenovirus (Ad-eNOS). eNOS expression was detected using quantitative polymerase chain reaction and western blot analysis. To evaluate the effect of eNOS overexpression, L02 cells were placed in a hypoxic environment for 12 h and immediately transferred to an oxygen-enriched atmosphere. For in vivo testing, rats pretreated with Ad-eNOS or control underwent small-for-size liver transplantation. At 6 h after reperfusion, the bile quantity, serum transaminase and nitric oxide (NO) levels, and histological outcomes were evaluated. Cell apoptosis was assessed by flow cytometry or TUNEL assay. In vitro, Ad-eNOS prevented apoptosis in L02 cells with an increase in the level of NO in culture supernatant. In vivo, Ad-eNOS pre-treatment significantly increased bile production, improved abnormal transaminase levels, diminished apoptosis among liver cells, and decreased hepatocellular damage at 6 h after I/R injury. The eNOS-mediated renal protective effects might be associated with the downregulation of tumor necrosis factor-α and a reduction in macrophage activation in the early stage of reperfusion in small-for-size liver allografts. eNOS-derived NO production significantly attenuates hepatic I/R injury. Thus, eNOS overexpression constitutes a promising therapeutic approach to prevent liver I/R injury following small-for-size liver transplantation. PMID:27882135

  18. Aortic Disease Presentation and Outcome Associated with ACTA2 mutations

    PubMed Central

    Regalado, Ellen S.; Guo, Dongchuan; Prakash, Siddharth; Bensend, Tracy A.; Flynn, Kelly; Estrera, Anthony; Safi, Hazim; Liang, David; Hyland, James; Child, Anne; Arno, Gavin; Boileau, Catherine; Jondeau, Guillaume; Braverman, Alan; Moran, Rocio; Morisaki, Takayuki; Morisaki, Hiroko; Consortium, Montalcino Aortic; Pyeritz, Reed; Coselli, Joseph; LeMaire, Scott; Milewicz, Dianna M.

    2015-01-01

    Background ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations. Methods and Results Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years, IQR 18–41 versus 36 years, IQR 26–45). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta and aortic arch. Overall cumulative risk of an aortic event at age 85 years was 0.76 (95% CI 0.64, 0.86). After adjustment for intra-familial correlation, gender and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared to other mutations. Conclusions ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations. PMID:25759435

  19. Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non-hypertensive mice: Mechanisms and implications.

    PubMed

    Miao, Xiao Niu; Siu, Kin Lung; Cai, Hua

    2015-10-01

    Rupture of abdominal aortic aneurysm (AAA) is a lethal event. No oral medicine has been available to prevent or treat AAA. We have recently identified a novel mechanism of eNOS uncoupling by which AAA develops, in angiotensin II (Ang II) infused hyperphenylalaninemia 1 (hph-1) mice. Using this unique model we investigated effects on AAA formation of the L-type calcium channel blocker nifedipine, in view of the unclear relationship between hypertension and AAA, and unclear mechanisms of aneurysm protective effects of some blood pressure lowering drugs. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 weeks, and fed nifedipine chow at two different doses (5 and 20 mg/kg/day). While the high dose of nifedipine reduced blood pressure, the lower dose had no effect. Interestingly, the incidence rate of AAA dropped from 71% to 7 and 12.5% for low and high dose nifedipine, respectively. Expansion of abdominal aorta, determined by ultrasound imaging, was abolished by both doses of nifedipine, which recoupled eNOS completely to improve NO bioavailability. Both also abrogated aortic superoxide production. Of note, Ang II activation of NADPH oxidase in vascular smooth muscle cells and endothelial cells, known to uncouple eNOS, was also attenuated by nifedipine. Although low dose was a sub-pressor while the high dose reduced blood pressure via inhibition of calcium channels, both doses were highly effective in preventing AAA by preserving eNOS coupling activity to eliminate sustained oxidative stress from uncoupled eNOS. These data demonstrate that oral treatment of nifedipine is highly effective in preserving eNOS function to attenuate AAA formation. Nifedipine may be used for AAA prevention either at low dose in AAA risk group, or at high dose in patients with co-existing hypertension.

  20. Nifedipine Attenuation of Abdominal Aortic Aneurysm in Hypertensive and non-Hypertensive Mice: Mechanisms and Implications

    PubMed Central

    Miao, Xiao Niu; Siu, Kin Lung; Cai, Hua

    2015-01-01

    Rupture of abdominal aortic aneurysm (AAA) is a lethal event. No oral medicine has been available to prevent or treat AAA. We have recently identified a novel mechanism of eNOS uncoupling by which AAA develops, in Angiotensin II (Ang II) infused hyperphenylalaninemia 1 (hph-1) mice. Using this unique model we investigated effects on AAA formation of the L-type calcium channel blocker nifedipine, in view of the unclear relationship between hypertension and AAA, and unclear mechanisms of aneurysm protective effects of some blood pressure lowering drugs. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 weeks, and fed nifedipine chow at two different doses (5 and 20 mg/kg/day). While the high dose of nifedipine reduced blood pressure, the lower dose had no effect. Interestingly, the incidence rate of AAA dropped from 71% to 7 and 12.5% for low and high dose nifedipine, respectively. Expansion of abdominal aorta, determined by ultrasound imaging, was abolished by both doses of nifedipine, which recoupled eNOS completely to improve NO bioavailability. Both also abrogated aortic superoxide production. Of note, Ang II activation of NADPH oxidase in vascular smooth muscle cells and endothelial cells, known to uncouple eNOS, was also attenuated by nifedipine. Although low dose was a sub-pressor while the high dose reduced blood pressure via inhibition of calcium channels, both doses were highly effective in preventing AAA by preserving eNOS coupling activity to eliminate sustained oxidative stress from uncoupled eNOS. These data demonstrate that oral treatment of nifedipine is highly effective in preserving eNOS function to attenuate AAA formation. Nifedipine may be used for AAA prevention either at low dose to AAA risk group, or at high dose to patients with co-existing hypertension. PMID:26254182

  1. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.

    PubMed Central

    Hernández-Perera, O; Pérez-Sala, D; Navarro-Antolín, J; Sánchez-Pascuala, R; Hernández, G; Díaz, C; Lamas, S

    1998-01-01

    Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 microg/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able to prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors. PMID:9637705

  2. Wogonin suppresses TNF-{alpha}-induced MMP-9 expression by blocking the NF-{kappa}B activation via MAPK signaling pathways in human aortic smooth muscle cells

    SciTech Connect

    Lee, Syng-Ook; Jeong, Yun-Jeong; Yu, Mi Hee; Lee, Ji-Won; Hwangbo, Mi Hyang; Kim, Cheorl-Ho; Lee, In-Seon . E-mail: inseon@kmu.ac.kr

    2006-12-08

    Matrix metalloproteinase-9 (MMP-9) plays a major role in the pathogenesis of atherosclerosis and restenosis by regulating both migration and proliferation of vascular smooth muscle cells (VSMC) after an arterial injury. In this study, we examined the inhibitory effect of three major flavonoids in Scutellariae Radix, baicalin, baicalein, and wogonin, on TNF-{alpha}-induced MMP-9 expression in human aortic smooth muscle cells (HASMC). Wogonin, but not baicalin and baicalein, significantly and selectively suppressed TNF-{alpha}-induced MMP-9 expression in HASMC. Reporter gene, electrophoretic mobility shift, and Western blotting assays showed that wogonin inhibits MMP-9 gene transcriptional activity by blocking the activation of NF-{kappa}B via MAPK signaling pathways. Moreover, the Matrigel migration assay showed that wogonin reduced TNF-{alpha}-induced HASMC migration. These results suggest that wogonin effectively suppresses TNF-{alpha}-induced HASMC migration through the selective inhibition of MMP-9 expression and represents a potential agent for the prevention of vascular disorders related to the migration of VSMC.

  3. Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Epigenetic Changes in the eNOS Gene

    PubMed Central

    Kheirandish-Gozal, Leila; Khalyfa, Abdelnaby; Gozal, David; Bhattacharjee, Rakesh

    2013-01-01

    Background: Obstructive sleep apnea (OSA) is a highly prevalent disorder that has been associated with an increased risk for cardiovascular morbidity, even in children. However, not all children with OSA manifest alterations in endothelial postocclusive hyperemia, an endothelial nitric oxide synthase (eNOS)-dependent response. Since expression of the eNOS gene is regulated by epigenetic mechanisms and OSA may cause epigenetic modifications such as DNA hypermethylation, we hypothesized that epigenetic modifications in the eNOS gene may underlie the differential vascular phenotypes in pediatric OSA. Methods: Age-, sex-, ethnicity-, and BMI-matched prepubertal children with polysomnographically confirmed OSA and either normal (OSAn) or abnormal (OSAab) postocclusive hyperemic responses, assessed as the time to attain peak reperfusion flow (Tmax) by laser Doppler flowmetry, were recruited. Blood genomic DNA was assessed for epigenetic modifications in the eNOS gene using pyrosequencing. Children with no evidence of OSA or endothelial dysfunction served as a control group. Results: The study comprised 36 children with OSA (11 with OSAab and 25 with OSAn) and 35 children in the control group. Overall, the mean age was 7.5 ± 2.4 years, 65% were boys, and 30% were obese; mean apnea-hypopnea index was 18 ± 8.6/h of sleep for the children with OSA. Tmax was 66.7 ± 8.8 s in the OSAab group and 30.1 ± 8.3 s in the OSAn group (P < .001). Pyrosequencing of the proximal promoter region of the eNOS gene revealed no significant differences in six of the seven CpG sites. However, a CpG site located at position -171 (relative to transcription start site), approximating important transcriptional elements, displayed significantly higher methylation levels in the OSAab group as compared with the OSAn or control groups (81.5% ± 3.5%, 74.8% ± 1.4%, and 74.5% ± 1.7%, respectively; P < .001). eNOS mRNA expression levels were assessed in a separate group of children and were

  4. Inhibitory role of Notch1 in calcific aortic valve disease.

    PubMed

    Acharya, Asha; Hans, Chetan P; Koenig, Sara N; Nichols, Haley A; Galindo, Cristi L; Garner, Harold R; Merrill, Walter H; Hinton, Robert B; Garg, Vidu

    2011-01-01

    Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

  5. Clathrin-dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to COX-2 protein expression in rat aortic vascular smooth muscle cells.

    PubMed

    Morinelli, Thomas A; Walker, Linda P; Velez, Juan Carlos Q; Ullian, Michael E

    2015-02-05

    The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT1A receptor activation. Certain effects initiated by AT1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by β-arrestin-dependent receptor internalization and NF-κB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT1A receptor mediates NF-κB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2׳s effects on AT1 receptor/GFP internalization in HEK-293 cells and p65 NF-κB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT1A receptor (44.7% ± 3.1% Control vs. 13.2% ± 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-κB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFα signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through β-arrestin mediated internalization of G protein-coupled receptors, such as AT1A receptors.

  6. Effects of benidipine, a dihydropyridine-Ca2+ channel blocker, on expression of cytokine-induced adhesion molecules and chemoattractants in human aortic endothelial cells.

    PubMed

    Matsubara, Masahiro; Hasegawa, Kazuhide

    2004-09-13

    Benidipine hydrochloride (benidipine) is a dihydropyridine-Ca2+ channel blocker with antioxidant properties. We examined the effects of benidipine on cytokine-induced expression of adhesion molecules and chemokines, which play important roles in the adhesion of monocytes to endothelium. Pretreatment of human aortic endothelial cells (HAECs) with benidipine (0.3-10 micromol/l) for 24 h significantly suppressed cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) mRNA and protein expression, resulting in reduced adhesion of THP-1 monocytes. Benidipine also suppressed induction of monocyte chemoattractant protein (MCP)-1 and interleukin-8. Benidipine inhibited redox-sensitive transcriptional nuclear factor-kappaB (NF-kappaB) pathway, as determined by Western blotting of inhibitory kappaB (IkappaB) phosphorylation and luciferase reporter assay. Results of analysis using optical isomers of benidipine and antioxidants suggested that these inhibitory effects were dependent on pharmacological effects other than Ca2+ antagonism such as antioxidant effects. Benidipine may thus have anti-inflammatory properties and benefits for in the treatment of atherosclerosis.

  7. Abdominal Aortic Aneurysm (AAA)

    MedlinePlus

    ... Professions Site Index A-Z Abdominal Aortic Aneurysm (AAA) Abdominal aortic aneurysm (AAA) occurs when atherosclerosis or plaque buildup causes the ... weak and bulge outward like a balloon. An AAA develops slowly over time and has few noticeable ...

  8. Abdominal aortic aneurysm

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000162.htm Abdominal aortic aneurysm To use the sharing features on this page, ... blood to the abdomen, pelvis, and legs. An abdominal aortic aneurysm occurs when an area of the aorta becomes ...

  9. Central Role of eNOS in the Maintenance of Endothelial Homeostasis

    PubMed Central

    Rodriguez-Mateos, Ana; Kelm, Malte

    2015-01-01

    Abstract Significance: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. Recent Advances: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a functional eNOS. These markers can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity with NO representing a central signaling molecule. Critical Issues: Improvements of reproducibility and observer independence of FMD measurements and definitions of relevant EMP and CAC subpopulations warrant further research. Future Directions: Endothelial homeostasis may be a clinical therapeutic target for cardiovascular health maintenance. Antioxid. Redox Signal. 22, 1230–1242. PMID:25330054

  10. Transcatheter aortic valve replacement

    MedlinePlus

    ... fully will restrict blood flow. This is called aortic stenosis. If there is also a leak, it is ... TAVR is used for people with severe aortic stenosis who aren't ... valve . In adults, aortic stenosis usually occurs due to calcium ...

  11. Evaluation of Protective Immune Responses Induced by Recombinant TrxLp and ENO2 Proteins against Toxoplasma gondii Infection in BALB/c Mice

    PubMed Central

    Wang, Meng; Yang, Xiao-Yu; Zhang, De-Lin

    2016-01-01

    Toxoplasma gondii is an obligate intracellular parasitic protozoan that can infect almost all species of warm-blooded animals. As any chemical-based drugs could not act against the tissue cyst stage of T. gondii, vaccination may be one of the ideal control strategies. In the present study, two new vaccine candidates, named TgENO2 and TgTrxLp, were purified from Escherichia coli with pET-30a(+) expression system and then were injected into BALB/c mice to evaluate the protective efficacy against acute and chronic toxoplasmosis. The results showed that both the recombinant proteins, either alone or in combination, could elicit strong humoral and cellular immune responses with a higher level of IgG antibodies, IFN-γ, IL-2, CD4+, and CD8+ T cells as compared to those in mice from control groups. After acute challenge with tachyzoites of the GJS strain, mice immunized with rTgTrxLp (8 ± 2.77 d), rTgENO2 (7.4 ± 1.81 d), and rTgTrxLp + rTgENO2 (8.38 ± 4.57 d) proteins showed significantly longer survival time than those that received Freund's adjuvant (6.78 ± 2.08 d) and PBS (6.38 ± 4.65 d) (χ2 = 9.687, df = 4, P = 0.046). The protective immunity of rTgTrxLp, rTgENO2, and rTgTrxLp + rTgENO2 proteins against chronic T. gondii infection showed 69.77%, 58.14%, and 20.93% brain cyst reduction as compared to mice that received PBS. The present study suggested that both TgENO2 and TgTrxLp were potential candidates for the development of multicomponent vaccines against toxoplasmosis. PMID:27803923

  12. Improvement of thoracic aortic vasoreactivity by continuous and intermittent exercise in high-fat diet-induced obese rats.

    PubMed

    Liu, Hongpeng; Yang, Zhen; Hu, Jian; Luo, Yan; Zhu, Lingqin; Yang, Huifang; Li, Guanghua

    2015-07-01

    The aim of the present study was to explore the effects of continuous and intermittent exercise on the thoracic aortic vasoreactivity and free radical metabolism in rats fed with a high-fat diet (HD). Sprague-Dawley (SD) rats were randomly divided into four groups (n=8, each group): Conventional diet (CD), HD, HD with continuous exercise (HCE) and HD with intermittent exercise (HIE). HCE rats swam once/day for 90 min; HIE rats performed swimming exercises 3 times/day, 30 min each time with an interval of 4 h. In these two groups, the exercise was conducted 5 days a week for 8 weeks. Rats in the CD and HD groups were fed without swimming training. At the end of the exercise, all the rats were sacrificed and the blood, thoracic aorta and myocardium were collected immediately. The thoracic aortic vasoreactivity, the plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), superoxide dismutase (SOD), malondialdehyde (MDA) and vascular endothelial nitric oxide synthase (eNOS) gene expression were measured. Compared to the control group, in the HD group the enhanced contractile response of the thoracic aortic rings to noradrenaline (NA) was observed (P<0.01). The levels of TC and LDL (P<0.01) were also increased in serum while the HDL level was reduced without statistical significance. In addition, the MDA content was upregulated in the myocardium, but the SOD level decreased (P<0.01). Furthermore, the expression of vascular eNOS mRNA was reduced (P<0.01). However, following the exercise the contraction of the thoracic aorta vascular rings to NA was reduced in the HCE and HIE groups (P<0.01), and the decreased contractile response was more evident in the HIE group compared to the HCE group (P<0.01). Additionally, in the HCE group the level of TG (P<0.01) was decreased, while the HDL (P<0.01) level was increased. Although the reduction of the TC and LDL level was also observed there was no significant difference

  13. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease.

    PubMed

    Cortese-Krott, Miriam M; Rodriguez-Mateos, Ana; Sansone, Roberto; Kuhnle, Gunter G C; Thasian-Sivarajah, Sivatharsini; Krenz, Thomas; Horn, Patrick; Krisp, Christoph; Wolters, Dirk; Heiß, Christian; Kröncke, Klaus-Dietrich; Hogg, Neil; Feelisch, Martin; Kelm, Malte

    2012-11-15

    A nitric oxide synthase (NOS)-like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the nitric oxide (NO)-imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Using immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-(3)H-arginine to L-(3)H-citrulline in a Ca(2+)/calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform, the activity of which is compromised in patients with coronary artery disease.

  14. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF-κB signaling, and inflammatory gene expression in human aortic valve cells

    PubMed Central

    Patel, Vishal; Carrion, Katrina; Hollands, Andrew; Hinton, Andrew; Gallegos, Thomas; Dyo, Jeffrey; Sasik, Roman; Leire, Emma; Hardiman, Gary; Mohamed, Salah A.; Nigam, Sanjay; King, Charles C.; Nizet, Victor; Nigam, Vishal

    2015-01-01

    Bicuspid aortic valves calcify at a significantly higher rate than normal aortic valves, a process that involves increased inflammation. Because we have previously found that bicuspid aortic valve experience greater stretch, we investigated the potential connection between stretch and inflammation in human aortic valve interstitial cells (AVICs). Microarray, quantitative PCR (qPCR), and protein assays performed on AVICs exposed to cyclic stretch showed that stretch was sufficient to increase expression of interleukin and metalloproteinase family members by more than 1.5-fold. Conditioned medium from stretched AVICs was sufficient to activate leukocytes. microRNA sequencing and qPCR experiments demonstrated that miR-148a-3p was repressed in both stretched AVICs (43% repression) and, as a clinical correlate, human bicuspid aortic valves (63% reduction). miR-148a-3p was found to be a novel repressor of IKBKB based on data from qPCR, luciferase, and Western blot experiments. Furthermore, increasing miR-148a-3p levels in AVICs was sufficient to decrease NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and NF-κB target gene expression. Our data demonstrate that stretch-mediated activation of inflammatory pathways is at least partly the result of stretch-repression of miR-148a-3p and a consequent failure to repress IKBKB. To our knowledge, we are the first to report that cyclic stretch of human AVICs activates inflammatory genes in a tissue-autonomous manner via a microRNA that regulates a central inflammatory pathway.—Patel, V., Carrion, K., Hollands, A., Hinton, A., Gallegos, T., Dyo, J., Sasik, R., Leire, E., Hardiman, G., Mohamed, S. A., Nigam, S., King, C. C., Nizet, V., Nigam V. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF-κB signaling, and inflammatory gene expression in human aortic valve cells. PMID:25630970

  15. Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner

    PubMed Central

    Hocher, Berthold; Haumann, Hannah; Rahnenführer, Jan; Reichetzeder, Christoph; Kalk, Philipp; Pfab, Thiemo; Tsuprykov, Oleg; Winter, Stefan; Hofmann, Ute; Li, Jian; Püschel, Gerhard P.; Lang, Florian; Schuppan, Detlef; Schwab, Matthias; Schaeffeler, Elke

    2016-01-01

    ABSTRACT Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood. PMID:27175980

  16. Function and role of voltage-gated sodium channel NaV1.7 expressed in aortic smooth muscle cells.

    PubMed

    Meguro, Kentaro; Iida, Haruko; Takano, Haruhito; Morita, Toshihiro; Sata, Masataka; Nagai, Ryozo; Nakajima, Toshiaki

    2009-01-01

    Voltage-gated Na(+) channel currents (I(Na)) are expressed in several types of smooth muscle cells. The purpose of this study was to evaluate the expression of I(Na), its functional role, pathophysiology in cultured human (hASMCs) and rabbit aortic smooth muscle cells (rASMCs), and its association with vascular intimal hyperplasia. In whole cell voltage clamp, I(Na) was observed at potential positive to -40 mV, was blocked by tetrodotoxin (TTX), and replacing extracellular Na(+) with N-methyl-d-glucamine in cultured hASMCs. In contrast to native aorta, cultured hASMCs strongly expressed SCN9A encoding Na(V)1.7, as determined by quantitative RT-PCR. I(Na) was abolished by the treatment with SCN9A small-interfering (si)RNA (P < 0.01). TTX and SCN9A siRNA significantly inhibited cell migration (P < 0.01, respectively) and horseradish peroxidase uptake (P < 0.01, respectively). TTX also significantly reduced the secretion of matrix metalloproteinase-2 6 and 12 h after the treatment (P < 0.01 and P < 0.05, respectively). However, neither TTX nor siRNA had any effect on cell proliferation. L-type Ca(2+) channel current was recorded, and I(Na) was not observed in freshly isolated rASMCs, whereas TTX-sensitive I(Na) was recorded in cultured rASMCs. Quantitative RT-PCR and immunostaining for Na(V)1.7 revealed the prominent expression of SCN9A in cultured rASMCs and aorta 48 h after balloon injury but not in native aorta. In conclusion, these studies show that I(Na) is expressed in cultured and diseased conditions but not in normal aorta. The Na(V)1.7 plays an important role in cell migration, endocytosis, and secretion. Na(V)1.7 is also expressed in aorta after balloon injury, suggesting a potential role for Na(V)1.7 in the progression of intimal hyperplasia.

  17. Living Water. Eno River State Park: An Environmental Education Learning Experience Designed for the Middle Grades.

    ERIC Educational Resources Information Center

    Hartley, Scott; Woods, Martha

    This learning packet, one in a series of eight, was developed by the Eno River State Park in North Carolina for Grades 5-6 to teach about various aspects of water life on the Eno River. Loose-leaf pages are presented in nine sections that contain: (1) introductions to the North Carolina State Park System, the Eno River State Park, and to the…

  18. Differential effects of eNOS uncoupling on conduit and small arteries in GTP-cyclohydrolase I-deficient hph-1 mice

    PubMed Central

    d'Uscio, Livius V.; Smith, Leslie A.

    2011-01-01

    In the present study, we used the hph-1 mouse, which displays GTP-cyclohydrolase I (GTPCH I) deficiency, to test the hypothesis that loss of tetrahydrobiopterin (BH4) in conduit and small arteries activates compensatory mechanisms designed to protect vascular wall from oxidative stress induced by uncoupling of endothelial nitric oxide synthase (eNOS). Both GTPCH I activity and BH4 levels were reduced in the aortas and small mesenteric arteries of hph-1 mice. However, the BH4-to-7,8-dihydrobiopterin ratio was significantly reduced only in hph-1 aortas. Furthermore, superoxide anion and 3-nitrotyrosine production were significantly enhanced in aortas but not in small mesenteric arteries of hph-1 mice. In contrast to the aorta, protein expression of copper- and zinc-containing superoxide dismutase (CuZnSOD) was significantly increased in small mesenteric arteries of hph-1 mice. Protein expression of catalase was increased in both aortas and small mesenteric arteries of hph-1 mice. Further analysis of endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) signaling demonstrated that protein expression of phosphorylated Ser1177-eNOS as well as basal cGMP levels and hydrogen peroxide was increased in hph-1 aortas. Increased production of hydrogen peroxide in hph-1 mice aortas appears to be the most likely mechanism responsible for phosphorylation of eNOS and elevation of cGMP. In contrast, upregulation of CuZnSOD and catalase in resistance arteries is sufficient to protect vascular tissue from increased production of reactive oxygen species generated by uncoupling of eNOS. The results of our study suggest that anatomical origin determines the ability of vessel wall to cope with oxidative stress induced by uncoupling of eNOS. PMID:21963838

  19. HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.

    PubMed

    Seker, F B; Kilic, U; Caglayan, B; Ethemoglu, M S; Caglayan, A B; Ekimci, N; Demirci, S; Dogan, A; Oztezcan, S; Sahin, F; Yilmaz, B; Kilic, E

    2015-01-22

    Apart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with

  20. Supravalvular aortic stenosis in adult with anomalies of aortic arch vessels and aortic regurgitation

    PubMed Central

    Valente, Acrisio Sales; Alencar, Polyanna; Santos, Alana Neiva; Lobo, Roberto Augusto de Mesquita; de Mesquita, Fernando Antônio; Guimarães, Aloyra Guedis

    2013-01-01

    The supravalvular aortic stenosis is a rare congenital heart defect being very uncommon in adults. We present a case of supravalvular aortic stenosis in adult associated with anomalies of the aortic arch vessels and aortic regurgitation, which was submitted to aortic valve replacement and arterioplasty of the ascending aorta with a good postoperative course. PMID:24598962

  1. Aortic valve surgery - minimally invasive

    MedlinePlus

    ... of the heart is reduced. This is called aortic stenosis. The aortic valve can be replaced using: Minimally ... RN, Wang A. Percutaneous heart valve replacement for aortic stenosis: state of the evidence. Ann Intern Med . 2010; ...

  2. Endothelial nitric oxide synthase (eNOS) T-786C, 4a4b, and G894T polymorphisms and male infertility: study for idiopathic asthenozoospermia and meta-analysis.

    PubMed

    Song, Pingping; Zou, Shasha; Chen, Tingting; Chen, Jianhua; Wang, Yanan; Yang, Juanjuan; Song, Zhijian; Jiang, Huayu; Shi, Huijuan; Huang, Yiran; Li, Zheng; Shi, Yongyong; Hu, Hongliang

    2015-02-01

    Recent studies on the eNOS gene and male infertility show that expression of eNOS regulates normal spermatogenesis in the testis, and the eNOS gene variants (T-786C, 4a4b, and G894T) are potentially involved in impairment of spermatogenesis and sperm function. Thus, we conducted this association and meta-analysis study to further validate whether variants of those three loci affected the risk of idiopathic asthenozoospermia (AZS) and male infertility. Approximately 340 Chinese idiopathic AZS patients and 342 healthy men were included for this case-control study, genotyped by gel electrophoresis analysis or direct sequencing of PCR products. The eNOS mRNA isolated from the semen of patients was further examined by quantitative real-time PCR. Also, a meta-analysis of association between eNOS gene polymorphisms and male infertility was performed. A significant association was identified on allelic level between 4a4b variant and AZS in our study (chi-squared = 7.53, corrected P = 0.018, odds ratio (OR) = 1.808), while there were no significant difference of T-786C and G894T for asthenozoospermia in both genotype and allele distributions. In addition, expression of eNOS was up-regulated in patients compared with controls (about 2.4-fold, P < 0.001). Furthermore, the results of the meta-analysis support the conclusion that the T-786C and 4a4b loci were associated with male infertility in both Asian and Caucasian populations. Our study provides genetic evidence for the eNOS gene being a risk factor for idiopathic AZS and male infertility. Considering genetic differences among populations and complex pathogenesis of male infertility, more validating studies using independent samples are suggested in the future.

  3. Aortic Valve Calcification is Mediated by a Differential Response of Aortic Valve Interstitial Cells to Inflammation

    PubMed Central

    Venardos, Neil; Nadlonek, Nicole A.; Zhan, Qiong; Weyant, Michael J.; Reece, T. Brett; Meng, Xianzhong; Fullerton, David A.

    2014-01-01

    Background While calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Pro-inflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary and tricuspid valves, our purpose was to compare the osteogenic response to pro-inflammatory stimulation via TLR-4. Materials And Methods Aortic, pulmonic, mitral, and tricuspid (n=4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with LPS (100-200ng/mL) for 24 or 48 hours. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). BMP-2 and intercellular adhesion molecule-1 (ICAM-1) production were determined (immunoblotting). Monocyte chemoattractant protein-1 (MCP-1) levels were determined by ELISA. Statistics were by Mann-Whitney U test. Results TLR-4 stimulation induced BMP-2 production only in aortic VICs (p<0.05). ICAM-1 production and MCP-1 secretion increased in a similar fashion among TLR4-stimulated VICs from all four valves. Conclusions Pro-inflammatory stimulation induces an osteogenic phenotype in aortic VICs but not mitral, pulmonic, or tricuspid VICs. We conclude that this differential osteogenic response of aortic VICs contributes to the pathogenesis of calcific aortic stenosis. PMID:24746950

  4. Aspalatone Prevents VEGF-Induced Lipid Peroxidation, Migration, Tube Formation, and Dysfunction of Human Aortic Endothelial Cells

    PubMed Central

    Sonowal, Himangshu; Pal, Pabitra B.; Shukla, Kirtikar

    2017-01-01

    Although aspalatone (acetylsalicylic acid maltol ester) is recognized as an antithrombotic agent with antioxidative and antiplatelet potential; its efficacy in preventing endothelial dysfunction is not known. In this study, we examined the antiangiogenic, antioxidative, and anti-inflammatory effect of aspalatone in human aortic endothelial cells (HAECs). Specifically, the effect of aspalatone on VEGF-induced HAECs growth, migration, tube formation, and levels of lipid peroxidation-derived malondialdehyde (MDA) was examined. Our results indicate that the treatment of HAECs with aspalatone decreased VEGF-induced cell migration, tube formation, and levels of MDA. Aspalatone also inhibited VEGF-induced decrease in the expression of eNOS and increase in the expression of iNOS, ICAM-1, and VCAM-1. Aspalatone also prevented the VEGF-induced adhesion of monocytes to endothelial cells. Furthermore, aspalatone also prevented VEGF-induced release of inflammatory markers such as Angiopoietin-2, Leptin, EGF, G-CSF, HB-EGF, and HGF in HAECs. Thus, our results suggest that aspalatone could be used to prevent endothelial dysfunction, an important process in the pathophysiology of cardiovascular diseases. PMID:28243353

  5. Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates

    PubMed Central

    Stratmann, Bernd; Engelbrecht, Britta; Espelage, Britta C.; Klusmeier, Nadine; Tiemann, Janina; Gawlowski, Thomas; Mattern, Yvonne; Eisenacher, Martin; Meyer, Helmut E.; Rabbani, Naila; Thornalley, Paul J.; Tschoepe, Diethelm; Poschmann, Gereon; Stühler, Kai

    2016-01-01

    Methylglyoxal (MG), an arginine-directed glycating agent, is implicated in diabetic late complications. MG is detoxified by glyoxalase 1 (GLO1) of the cytosolic glyoxalase system. The aim was to investigate the effects of MG accumulation by GLO1-knockdown under hyperglycaemic conditions in human aortic endothelial cells (HAECs) hypothesizing that the accumulation of MG accounts for the deleterious effects on vascular function. SiRNA-mediated knockdown of GLO1 was performed and MG concentrations were determined. The impact of MG on the cell proteome and targets of MG glycation was analysed, and confirmed by Western blotting. Markers of endothelial function and apoptosis were assessed. Collagen content was assayed in cell culture supernatant. GLO1-knockdown increased MG concentration in cells and culture medium. This was associated with a differential abundance of cytoskeleton stabilisation proteins, intermediate filaments and proteins involved in posttranslational modification of collagen. An increase in fibrillar collagens 1 and 5 was detected. The extracellular concentration of endothelin-1 was increased following GLO1-knockdown, whereas the phosphorylation and amount of eNOS was not influenced by GLO1-knockdown. The expression of ICAM-1, VCAM-1 and of MCP-1 was elevated and apoptosis was increased. MG accumulation by GLO1-knockdown provoked collagen expression, endothelial inflammation and dysfunction and apoptosis which might contribute to vascular damage. PMID:27898103

  6. β-Cyclodextrins Decrease Cholesterol Release and ABC-Associated Transporter Expression in Smooth Muscle Cells and Aortic Endothelial Cells

    PubMed Central

    Coisne, Caroline; Hallier-Vanuxeem, Dorothée; Boucau, Marie-Christine; Hachani, Johan; Tilloy, Sébastien; Bricout, Hervé; Monflier, Eric; Wils, Daniel; Serpelloni, Michel; Parissaux, Xavier; Fenart, Laurence; Gosselet, Fabien

    2016-01-01

    Atherosclerosis is an inflammatory disease that leads to an aberrant accumulation of cholesterol in vessel walls forming atherosclerotic plaques. During this process, the mechanism regulating complex cellular cholesterol pools defined as the reverse cholesterol transport (RCT) is altered as well as expression and functionality of transporters involved in this process, namely ABCA1, ABCG1, and SR-BI. Macrophages, arterial endothelial and smooth muscle cells (SMCs) have been involved in the atherosclerotic plaque formation. As macrophages are widely described as the major cell type forming the foam cells by accumulating intracellular cholesterol, RCT alterations have been poorly studied at the arterial endothelial cell and SMC levels. Amongst the therapeutics tested to actively counteract cellular cholesterol accumulation, the methylated β-cyclodextrin, KLEPTOSE® CRYSMEβ, has recently shown promising effects on decreasing the atherosclerotic plaque size in atherosclerotic mouse models. Therefore we investigated in vitro the RCT process occurring in SMCs and in arterial endothelial cells (ABAE) as well as the ability of some modified β-CDs with different methylation degree to modify RCT in these cells. To this aim, cells were incubated in the presence of different methylated β-CDs, including KLEPTOSE® CRYSMEβ. Both cell types were shown to express basal levels of ABCA1 and SR-BI whereas ABCG1 was solely found in ABAE. Upon CD treatments, the percentage of membrane-extracted cholesterol correlated to the methylation degree of the CDs independently of the lipid composition of the cell membranes. Decreasing the cellular cholesterol content with CDs led to reduce the expression levels of ABCA1 and ABCG1. In addition, the cholesterol efflux to ApoA-I and HDL particles was significantly decreased suggesting that cells forming the blood vessel wall are able to counteract the CD-induced loss of cholesterol. Taken together, our observations suggest that methylated

  7. Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways.

    PubMed

    Erdogdu, Ozlem; Eriksson, Linnéa; Xu, Hua; Sjöholm, Ake; Zhang, Qimin; Nyström, Thomas

    2013-04-01

    Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

  8. Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites.

    PubMed

    Farah, C; Kleindienst, A; Bolea, G; Meyer, G; Gayrard, S; Geny, B; Obert, P; Cazorla, O; Tanguy, S; Reboul, Cyril

    2013-11-01

    Exercise is an efficient strategy for myocardial protection against ischemia-reperfusion (IR) injury. Although endothelial nitric oxide synthase (eNOS) is phosphorylated and activated during exercise, its role in exercise-induced cardioprotection remains unknown. This study investigated whether modulation of eNOS activation during IR could participate in the exercise-induced cardioprotection against IR injury. Hearts isolated from sedentary or exercised rats (5 weeks training) were perfused with a Langendorff apparatus and IR performed in the presence or absence of NOS inhibitors [N-nitro-L-arginine methyl ester, L-NAME or N5-(1-iminoethyl)-L-ornithine, L-NIO] or tetrahydrobiopterin (BH₄). Exercise training protected hearts against IR injury and this effect was abolished by L-NAME or by L-NIO treatment, indicating that exercise-induced cardioprotection is eNOS dependent. However, a strong reduction of eNOS phosphorylation at Ser1177 (eNOS-PSer1177) and of eNOS coupling during early reperfusion was observed in hearts from exercised rats (which showed higher eNOS-PSer1177 and eNOS dimerization at baseline) in comparison to sedentary rats. Despite eNOS uncoupling, exercised hearts had more S-nitrosylated proteins after early reperfusion and also less nitro-oxidative stress, indexed by lower malondialdehyde content and protein nitrotyrosination compared to sedentary hearts. Moreover, in exercised hearts, stabilization of eNOS dimers by BH4 treatment increased nitro-oxidative stress and then abolished the exercise-induced cardioprotection, indicating that eNOS uncoupling during IR is required for exercise-induced myocardial cardioprotection. Based on these results, we hypothesize that in the hearts of exercised animals, eNOS uncoupling associated with the improved myocardial antioxidant capacity prevents excessive NO synthesis and limits the reaction between NO and O₂·- to form peroxynitrite (ONOO⁻), which is cytotoxic.

  9. Stromal cell–derived factor 2 is critical for Hsp90-dependent eNOS activation

    PubMed Central

    Siragusa, Mauro; Fröhlich, Florian; Park, Eon Joo; Schleicher, Michael; Walther, Tobias C.; Sessa, William C.

    2016-01-01

    Endothelial nitric oxide synthase (eNOS) catalyzes the conversion of l-arginine and molecular oxygen into l-citrulline and nitric oxide (NO), a gaseous second messenger that influences cardiovascular physiology and disease. Several mechanisms regulate eNOS activity and function, including phosphorylation at Ser and Thr residues and protein-protein interactions. Combining a tandem affinity purification approach and mass spectrometry, we identified stromal cell–derived factor 2 (SDF2) as a component of the eNOS macromolecular complex in endothelial cells. SDF2 knockdown impaired agonist-stimulated NO synthesis and decreased the phosphorylation of eNOS at Ser1177, a key event required for maximal activation of eNOS. Conversely, SDF2 overexpression dose-dependently increased NO synthesis through a mechanism involving Akt and calcium (induced with ionomycin), which increased the phosphorylation of Ser1177 in eNOS. NO synthesis by iNOS (inducible NOS) and nNOS (neuronal NOS) was also enhanced upon SDF2 overexpression. We found that SDF2 was a client protein of the chaperone protein Hsp90, interacting preferentially with the M domain of Hsp90, which is the same domain that binds to eNOS. In endothelial cells exposed to vascular endothelial growth factor (VEGF), SDF2 was required for the binding of Hsp90 and calmodulin to eNOS, resulting in eNOS phosphorylation and activation. Thus, our data describe a function for SDF2 as a component of the Hsp90-eNOS complex that is critical for signal transduction in endothelial cells. PMID:26286023

  10. Aortic Remodeling Following Transverse Aortic Constriction in Mice is Attenuated with AT1 Receptor Blockade

    PubMed Central

    Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K.; Cao, Jiu-Mei; Guo, Steven; Villamizar, Carlos; Kwartler, Callie S.; Ju, Xiaoxi; Brasier, Allan R.; Milewicz, Dianna M.

    2016-01-01

    Objective Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of Ang II type 1 (AT1) receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. Approach and Results Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation, aortic wall thickening and medial hypertrophy. Significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density due to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC induced adventitial hyperplasia, collagen accumulation and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas was effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked Erk activation and ROS production in the TAC ascending aorta. Conclusions Inhibition of the AT1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased TGF- β1 expression, adventitial Smad2 signaling and collagen accumulation. These results help to delineate the aortic TGF-β signaling that is dependent and independent of the AT1 receptor after TAC. PMID:23868934

  11. Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression

    PubMed Central

    Xia, Peng; Jin, Hao; Zhang, Yan

    2016-01-01

    Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group) were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1), and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation. PMID:28050227

  12. Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression.

    PubMed

    He, Yunqiang; Xia, Peng; Jin, Hao; Zhang, Yan; Chen, Bicheng; Xu, Ziqiang

    2016-01-01

    Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group) were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1), and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation.

  13. Sildenafil Ameliorates Gentamicin-Induced Nephrotoxicity in Rats: Role of iNOS and eNOS

    PubMed Central

    Morsy, Mohamed A.; Ibrahim, Salwa A.; Amin, Entesar F.; Kamel, Maha Y.; Rifaai, Rehab A.; Hassan, Magdy K.

    2014-01-01

    Gentamicin, an aminoglycoside antibiotic, is used for the treatment of serious Gram-negative infections. However, its usefulness is limited by its nephrotoxicity. Sildenafil, a selective phosphodiesterase-5 inhibitor, was reported to prevent or decrease tissue injury. The aim of this study is to evaluate the potential protective effects of sildenafil on gentamicin-induced nephrotoxicity in rats. Male Wistar rats were injected with gentamicin (100 mg/kg/day, i.p.) for 6 days with and without sildenafil. Sildenafil administration resulted in nephroprotective effect in gentamicin-intoxicated rats as it significantly decreased serum creatinine and urea, urinary albumin, and renal malondialdehyde and nitrite/nitrate levels, with a concomitant increase in renal catalase and superoxide dismutase activities compared to gentamicin-treated rats. Moreover, immunohistochemical examination revealed that sildenafil treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced. The protective effects of sildenafil were verified histopathologically. In conclusion, sildenafil protects rats against gentamicin-induced nephrotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS production. PMID:25120567

  14. Prunella vulgaris suppresses HG-induced vascular inflammation via Nrf2/HO-1/eNOS activation.

    PubMed

    Hwang, Sun Mi; Lee, Yun Jung; Yoon, Jung Joo; Lee, So Min; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2012-01-01

    Vascular inflammation is an important factor which can promote diabetic complications. In this study, the inhibitory effects of aqueous extract from Prunella vulgaris (APV) on high glucose (HG)-induced expression of cell adhesion molecules in human umbilical vein endothelial cells (HUVEC) are reported. APV decreased HG-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. APV also dose-dependently inhibited HG-induced adhesion of HL-60 monocytic cells. APV suppressed p65 NF-κB activation in HG-treated cells. APV significantly inhibited the formation of intracellular reactive oxygen species (ROS). HG-stimulated HUVEC secreted gelatinases, however, APV inhibited it. APV induced Akt phosphorylation as well as activation of heme oxygenase-1 (HO-1), eNOS, and nuclear factor E2-related factor 2 (Nrf2), which may protect vascular inflammation caused by HG. In conclusion, APV exerts anti-inflammatory effect via inhibition of ROS/NF-κB pathway by inducing HO-1 and eNOS expression mediated by Nrf2, thereby suggesting that Prunella vulgaris may be a possible therapeutic approach to the inhibition of diabetic vascular diseases.

  15. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.

    PubMed

    Kuang, Shao-Qing; Medina-Martinez, Olga; Guo, Dong-Chuan; Gong, Limin; Regalado, Ellen S; Reynolds, Corey L; Boileau, Catherine; Jondeau, Guillaume; Prakash, Siddharth K; Kwartler, Callie S; Zhu, Lawrence Yang; Peters, Andrew M; Duan, Xue-Yan; Bamshad, Michael J; Shendure, Jay; Nickerson, Debbie A; Santos-Cortez, Regie L; Dong, Xiurong; Leal, Suzanne M; Majesky, Mark W; Swindell, Eric C; Jamrich, Milan; Milewicz, Dianna M

    2016-03-01

    The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

  16. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

    PubMed Central

    Kuang, Shao-Qing; Medina-Martinez, Olga; Guo, Dong-chuan; Gong, Limin; Regalado, Ellen S.; Reynolds, Corey L.; Boileau, Catherine; Jondeau, Guillaume; Prakash, Siddharth K.; Kwartler, Callie S.; Zhu, Lawrence Yang; Peters, Andrew M.; Duan, Xue-Yan; Bamshad, Michael J.; Shendure, Jay; Nickerson, Debbie A.; Santos-Cortez, Regie L.; Dong, Xiurong; Leal, Suzanne M.; Majesky, Mark W.; Swindell, Eric C.; Jamrich, Milan; Milewicz, Dianna M.

    2016-01-01

    The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3–/– mice with p53–/– mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease. PMID:26854927

  17. Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A–dependent eNOS inactivation

    PubMed Central

    García, Celina; Aranda, Jorge; Arnold, Edith; Thébault, Stéphanie; Macotela, Yazmín; López-Casillas, Fernando; Mendoza, Valentín; Quiroz-Mercado, Hugo; Hernández-Montiel, Hebert Luis; Lin, Sue-Hwa; de la Escalera, Gonzalo Martínez; Clapp, Carmen

    2008-01-01

    Increased retinal vasopermeability contributes to diabetic retinopathy, the leading cause of blindness in working-age adults. Despite clinical progress, effective therapy remains a major need. Vasoinhibins, a family of peptides derived from the protein hormone prolactin (and inclusive of the 16-kDa fragment of prolactin), antagonize the proangiogenic effects of VEGF, a primary mediator of retinal vasopermeability. Here, we demonstrate what we believe to be a novel function of vasoinhibins as inhibitors of the increased retinal vasopermeability associated with diabetic retinopathy. Vasoinhibins inhibited VEGF-induced vasopermeability in bovine aortic and rat retinal capillary endothelial cells in vitro. In vivo, vasoinhibins blocked retinal vasopermeability in diabetic rats and in response to intravitreous injection of VEGF or of vitreous from patients with diabetic retinopathy. Inhibition by vasoinhibins was similar to that achieved following immunodepletion of VEGF from human diabetic retinopathy vitreous or blockage of NO synthesis, suggesting that vasoinhibins inhibit VEGF-induced NOS activation. We further showed that vasoinhibins activate protein phosphatase 2A (PP2A), leading to eNOS dephosphorylation at Ser1179 and, thereby, eNOS inactivation. Moreover, intravitreous injection of okadaic acid, a PP2A inhibitor, blocked the vasoinhibin effect on endothelial cell permeability and retinal vasopermeability. These results suggest that vasoinhibins have the potential to be developed as new therapeutic agents to control the excessive retinal vasopermeability observed in diabetic retinopathy and other vasoproliferative retinopathies. PMID:18497878

  18. Bovine aortic arch with supravalvular aortic stenosis.

    PubMed

    Idhrees, Mohammed; Cherian, Vijay Thomas; Menon, Sabarinath; Mathew, Thomas; Dharan, Baiju S; Jayakumar, K

    2016-09-01

    A 5-year-old boy was diagnosed to have supravalvular aortic stenosis (SVAS). On evaluation of CT angiogram, there was associated bovine aortic arch (BAA). Association of BAA with SVAS has not been previously reported in literature, and to best of our knowledge, this is the first case report of SVAS with BAA. Recent studies show BAA as a marker for aortopathy. SVAS is also an arteriopathy. In light of this, SVAS can also possibly be a manifestation of aortopathy associated with BAA.

  19. On the application of ENO scheme with subcell resolution to conservation laws with stiff source terms

    NASA Technical Reports Server (NTRS)

    Chang, Shih-Hung

    1991-01-01

    Two approaches are used to extend the essentially non-oscillatory (ENO) schemes to treat conservation laws with stiff source terms. One approach is the application of the Strang time-splitting method. Here the basic ENO scheme and the Harten modification using subcell resolution (SR), ENO/SR scheme, are extended this way. The other approach is a direct method and a modification of the ENO/SR. Here the technique of ENO reconstruction with subcell resolution is used to locate the discontinuity within a cell and the time evolution is then accomplished by solving the differential equation along characteristics locally and advancing in the characteristic direction. This scheme is denoted ENO/SRCD (subcell resolution - characteristic direction). All the schemes are tested on the equation of LeVeque and Yee (NASA-TM-100075, 1988) modeling reacting flow problems. Numerical results show that these schemes handle this intriguing model problem very well, especially with ENO/SRCD which produces perfect resolution at the discontinuity.

  20. Sutureless aortic valve replacement

    PubMed Central

    Phan, Kevin

    2015-01-01

    The increasing incidence of aortic stenosis and greater co-morbidities and risk profiles of the contemporary patient population has driven the development of minimally invasive aortic valve surgery and percutaneous transcatheter aortic valve implantation (TAVI) techniques to reduce surgical trauma. Recent technological developments have led to an alternative minimally invasive option which avoids the placement and tying of sutures, known as “sutureless” or rapid deployment aortic valves. Potential advantages for sutureless aortic prostheses include reducing cross-clamp and cardiopulmonary bypass (CPB) duration, facilitating minimally invasive surgery and complex cardiac interventions, whilst maintaining satisfactory hemodynamic outcomes and low paravalvular leak rates. However, given its recent developments, the majority of evidence regarding sutureless aortic valve replacement (SU-AVR) is limited to observational studies and there is a paucity of adequately-powered randomized studies. Recently, the International Valvular Surgery Study Group (IVSSG) has formulated to conduct the Sutureless Projects, set to be the largest international collaborative group to investigate this technology. This keynote lecture will overview the use, the potential advantages, the caveats, and current evidence of sutureless and rapid deployment aortic valve replacement (AVR). PMID:25870807

  1. HSP70-1 is required for interleukin-5-induced angiogenic responses through eNOS pathway

    PubMed Central

    Park, Sung Lyea; Chung, Tae-Wook; Kim, Sangtae; Hwang, Byungdoo; Kim, Jung Min; Lee, Hwan Myung; Cha, Hee-Jae; Seo, Yoonhee; Choe, Soo Young; Ha, Ki-Tae; Kim, Gonhyung; Yun, Seok-Joong; Park, Sung-Soo; Choi, Yung Hyun; Kim, Bo Kyung; Kim, Won-Tae; Cha, Eun-Jong; Patterson, Cam; Kim, Wun-Jae; Moon, Sung-Kwon

    2017-01-01

    We report a pivotal role for IL-5 as an angiogenic activator. IL-5 increased proliferation, migration and colony tube formation in HUVECs associated with the phosphorylation of ERK and AKT/eNOS, and promoted microvessel sprouting from an angiogenesis animal model. The angiogenic effects were confirmed in IL-5-deficient mice and addition of IL-5 antibody. HSP70-1 was identified via expression profiling following IL-5 stimulation. A siRNA knockdown of HSP70-1 suppressed angiogenic responses and eNOS phosphorylation induced by IL-5. HSP70-1 overexpression enhanced IL-5-induced angiogenic responses. In addition, IL-5-induced neo-vascular formation was verified in both HSP70-1 knockout and HSP70-1 transgenic mice. Furthermore, transcription factor AP-1 was a main factor in IL-5-induced HSP70-1 in response to ERK and AKT signaling pathway. Angiogenic responses induced by VEGF had no effect in either HSP70-1 siRNA in vitro or HSP70-1 knockout mice. IL-5-induced angiogenic responses depended on the binding of IL-5Rα. Our data demonstrate that binding of IL-5 to IL-5Rα receptors enhances angiogenic responses by stimulating the expression of HSP70-1 via the eNOS signaling pathway. PMID:28317868

  2. An ethanol root extract of Cynanchum wilfordii containing acetophenones suppresses the expression of VCAM-1 and ICAM-1 in TNF-α-stimulated human aortic smooth muscle cells through the NF-κB pathway

    PubMed Central

    KOO, HYUN JUNG; SOHN, EUN-HWA; PYO, SUHKNEUNG; WOO, HAN GOO; PARK, DAE WON; HAM, YOUNG-MIN; JANG, SEON-A; PARK, SOO-YEONG; KANG, SE CHAN

    2015-01-01

    The root of Cynanchum wilfordii (C. wilfordii) contains several biologically active compounds which have been used as traditional medicines in Asia. In the present study, we evaluated the anti-inflammatory effects of an ethanol root extract of C. wilfordii (CWE) on tumor necrosis factor (TNF)-α-stimulated human aortic smooth muscle cells (HASMCs). The inhibitory effects of CWE on vascular cell adhesion molecule (VCAM)-1 expression under an optimum extraction condition were examined. CWE suppressed the expression of VCAM-1 and ICAM-1 and the adhesion of THP-1 monocytes to the TNF-α-stimulated HASMCs. Consistent with the in vitro observations, CWE inhibited the aortic expression of ICAM-1 and VCAM-1 in atherogenic diet-fed mice. CWE also downregulated the expression of nuclear factor-κB (NF-κB p65) and its uclear translocation in the stimulated HASMCs. In order to identify the active components in CWE, we re-extracted CWE using several solvents, and found that the ethyl acetate fraction was the most effective in suppressing the expression of VCAM-1 and ICAM-1. Four major acetophenones were purified from the ethyl acetate fraction, and two components, p-hydroxyacetophenone and cynandione A, potently inhibited the expression of ICAM-1 and VCAM-1 in the stimulated HASMCs. We assessed and determined the amounts of these two active components from CWE, and our results suggested that the root of C. wilfordii and its two bioactive acetophenones may be used for the prevention and treatment of atherosclerosis and vascular inflammatory diseases. PMID:25716870

  3. Erythropoietin Reverses Sepsis-Induced Vasoplegia to Norepinephrine Through Preservation of α1D-Adrenoceptor mRNA Expression and Inhibition of GRK2-Mediated Desensitization in Mouse Aorta.

    PubMed

    Kandasamy, Kannan; Choudhury, Soumen; Singh, Vishakha; Addison, M Pule; Darzi, Sazad Ahmad; Kasa, Jaya Kiran; Thangamalai, Ramasamy; Dash, Jeevan Ranjan; Kumar, Tarun; Sultan, Faheem; Singh, Thakur Uttam; Parida, Subhashree; Mishra, Santosh Kumar

    2016-01-01

    We investigated the effect of erythropoietin (EPO) posttreatment on survival time and vascular functions in a mouse model of sepsis. Sepsis was induced by cecal ligation and puncture. After 20 ± 2 hours of sepsis, thoracic aorta was isolated for assessing its reactivity to norepinephrine (NE) and acetylcholine (ACh). We also measured the tissue nitric oxide (NO) level, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), G protein-coupled receptor kinase 2 (GRK2), and α1D adrenoceptor messenger RNA (mRNA)/protein expression. In septic mice, EPO moderately improved the survival time from 19.68 ± 0.75 to 34.7 ± 3.2 hours. Sepsis significantly decreased the aortic contractile response to NE along with reduced α1D mRNA and protein expression. Erythropoietin significantly preserved the α1D receptor expression and restored NE-induced contractions to control levels in septic mice. Further, it attenuated the aortic α1D receptor desensitization in sepsis which was evident from reduced GRK2 mRNA expression. Accordingly, a selective GRK2 inhibitor markedly restored the contractile responses to NE in sepsis. Erythropoietin treatment attenuated iNOS mRNA expression and iNOS-induced overproduction of NO, but improved endothelium-dependent relaxation to ACh associated with increased eNOS mRNA expression. In conclusion, EPO seems to reverse sepsis-induced vasoplegia to NE through the preservation of α1D adrenoceptor mRNA/protein expression, inhibition of GRK2-mediated desensitization, and attenuation of NO overproduction in the mouse aorta.

  4. Aortic Aneurysm Statistics

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Heart Disease Stroke High Blood Pressure Salt ... to Prevent and Control Chronic Diseases Million Hearts® Web Sites with More Information About Aortic Aneurysm For ...

  5. Bicuspid aortic valve

    MedlinePlus

    ... stiff and not open up. This is called aortic stenosis , which causes the heart to pump harder than usual to get blood through the valve. The aorta may become enlarged with this condition. BAV is ...

  6. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Ziaja, K; Sedlak, L; Urbanek, T; Kostyra, J; Ludyga, T

    2000-01-01

    The reported incidence of inflammatory abdominal aortic aneurysm (IAAA) is from 2% to 14% of patients with abdominal aortic aneurysm and the etiology of this disease is still discussed--according to the literature several pathogenic theories have been proposed. From 1992 to 1997 32 patients with IAAA were operated on. The patients were mostly symptomatic--abdominal pain was present in 68.75% cases, back pain in 31.25%, fever in 12.5% and weight loss in 6.25% of the operated patients. In all the patients ultrasound examination was performed, in 4 patients CT and in 3 cases urography. All the patients were operated on and characteristic signs of inflammatory abdominal aortic aneurysm like: thickened aortic wall, perianeurysmal infiltration or retroperitoneal fibrosis with involvement of retroperitoneal structures were found. In all cases surgery was performed using transperitoneal approach; in three cases intraoperatively contiguous abdominal organs were injured, which was connected with their involvement into periaortic inflammation. In 4 cases clamping of the aorta was done at the level of the diaphragmatic hiatus. 3 patients (9.37%) died (one patient with ruptured abdominal aortic aneurysm). Authors present diagnostic procedures and the differences in the surgical tactic, emphasizing the necessity of the surgical therapy in patients with inflammatory abdominal aortic aneurysm.

  7. A central role of eNOS in the protective effect of wine against metabolic syndrome.

    PubMed

    Leighton, Federico; Miranda-Rottmann, Soledad; Urquiaga, Inés

    2006-01-01

    The positive health effects derived from moderate wine consumption are pleiotropic. They appear as improvements in cardiovascular risk factors such as plasma lipids, haemostatic mechanisms, endothelial function and antioxidant defences. The active principles would be ethanol and mainly polyphenols. Results from our and other laboratories support the unifying hypothesis that the improvements in risk factors after red wine consumption are mediated by endothelial nitric oxide synthase (eNOS). Many genes are involved, but the participation of eNOS would be a constant feature. The metabolic syndrome is a cluster of metabolic risk factors associated with high risk of cardiovascular disease (CVD). The National Cholesterol Education Programmmes Adult Treatment Panel III (NCEPATP III) clinical definition of the metabolic syndrome requires the presence of at least three risk factors, from among abdominal obesity, high plasma triacylglycerols, low plasma HDL, high blood pressure and high fasting plasma glucose. The molecular mechanisms responsible for the metabolic syndrome are not known. Since metabolic syndrome apparently affects 10-30% of the population in the world, research on its pathogenesis and control is needed. The recent finding that eNOS knockout mice present a cluster of cardiovascular risk factors comparable to those of the metabolic syndrome suggests that defects in eNOS function may cause human metabolic syndrome. These mice are hypertensive, insulin resistant and dyslipidemic. Further support for a pathogenic role of eNOS comes from the finding in humans that eNOS polymorphisms associate with insulin resistance and diabetes, with hypertension, with inflammatory and oxidative stress markers and with albuminuria. So, the data sustain the hypothesis that eNOS enhancement should reduce metabolic syndrome incidence and its consequences. Therefore red wine, since it enhances eNOS function, should be considered as a potential tool for the control of metabolic

  8. New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

    PubMed

    Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

    2016-03-23

    Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (-786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles -786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2-5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue.

  9. Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC

    SciTech Connect

    Murakami, Hisashi; Murakami, Ryuichiro . E-mail: ryuichi@med.nagoya-u.ac.jp; Kambe, Fukushi; Cao, Xia; Takahashi, Ryotaro; Asai, Toru; Hirai, Toshihisa; Numaguchi, Yasushi; Okumura, Kenji; Seo, Hisao; Murohara, Toyoaki

    2006-03-24

    Fenofibrate improves endothelial function by lipid-lowering and anti-inflammatory effects. Additionally, fenofibrate has been demonstrated to upregulate endothelial nitric oxide synthase (eNOS). AMP-activated protein kinase (AMPK) has been reported to phosphorylate eNOS at Ser-1177 and stimulate vascular endothelium-derived nitric oxide (NO) production. We report here that fenofibrate activates AMPK and increases eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVEC). Incubation of HUVEC with fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase. Fenofibrate simultaneously increased eNOS phosphorylation and NO production. Inhibitors of protein kinase A and phosphatidylinositol 3-kinase failed to suppress the fenofibrate-induced eNOS phosphorylation. Neither bezafibrate nor WY-14643 activated AMPK in HUVEC. Furthermore, fenofibrate activated AMPK without requiring any transcriptional activities. These results indicate that fenofibrate stimulates eNOS phosphorylation and NO production through AMPK activation, which is suggested to be a novel characteristic of this agonist and unrelated to its effects on peroxisome proliferator-activated receptor {alpha}.

  10. Are Aortic Stent Grafts Safe in Pregnancy?

    PubMed Central

    Khandanpour, Nader; Mehta, Tapan A.; Adiseshiah, M.; Meyer, Felicity J.

    2015-01-01

    Aortic stent grafts are increasingly used to treat aortic aneurysms and also other aortic pathologies. The safety of aortic stent grafts in pregnancy has never been studied or reported. We report on two cases of aortic stent grafts in pregnant women and discuss the effect of pregnancy on these aortic stent grafts. PMID:26229702

  11. Successful transfemoral aortic valve implantation through aortic stent graft after endovascular repair of abdominal aortic aneurysm.

    PubMed

    Kawashima, Hideyuki; Watanabe, Yusuke; Kozuma, Ken

    2017-04-01

    The patient was a 91-year-old woman presenting with severe aortic valve stenosis. Pre-procedural computed tomography scan revealed a 45-mm abdominal aortic aneurysm (AAA). Transfemoral transcatheter aortic valve implantation (TF-TAVI) was performed after endovascular aortic repair (EVAR) of the AAA. The 23-mm Edwards Sapien XT system passed through the aortic stent graft smoothly. This is the first case report showing that successful TF-TAVI can be performed through a prior abdominal aortic stent graft. TF-TAVI after EVAR of AAA is a feasible option for patients with extremely poor access.

  12. Aortic aneurysm repair - endovascular- discharge

    MedlinePlus

    ... MRI scan Aortic aneurysm repair - endovascular Aortic angiography Hardening of ... Center-Shreveport, Shreveport, LA. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla ...

  13. Upregulation of ERK1/2-eNOS via AT2 Receptors Decreases the Contractile Response to Angiotensin II in Resistance Mesenteric Arteries from Obese Rats

    PubMed Central

    Hagihara, Graziela N.; Lobato, Nubia S.; Filgueira, Fernando P.; Akamine, Eliana H.; Aragão, Danielle S.; Casarini, Dulce E.; Carvalho, Maria Helena C.; Fortes, Zuleica B.

    2014-01-01

    It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats. PMID:25170617

  14. Aortic Input Impedance during Nitroprusside Infusion

    PubMed Central

    Pepine, Carl J.; Nichols, W. W.; Curry, R. C.; Conti, C. Richard

    1979-01-01

    Beneficial effects of nitroprusside infusion in heart failure are purportedly a result of decreased afterload through “impedance” reduction. To study the effect of nitroprusside on vascular factors that determine the total load opposing left ventricular ejection, the total aortic input impedance spectrum was examined in 12 patients with heart failure (cardiac index <2.0 liters/min per m2 and left ventricular end diastolic pressure >20 mm Hg). This input impedance spectrum expresses both mean flow (resistance) and pulsatile flow (compliance and wave reflections) components of vascular load. Aortic root blood flow velocity and pressure were recorded continuously with a catheter-tip electromagnetic velocity probe in addition to left ventricular pressure. Small doses of nitroprusside (9-19 μg/min) altered the total aortic input impedance spectrum as significant (P < 0.05) reductions in both mean and pulsatile components were observed within 60-90 s. With these acute changes in vascular load, left ventricular end diastolic pressure declined (44%) and stroke volume increased (20%, both P < 0.05). Larger nitroprusside doses (20-38 μg/min) caused additional alteration in the aortic input impedance spectrum with further reduction in left ventricular end diastolic pressure and increase in stroke volume but no additional changes in the impedance spectrum or stroke volume occurred with 39-77 μg/min. Improved ventricular function persisted when aortic pressure was restored to control values with simultaneous phenylephrine infusion in three patients. These data indicate that nitroprusside acutely alters both the mean and pulsatile components of vascular load to effect improvement in ventricular function in patients with heart failure. The evidence presented suggests that it may be possible to reduce vascular load and improve ventricular function independent of aortic pressure reduction. PMID:457874

  15. [Congenital aortic stenosis].

    PubMed

    Yamaguchi, M

    2001-08-01

    Recent advances in and controversies concerning the management of children with congenital valvular aortic stenosis are discussed. In neonates with critical aortic stenosis, improved survival has recently been reported after surgical open valvotomy and balloon valvuloplasty, although it is difficult at this point to compare the results of the two procedures and determine their differential indications. Good results have also been achieved after extended aortic valvuloplasty for recurrent aortic stenosis and/or insufficiency, but the length of follow-up in these patients is still short. The technique first reported in 1991 for bilateral enlargement fo a small annulus permits the insertion of an aortic valve 3-4 sizes larger than the native annulus. It entails no risk of distorting the mitral valve, damaging the conduction system or important branches of the coronary arteries, or resulting in left ventricular dysfunction. The Ross procedure is now widely applied in the West, with reports of early mortality rates of less than 5% and event-free survival rates of 80-90% during follow-up of 4-8 years. Longer follow-up and continued careful evaluation are required to resolve the issue of possible dilatation and subsequent neoaortic valve dysfunction and pulmonary stenosis due to allograft degeneration after pulmonary autograft root replacement in children.

  16. Influence of coronary artery diameter on eNOS protein content

    NASA Technical Reports Server (NTRS)

    Laughlin, M. H.; Turk, J. R.; Schrage, W. G.; Woodman, C. R.; Price, E. M.

    2003-01-01

    The purpose of this study was to test the hypothesis that the content of endothelial nitric oxide synthase (eNOS) protein (eNOS protein/g total artery protein) increases with decreasing artery diameter in the coronary arterial tree. Content of eNOS protein was determined in porcine coronary arteries with immunoblot analysis. Arteries were isolated in six size categories from each heart: large arteries [301- to 2,500-microm internal diameter (ID)], small arteries (201- to 300-microm ID), resistance arteries (151- to 200-microm ID), large arterioles (101- to 150-microm ID), intermediate arterioles (51- to 100-microm ID), and small arterioles(<50-microm ID). To obtain sufficient protein for analysis from small- and intermediate-sized arterioles, five to seven arterioles 1-2 mm in length were pooled into one sample for each animal. Results establish that the number of smooth muscle cells per endothelial cell decreases from a number of 10 to 15 in large coronary arteries to 1 in the smallest arterioles. Immunohistochemistry revealed that eNOS is located only in endothelial cells in all sizes of coronary artery and in coronary capillaries. Contrary to our hypothesis, eNOS protein content did not increase with decreasing size of coronary artery. Indeed, the smallest coronary arterioles had less eNOS protein per gram of total protein than the large coronary arteries. These results indicate that eNOS protein content is greater in the endothelial cells of conduit arteries, resistance arteries, and large arterioles than in small coronary arterioles.

  17. (−)-Epicatechin activation of endothelial cell eNOS, NO and related signaling pathways

    PubMed Central

    Ramirez-Sanchez, Israel; Maya, Lisandro; Ceballos, Guillermo; Villarreal, Francisco

    2010-01-01

    Recent reports indicate that (−)-epicatechin can exert cardioprotective actions, which may involve eNOS-mediated nitric oxide production in endothelial cells. However, the mechanism by which (−)-epicatechin activates eNOS remains unclear. In this study, we proposed to identify the intracellular pathways involved in (−)-epicatechin-induced effects on eNOS, utilizing human coronary artery endothelial cells in culture. Treatment of cells with (−)-epicatechin leads to time- and dose-dependent effects, which peaked at 10 min at 1 μmol/L. (−)-Epicatechin treatment activates eNOS via serine-633 and serine-1177 phosphorylation and threonine-495 dephosphorylation. Using specific inhibitors, we have established the participation of the PI3K pathway in eNOS activation. (−)-Epicatechin induces eNOS uncoupling from caveolin-1 and its association with calmodulin-1, suggesting the involvement of intracellular calcium. These results allowed us to propose that (−) epicatechin effects may be dependent on actions exerted at the cell membrane level. To test this hypothesis, cells were treated with the phospholipase C inhibitor U73122, which blocked (−)-epicatechin-induced eNOS activation. We also demonstrated inositol phosphate accumulation in (−)-epicatechin-treated cells. The inhibitory effects of the pre-incubation of cells with the CaMKII inhibitor KN-93 indicate that (−)-epicatechin-induced eNOS activation is at least partially mediated via the Ca2+/CaMKII pathway. The (−)-epicatechin stereoisomer catechin was only able to partially stimulate nitric oxide production in cells. Altogether, these results strongly suggest the presence of a cell surface acceptor-effector for the cacao flavanol (−)-epicatechin, which may mediate its cardiovascular effects. PMID:20404222

  18. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Mikami, Y; Kyogoku, M

    1994-08-01

    Inflammatory abdominal aortic aneurysm (IAAA) is a distinct clinicopathological entity, characterized by: (1) clinical presentation, such as back pain, weight loss, and increased ESR, (2) patchy and/or diffuse lymphoplasmacytic infiltration, and (3) marked periaortic fibrosis resulting in thickening of the aneurysmal wall and occasional retroperitoneal fibrosis. Its pathogenesis is unknown, but some authors support the theory that IAAA is a subtype of atherosclerotic abdominal aortic aneurysm because of close relationship between IAAA and atherosclerotic change. In this article, we describe clinical and histological features of IAAA on the basis of the literature and our review of 6 cases of IAAA, emphasizing the similarity and difference between IAAA and atherosclerotic abdominal aortic aneurysm. Our review supports that marked lamellar fibrosis completely replacing the media and adventitia, patchy lymphocytic infiltration (mostly B cells) and endarteritis obliterans are characteristic features of IAAA.

  19. Robotic aortic surgery.

    PubMed

    Duran, Cassidy; Kashef, Elika; El-Sayed, Hosam F; Bismuth, Jean

    2011-01-01

    Surgical robotics was first utilized to facilitate neurosurgical biopsies in 1985, and it has since found application in orthopedics, urology, gynecology, and cardiothoracic, general, and vascular surgery. Surgical assistance systems provide intelligent, versatile tools that augment the physician's ability to treat patients by eliminating hand tremor and enabling dexterous operation inside the patient's body. Surgical robotics systems have enabled surgeons to treat otherwise untreatable conditions while also reducing morbidity and error rates, shortening operative times, reducing radiation exposure, and improving overall workflow. These capabilities have begun to be realized in two important realms of aortic vascular surgery, namely, flexible robotics for exclusion of complex aortic aneurysms using branched endografts, and robot-assisted laparoscopic aortic surgery for occlusive and aneurysmal disease.

  20. Chronic Type A Aortic Dissection and Giant Aortic Root Aneurysm After Aortic Valve Replacement

    PubMed Central

    Puga, Andrés Enríquez; Rodríguez, Sara Castaño; Pañero, Blanca Mateos; Moreira, Beatriz Castaño; López Almodóvar, Luis Fernando

    2016-01-01

    We describe the case of a 61-year-old male with a giant aortic root aneurysm associated with chronic aortic Type A dissection. The patient had been operated on 16 years before due to aortic annuloectasia with mechanical valve replacement. The patient underwent revision aortic surgery with a Bentall-De Bono operation with Svensson modification, using a #21 On-X Valsalva mechanical valve conduit. The postoperative course was uneventful. PMID:28097190

  1. Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth

    PubMed Central

    Barbieri, Antonio; Palma, Giuseppe; Rosati, Alessandra; Giudice, Aldo; Falco, Antonia; Petrillo, Antonella; Petrillo, Mario; Bimonte, Sabrina; Benedetto, Maria Di; Esposito, Giuseppe; Stiuso, Paola; Abbruzzese, Alberto; Caraglia, Michele; Arra, Claudio

    2012-01-01

    Abstract Accumulating evidence suggests that chronic stress can be a cofactor for the initiation and progression of cancer. Here we evaluated the role of endothelial nitric oxide synthase (eNOS) in stress-promoted tumour growth of murine B16F10 melanoma cell line in C57BL/6 mice. Animals subjected to restraint stress showed increased levels adrenocorticotropic hormone, enlarged adrenal glands, reduced thymus weight and a 3.61-fold increase in tumour growth in respect to no-stressed animals. Tumour growth was significantly reduced in mice treated with the β-antagonist propranolol. Tumour samples obtained from stressed mice displayed high levels of vascular endothelial growth factor (VEGF) protein in immunohistochemistry. Because VEGF can induce eNOS increase, and nitric oxide is a relevant factor in angiogenesis, we assessed the levels of eNOS protein by Western blot analysis. We found a significant increase in eNOS levels in tumour samples from stressed mice, indicating an involvement of this enzyme in stress-induced tumour growth. Accordingly, chronic stress did not promote tumour growth in eNOS−/− mice. These results disclose for the first time a pivotal role for eNOS in chronic stress-induced initiation and promotion of tumour growth. PMID:21722303

  2. Extensive Ethnogenomic Diversity of Endothelial Nitric Oxide Synthase (eNOS) Polymorphisms

    PubMed Central

    Thomas, Bolaji N.; Thakur, Tanya J.; Yi, Li; Guindo, Aldiouma; Diallo, Dapa A.; Ott, Jurg

    2013-01-01

    Nitric oxide (NO) is highly reactive, produced in endothelial cells by endothelial NO synthase (eNOS) and has been implicated in sickle cell pathophysiology. We evaluated the distribution of functionally significant eNOS variants (the T786C variant in the promoter region, the Glu298Asp variant in exon 7, and the variable number of tandem repeats (VNTR) in intron 4) in Africans, African Americans and Caucasians. The C-786 variant was more common in Caucasians than in Africans and African Americans. Consistent with other findings, the Asp-298 variant had the highest frequency in Caucasians followed by African Americans, but was completely absent in Africans. The very rare intron 4 allele, eNOS 4c, was found in some Africans and African Americans, but not in Caucasians. eNOS 4d allele was present in 2 Africans. These findings suggest a consistent and widespread genomic diversity in the distribution of eNOS variants in Africans, comparative to African Americans and Caucasians. PMID:23400313

  3. Lipid Interventions in Aortic Valvular Disease.

    PubMed

    Choi, Kwang Jin; Tsomidou, Christiana; Lerakis, Stamatios; Madanieh, Raef; Vittorio, Timothy J; Kosmas, Constantine E

    2015-10-01

    Aortic valve stenosis is the most common valvular disease in the elderly population. Presently, there is increasing evidence that aortic stenosis (AS) is an active process of lipid deposition, inflammation, fibrosis and calcium deposition. The pathogenesis of AS shares many similarities to that of atherosclerosis; therefore, it was hypothesized that certain lipid interventions could prevent or slow the progression of aortic valve stenosis. Despite the early enthusiasm that statins may slow the progression of AS, recent large clinical trials did not consistently demonstrate a decrease in the progression of AS. However, some researchers believe that statins may have a benefit early on in the disease process, where inflammation (and not calcification) is the predominant process, in contrast to severe or advanced AS, where calcification (and not inflammation) predominates. Positron emission tomography using 18F-fluorodeoxyglucose and 18F-sodium fluoride can demonstrate the relative contributions of valvular calcification and inflammation in AS, and thus this method might potentially be useful in providing the answer as to whether lipid interventions at the earlier stages of AS would be more effective in slowing the progression of the disease. Currently, there is a strong interest in recombinant apolipoprotein A-1 Milano and in the development of new pharmacological agents, targeting reduction of lipoprotein (a) levels and possibly reduction of the expression of lipoprotein-associated phospholipase A2, as potential means to slow the progression of aortic valvular stenosis.

  4. Upregulation of MicroRNA-15a Contributes to Pathogenesis of Abdominal Aortic Aneurysm (AAA) by Modulating the Expression of Cyclin-Dependent Kinase Inhibitor 2B (CDKN2B).

    PubMed

    Gao, Peng; Si, Jiyuan; Yang, Bin; Yu, Jixiang

    2017-02-18

    BACKGROUND The objective of the present study was to identify the association between miR-15a-5p and CDKN2B, and their roles in regulating the development of abdominal aortic aneurysm (AAA). MATERIAL AND METHODS We searched the miRNA database online (www.mirdb.org) and used a luciferase reporter assay system to study the regulatory relationship between miR-15a-5p and CDKN2B. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CDKN2B among different patient groups (participants with abdominal aortic aneurysm (AAA) and normal controls) or cells treated with scramble control, miR-15a-5p mimics, CDKN2B siRNA, and miR-15a-5p inhibitors. RESULTS We found that CDKN2B was a virtual target of miR-15a-5p with potential binding sites in the 3'UTR of CDKN2B (77-83 bp). We also showed that miR-15a-5p could bind to the CDKN2B 3'UTR, resulting in a significant decrease in luciferase activity compared with the scramble control. Furthermore, we found that the cells isolated from AAA participants showed an over-expression of miR-15a-5p compared to the normal controls, while the CDKN2B mRNA and protein expression level of the AAA group were much lower than the normal control group. Additionally, the expression of CDKN2B mRNA and the protein of the cells transfected with miR-15a-5p mimics and CDKN2B siRNA was downregulated, while the cells showed upregulated expression subsequent to transfection with miR-15a-5p inhibitors compared to the scramble control. CONCLUSIONS The data revealed a negative regulatory role of miR-15a-5p in the apoptosis of smooth muscle cells via targeting CDKN2B, and showed that miR-15a-5p could be a novel therapeutic target of AAA.

  5. Upregulation of MicroRNA-15a Contributes to Pathogenesis of Abdominal Aortic Aneurysm (AAA) by Modulating the Expression of Cyclin-Dependent Kinase Inhibitor 2B (CDKN2B)

    PubMed Central

    Gao, Peng; Si, Jiyuan; Yang, Bin; Yu, Jixiang

    2017-01-01

    Background The objective of the present study was to identify the association between miR-15a-5p and CDKN2B, and their roles in regulating the development of abdominal aortic aneurysm (AAA). Material/Methods We searched the miRNA database online (www.mirdb.org) and used a luciferase reporter assay system to study the regulatory relationship between miR-15a-5p and CDKN2B. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CDKN2B among different patient groups (participants with abdominal aortic aneurysm (AAA) and normal controls) or cells treated with scramble control, miR-15a-5p mimics, CDKN2B siRNA, and miR-15a-5p inhibitors. Results We found that CDKN2B was a virtual target of miR-15a-5p with potential binding sites in the 3′UTR of CDKN2B (77–83 bp). We also showed that miR-15a-5p could bind to the CDKN2B 3′UTR, resulting in a significant decrease in luciferase activity compared with the scramble control. Furthermore, we found that the cells isolated from AAA participants showed an over-expression of miR-15a-5p compared to the normal controls, while the CDKN2B mRNA and protein expression level of the AAA group were much lower than the normal control group. Additionally, the expression of CDKN2B mRNA and the protein of the cells transfected with miR-15a-5p mimics and CDKN2B siRNA was downregulated, while the cells showed upregulated expression subsequent to transfection with miR-15a-5p inhibitors compared to the scramble control. Conclusions The data revealed a negative regulatory role of miR-15a-5p in the apoptosis of smooth muscle cells via targeting CDKN2B, and showed that miR-15a-5p could be a novel therapeutic target of AAA. PMID:28214350

  6. Intact mitochondrial Ca2+ uniport is essential for agonist-induced activation of endothelial nitric oxide synthase (eNOS)

    PubMed Central

    Charoensin, Suphachai; Eroglu, Emrah; Opelt, Marissa; Bischof, Helmut; Madreiter-Sokolowski, Corina T.; Kirsch, Andrijana; Depaoli, Maria R.; Frank, Saša; Schrammel, Astrid; Mayer, Bernd; Waldeck-Weiermair, Markus; Graier, Wolfgang F.; Malli, Roland

    2017-01-01

    Mitochondrial Ca2+ uptake regulates diverse endothelial cell functions and has also been related to nitric oxide (NO•) production. However, it is not entirely clear if the organelles support or counteract NO• biosynthesis by taking up Ca2+. The objective of this study was to verify whether or not mitochondrial Ca2+ uptake influences Ca2+-triggered NO• generation by endothelial NO• synthase (eNOS) in an immortalized endothelial cell line (EA.hy926), respective primary human umbilical vein endothelial cells (HUVECs) and eNOS-RFP (red fluorescent protein) expressing human embryonic kidney (HEK293) cells. We used novel genetically encoded fluorescent NO• probes, the geNOps, and Ca2+ sensors to monitor single cell NO• and Ca2+ dynamics upon cell treatment with ATP, an inositol 1,4,5-trisphosphate (IP3)-generating agonist. Mitochondrial Ca2+ uptake was specifically manipulated by siRNA-mediated knock-down of recently identified key components of the mitochondrial Ca2+ uniporter machinery. In endothelial cells and the eNOS-RFP expressing HEK293 cells we show that reduced mitochondrial Ca2+ uptake upon the knock-down of the mitochondrial calcium uniporter (MCU) protein and the essential MCU regulator (EMRE) yield considerable attenuation of the Ca2+-triggered NO• increase independently of global cytosolic Ca2+ signals. The knock-down of mitochondrial calcium uptake 1 (MICU1), a gatekeeper of the MCU, increased both mitochondrial Ca2+ sequestration and Ca2+-induced NO• signals. The positive correlation between mitochondrial Ca2+ elevation and NO• production was independent of eNOS phosphorylation at serine1177. Our findings emphasize that manipulating mitochondrial Ca2+ uptake may represent a novel strategy to control eNOS-mediated NO• production. PMID:27923677

  7. Inflammatory abdominal aortic aneurysm.

    PubMed

    Savarese, R P; Rosenfeld, J C; DeLaurentis, D A

    1986-05-01

    Between January 1976 and December 1982, 181 patients with abdominal aortic aneurysms were treated surgically, and in 13 patients the aneurysms were found to be inflammatory. Inflammatory aneurysms of the abdominal aorta (IAAA) share important characteristics with typical atherosclerotic abdominal aortic aneurysms. Diagnosis and surgical management of IAAA are distinctive which suggests that IAAA should be considered separately, as a varient of typical abdominal aortic aneurysms. IAAA occur predominantly in males. The presenting symptoms are often idiosyncratic and include severe abdominal or back pain, or both, and ureteral obstruction; the diagnosis of IAAA should be considered when these symptoms are present. Although grossly and microscopically, the perianeurysmal fibrosis resembles idiopathic retroperitoneal fibrosis, the two conditions can be differentiated. At the present time, ultrasonography and computed tomography appear to offer reliable means for diagnosing IAAA. The presence of IAAA, whether established preoperatively or discovered unexpectedly at operation, necessitate certain modifications in the surgical approach, in order to avoid injuring the duodenum and the venous structures. Most patients can be successfully treated by resection and graft replacement. Rupture of the aneurysm in IAAA appears to be less frequent than in typical atherosclerotic abdominal aortic aneurysm.

  8. Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size

    PubMed Central

    Li, Qian; Atochin, Dmitriy; Kashiwagi, Satoshi; Earle, John; Wang, Annie; Mandeville, Emiri; Hayakawa, Kazuhide; d'Uscio, Livius V.; Lo, Eng H.; Katusic, Zvonimir; Sessa, William; Huang, Paul

    2013-01-01

    Background and Purpose Phosphorylation of eNOS, an important post-translational modulator of its enzymatic activity, is reduced in diabetes. We hypothesized that modulation of eNOS phosphorylation could overcome diabetic vascular dysfunction and improves the outcome to stroke. Methods We used the db/db mouse model of type 2 diabetes. We mated db/db mice with eNOS knockin mice that carry single-amino acid mutations at the S1176 phosphorylation site; the phosphomimetic SD mutation shows increased eNOS enzymatic activity, while the unphosphorylatable SA mutation shows decreased eNOS activity. We characterized the vascular anatomy, baseline physiologic parameters and vascular reactivity. We used the middle cerebral artery occlusion model of stroke and measured infarct volume and neurological deficits. Results db/db mice showed diminished eNOS phosphorylation at S1176. eNOS SD and SA mutations do not change the vascular anatomy at the Circle of Willis, brain capillary density, heart rate, or arterial blood gases of db/db mice. The eNOS SD mutation, but not the SA mutation, lowers blood pressure and improves vascular reactivity to acetylcholine in db/db mice. The eNOS SD mutation reduces stroke size and neurologic deficit following middle cerebral artery occlusion. Conclusion Diminished eNOS phosphorylation is a mechanism of vascular dysfunction in db/db mice. We show here that modulation of the eNOS S1176 phosphorylation site in db/db mice is associated with improved vascular reactivity and improved outcome to stroke following middle cerebral artery occlusion. PMID:23988642

  9. Genetic variants of eNOS gene may modify the susceptibility to idiopathic male infertility.

    PubMed

    Ying, Hou-Qun; Pu, Xiao-Ying; Liu, Shuo-Ran; A, Zhou-Cun

    2013-08-01

    In testis, eNOS is responsible for synthesis of nitric oxide (NO) which is an essential gas message regulator in spermatogenesis, suggesting that eNOS gene plays a role in normal spermatogenesis and the genetic variants of eNOS gene may be potential genetic risk factors of spermatogenesis impairment. In this study, the polymorphic distributions of three common polymorphism loci including T-786C, 4A4B and G894T in eNOS gene were investigated in 355 Chinese infertile patients with azoospermia or oligozoospermia and 246 healthy fertile men and a meta-analysis was carried in order to explore the possible relationship between the three loci of eNOS gene and male infertility with spermatogenesis impairment. As a result, allele -786C of T-786C (11.4% versus 6.5%, p = 0.004) and 4A of 4A4B (11.0% versus 6.3%, p = 0.005) as well as genotype TC of T-786C (22.8% versus 13.0%, p = 0.002) and AB of 4A4B (18% versus 11%, p = 0.015) were significantly associated with idiopathic male infertility. The haplotypes T-4A-G (7.4% versus 4.1%, p = 0.015) and C-4B-G (7.6% versus 4.4%, p = 0.028) could increase the susceptibility to male infertility, whereas haplotype T-4B-G (67.0% versus 75.2%, p = 0.002) might be a protective factor for male infertility. The results of meta-analysis revealed that the polymorphism of T-786C was associated with male infertility. These findings suggested that the variants of eNOS gene may modify the susceptibility to male infertility with impaired spermatogenesis.

  10. Innate and Adaptive Immunity in Calcific Aortic Valve Disease.

    PubMed

    Mathieu, Patrick; Bouchareb, Rihab; Boulanger, Marie-Chloé

    2015-01-01

    Calcific aortic valve disease (CAVD) is the most common heart valve disorder. CAVD is a chronic process characterized by a pathologic mineralization of valve leaflets. Ectopic mineralization of the aortic valve involves complex relationships with immunity. Studies have highlighted that both innate and adaptive immunity play a role in the development of CAVD. In this regard, accumulating evidence indicates that fibrocalcific remodelling of the aortic valve is associated with activation of the NF-κB pathway. The expression of TNF-α and IL-6 is increased in human mineralized aortic valves and promotes an osteogenic program as well as the mineralization of valve interstitial cells (VICs), the main cellular component of the aortic valve. Different factors, including oxidized lipid species, activate the innate immune response through the Toll-like receptors. Moreover, VICs express 5-lipoxygenase and therefore produce leukotrienes, which may amplify the inflammatory response in the aortic valve. More recently, studies have emphasized that an adaptive immune response is triggered during CAVD. Herein, we are reviewing the link between the immune response and the development of CAVD and we have tried, whenever possible, to keep a translational approach.

  11. High-order ENO schemes applied to two- and three-dimensional compressible flow

    NASA Technical Reports Server (NTRS)

    Shu, Chi-Wang; Erlebacher, Gordon; Zang, Thomas A.; Whitaker, David; Osher, Stanley

    1991-01-01

    High order essentially non-oscillatory (ENO) finite difference schemes are applied to the 2-D and 3-D compressible Euler and Navier-Stokes equations. Practical issues, such as vectorization, efficiency of coding, cost comparison with other numerical methods, and accuracy degeneracy effects, are discussed. Numerical examples are provided which are representative of computational problems of current interest in transition and turbulence physics. These require both nonoscillatory shock capturing and high resolution for detailed structures in the smooth regions and demonstrate the advantage of ENO schemes.

  12. Grape seed proanthocyanidin extracts enhance endothelial nitric oxide synthase expression through 5'-AMP activated protein kinase/Surtuin 1-Krüpple like factor 2 pathway and modulate blood pressure in ouabain induced hypertensive rats.

    PubMed

    Cui, Xiaopei; Liu, Xiangju; Feng, Hua; Zhao, Shaohua; Gao, Haiqing

    2012-01-01

    Grape seed proanthocyanidin extracts (GSPE) belonging to polyphenols, possess various biological effects including anti-inflammation, anti-oxidant, anti-aging, anti-atherosclerosis, etc. GSPE is potential in regulating endothelial function. However, the underlying mechanism is not clear yet. In this study, by small interfering RNA (siRNA) knocking down, we proved that GSPE increase endothelial nitric oxide synthase (eNOS) expression in human umbilical vessel cells (HUVECs) in vitro, which was attributed to its transcription factor Krüpple like factor 2 (KLF2) induction. Furthermore, GSPE activate 5'-AMP activated protein kinase (AMPK) and increase surtuin 1 (SIRT1) protein level, critical for KLF2 induction. We also illuminated the role of GSPE in hypertension treatment. By chronic administration of GSPE in ouabain induced hypertensive rats model, we access the effect of GSPE on blood pressure regulation and the possible mechanisms involved. After 5 weeks feeding, GSPE significantly block the ouabain induced blood pressure increase. The aortic NO production impaired by ouabain was improved. In conclusion, GSPE increase eNOS expression and NO production in an AMPK/SIRT1 dependent manner through KLF2 induction, and attenuate ouabain induced hypertension.

  13. Aortic coarctation with persistent fifth left aortic arch.

    PubMed

    Santoro, Giuseppe; Caianiello, Giuseppe; Palladino, Maria Teresa; Iacono, Carola; Russo, Maria Giovanna; Calabrò, Raffaele

    2009-08-14

    A neonate with severe aortic coarctation showed a double lumen transverse aorta (persistent fifth aortic arch) with both channels joining at the isthmus where the obstruction was confirmed by echocardiography and cardiac catheterization. Surgical repair was performed with a pantaloon-shaped patch. Persistent fifth aortic arch does not result in a vascular ring and, per se, is not hemodynamically significant unless associated with other cardiac malformations.

  14. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in association with neovascularization in human primary astrocytoma*

    PubMed Central

    Pan, Jian-wei; Zhan, Ren-ya; Tong, Ying; Zhou, Yong-qing; Zhang, Ming

    2005-01-01

    Objective: To investigate the relationship between the expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and angiogenesis in primary astrocytoma. Methods: Thirty-seven primary astrocytomas and 4 astrocytic hyperplasia samples were collected and divided into three groups according to histological grade. The expression of eNOS, VEGF and factor VIII related antigen (FVIIIRAg) were assayed by immunohistochemistry. Microvascular density was assessed by FVIIIRAg immunoreactivity. The intensity of immunoreactivity was graded according to the percentage of positive tumor cells. Results: No eNOS and VEGF were expressed in the astrocytes and vascular endothelium in astrocytic hyperplasia. The expression of eNOS or VEGF was light in low-grade astrocytoma and strong in glioblastoma. eNOS expression in astrocytoma was very positively correlated with VEGF. eNOS and VEGF expression in anaplastic astrocytoma was median in contrast to the low grade astrocytoma and glioblastoma. Lower microvascular density was found in low grade astrocytoma than that in higher grade malignant ones. The expressions of eNOS and VEGF were correlated with microvascular density and tumor malignancy. Conclusion: This finding suggests that eNOS and VEGF may have cooperative effect in tumor angiogenesis and play an important role in the pathogenesis of primary astrocytoma. PMID:15973775

  15. Identification of Reference Genes for Quantitative RT-PCR in Ascending Aortic Aneurysms

    PubMed Central

    Henn, Dominic; Bandner-Risch, Doris; Perttunen, Hilja; Schmied, Wolfram; Porras, Carlos; Ceballos, Francisco; Rodriguez-Losada, Noela; Schäfers, Hans-Joachim

    2013-01-01

    Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue. PMID:23326585

  16. Genetics Home Reference: supravalvular aortic stenosis

    MedlinePlus

    ... Genetics Home Health Conditions supravalvular aortic stenosis supravalvular aortic stenosis Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Supravalvular aortic stenosis (SVAS) is a heart defect that develops before ...

  17. New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors

    PubMed Central

    Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

    2016-01-01

    Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (−786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles −786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2–5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue. PMID:27004986

  18. [Stent Grafting for Aortic Dissection].

    PubMed

    Uchida, Naomichi

    2016-07-01

    The purpose of stent graft for aortic dissection is to terminate antegrade blood flow into the false lumen through primary entry. Early intervention for primary entry makes excellent aortic remodeling and emergent stent grafting for complicated acute type B aortic dissection is supported as a class I. On the other hand stent grafting for chronic aortic dissection is controversial. Early stent grafting is considered with in 6 months after on-set if the diameter of the descending aorta is more than 40 mm. Additional interventions for residual false lumen on the downstream aorta are still required. Stent graft for re-entry, candy-plug technique, and double stenting, other effective re-interventions were reported. Best treatment on the basis of each anatomical and physical characteristics should be selected in each institution. Frozen elephant trunk is alternative procedure for aortic dissection without the need to take account of proximal anatomical limitation and effective for acute type A aortic dissection.

  19. Circadian rhythms in heart rate, motility, and body temperature of wild-type C57 and eNOS knock-out mice under light-dark, free-run, and after time zone transition.

    PubMed

    Arraj, M; Lemmer, B

    2006-01-01

    The nitric oxide (NO) system is involved in the regulation of the cardiovascular system in controlling central and peripheral vascular tone and cardiac functions. It was the aim of this study to investigate in wild-type C57BL/6 and endothelial nitric oxide synthase (eNOS) knock-out mice (eNOS-/-) the contribution of NO on the circadian rhythms in heart rate (HR), motility (motor activity [MA]), and body temperature (BT) under various environmental conditions. Experiments were performed in 12:12 h of a light:dark cycle (LD), under free-run in total darkness (DD), and after a phase delay shift of the LD cycle by -6 h (i.e., under simulation of a westward time zone transition). All parameters were monitored by radiotelemetry in freely moving mice. In LD, no significant differences in the rhythms of HR and MA were observed between the two strains of mice. BT, however, was significantly lower during the light phase in eNOS-/- mice, resulting in a significantly greater amplitude. The period of the free-running rhythm in DD was slightly shorter for all variables, though not significant. In general, rhythmicity was greater in eNOS-/- than in C57 mice both in LD and DD. After a delay shift of the LD cycle, HR and BT were resynchronized to the new LD schedule within 5-6 days, and resynchronization of MA occurred within 2-3 days. The results in telemetrically instrumented mice show that complete knock-out of the endothelial NO system--though expressed in the suprachiasmatic nuclei and in peripheral tissues--did not affect the circadian organization of heart rate and motility. The circadian regulation of the body temperature was slightly affected in eNOS-/- mice.

  20. Ruptured abdominal aortic aneurysm.

    PubMed

    Sachs, T; Schermerhorn, M

    2010-06-01

    Ruptured abdominal aortic aneurysm (AAA) continues to be one of the most lethal vascular pathologies we encounter. Its management demands prompt and efficient evaluation and repair. Open repair has traditionally been the mainstay of treatment. However, the introduction of endovascular techniques has altered the treatment algorithm for ruptured AAA in most major medical centers. We present recent literature and techniques for ruptured AAA and its surgical management.

  1. Aortic dimensions in Turner syndrome.

    PubMed

    Quezada, Emilio; Lapidus, Jodi; Shaughnessy, Robin; Chen, Zunqiu; Silberbach, Michael

    2015-11-01

    In Turner syndrome, linear growth is less than the general population. Consequently, to assess stature in Turner syndrome, condition-specific comparators have been employed. Similar reference curves for cardiac structures in Turner syndrome are currently unavailable. Accurate assessment of the aorta is particularly critical in Turner syndrome because aortic dissection and rupture occur more frequently than in the general population. Furthermore, comparisons to references calculated from the taller general population with the shorter Turner syndrome population can lead to over-estimation of aortic size causing stigmatization, medicalization, and potentially over-treatment. We used echocardiography to measure aortic diameters at eight levels of the thoracic aorta in 481 healthy girls and women with Turner syndrome who ranged in age from two to seventy years. Univariate and multivariate linear regression analyses were performed to assess the influence of karyotype, age, body mass index, bicuspid aortic valve, blood pressure, history of renal disease, thyroid disease, or growth hormone therapy. Because only bicuspid aortic valve was found to independently affect aortic size, subjects with bicuspid aortic valve were excluded from the analysis. Regression equations for aortic diameters were calculated and Z-scores corresponding to 1, 2, and 3 standard deviations from the mean were plotted against body surface area. The information presented here will allow clinicians and other caregivers to calculate aortic Z-scores using a Turner-based reference population. © 2015 Wiley Periodicals, Inc.

  2. Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

    PubMed

    Li, Chao; Zhang, Yu Yao; Frieler, Ryan A; 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.

  3. L-theanine promotes nitric oxide production in endothelial cells through eNOS phosphorylation.

    PubMed

    Siamwala, Jamila H; Dias, Paul M; Majumder, Syamantak; Joshi, Manoj K; Sinkar, Vilas P; Banerjee, Gautam; Chatterjee, Suvro

    2013-03-01

    Consumption of tea (Camellia sinensis) improves vascular function and is linked to lowering the risk of cardiovascular disease. Endothelial nitric oxide is the key regulator of vascular functions in endothelium. In this study, we establish that l-theanine, a non-protein amino-acid found in tea, promotes nitric oxide (NO) production in endothelial cells. l-theanine potentiated NO production in endothelial cells was evaluated using Griess reaction, NO sensitive electrode and a NO specific fluorescent probe (4-amino-5-methylamino-2',7'-difluororescein diacetate). l-Theanine induced NO production was partially attenuated in presence of l-NAME or l-NIO and completely abolished using eNOS siRNA. eNOS activation was Ca(2+) and Akt independent, as assessed by fluo-4AM and immunoblotting experiments, respectively and was associated with phosphorylation of eNOS Ser 1177. eNOS phosphorylation was inhibited in the presence of ERK1/2 inhibitor, PD-98059 and partially inhibited by PI3K inhibitor, LY-294002 and Wortmanin suggesting PI3K-ERK1/2 dependent pathway. Increased NO production was associated with vasodilation in ex ovo (chorioallantoic membrane) model. These results demonstrated that l-theanine administration in vitro activated ERK/eNOS resulting in enhanced NO production and thereby vasodilation in the artery. The results of our experiments are suggestive of l-theanine mediated vascular health benefits of tea.

  4. VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF ENOS

    EPA Science Inventory

    VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF eNOS.

    Zhuowei Li, Jacqueline D. Carter, Lisa A. Dailey, Joleen Soukup, Yuh-Chin T. Huang. CEMALB, University of North Carolina and NHEERL, US EPA, Chapel Hill, North Ca...

  5. VANADL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF ENOS

    EPA Science Inventory

    VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF eNOS. Zhuowei Li, Jacqueline D. Carter, Lisa A. Dailey, Joleen Soukup, Yuh-Chin T. Huang. CEMALB, University of North Carolina and ORD, US EPA, Chapel Hill, North Carolina
    V...

  6. Expression and regulation of endothelial nitric oxide synthase by vascular endothelial growth factor in ECV 304 cells.

    PubMed Central

    Park, Jong Seon; Hong, Gu Ru; Baek, Suk Whan; Shin, Dong Gu; Kim, Young Jo; Shim, Bong Sup

    2002-01-01

    Nitric oxide (NO) seems to play a pivotal role in the vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation. This study was designed to investigate the role and intracellular signal pathway of endothelial nitric oxide synthase (eNOS) activation induced by VEGF. ECV 304 cells were treated with VEGF(165) and then cell proliferation, eNOS protein and mRNA expression levels were analyzed to elucidate the functional role of eNOS in cell proliferation induced by VEGF. After exposure of cells to VEGF(165), eNOS activity and cell growth were increased by approximately two-fold in the VEGF(165) -treated cells compared to the untreated cells. In addition, VEGF stimulated eNOS expression at both the mRNA and protein levels in a dose-dependent manner. Phosphatidylinositol-3 kinase (PI-3K) inhibitors were used to assess PI-3K involvement in eNOS regulation. LY294002 was found to attenuate VEGF-stimulated eNOS expression. Wortmannin was not as effective as LY294002, but the reduction effect was detectable. Cells activated by VEGF showed increased ERK1/2 levels. Moreover, the VEGF-induced eNOS expression was reduced by the PD98059, MAPK pathway inhibitor. This suggests that eNOS expression might be regulated by PI-3K and the ERK1/2 signaling pathway. In conclusion, VEGF(165) induces ECV 304 cell proliferation via the NO produced by eNOS. In addition, eNOS may be regulated by the PI-3K or mitogen-activated protein kinase pathway. PMID:11961297

  7. MAT2A mutations predispose individuals to thoracic aortic aneurysms.

    PubMed

    Guo, Dong-chuan; Gong, Limin; Regalado, Ellen S; Santos-Cortez, Regie L; Zhao, Ren; Cai, Bo; Veeraraghavan, Sudha; Prakash, Siddharth K; Johnson, Ralph J; Muilenburg, Ann; Willing, Marcia; Jondeau, Guillaume; Boileau, Catherine; Pannu, Hariyadarshi; Moran, Rocio; Debacker, Julie; Bamshad, Michael J; Shendure, Jay; Nickerson, Deborah A; Leal, Suzanne M; Raman, C S; Swindell, Eric C; Milewicz, Dianna M

    2015-01-08

    Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.

  8. MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms

    PubMed Central

    Guo, Dong-chuan; Gong, Limin; Regalado, Ellen S.; Santos-Cortez, Regie L.; Zhao, Ren; Cai, Bo; Veeraraghavan, Sudha; Prakash, Siddharth K.; Johnson, Ralph J.; Muilenburg, Ann; Willing, Marcia; Jondeau, Guillaume; Boileau, Catherine; Pannu, Hariyadarshi; Moran, Rocio; Debacker, Julie; Bamshad, Michael J.; Shendure, Jay; Nickerson, Deborah A.; Leal, Suzanne M.; Raman, C.S.; Swindell, Eric C.; Milewicz, Dianna M.

    2015-01-01

    Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease. PMID:25557781

  9. Management of Acute Aortic Syndrome and Chronic Aortic Dissection

    SciTech Connect

    Nordon, Ian M. Hinchliffe, Robert J.; Loftus, Ian M.; Morgan, Robert A.; Thompson, Matt M.

    2011-10-15

    Acute aortic syndrome (AAS) describes several life-threatening aortic pathologies. These include intramural hematoma, penetrating aortic ulcer, and acute aortic dissection (AAD). Advances in both imaging and endovascular treatment have led to an increase in diagnosis and improved management of these often catastrophic pathologies. Patients, who were previously consigned to medical management or high-risk open surgical repair, can now be offered minimally invasive solutions with reduced morbidity and mortality. Information from the International Registry of Acute Aortic Dissection (IRAD) database demonstrates how in selected patients with complicated AAD the 30-day mortality from open surgery is 17% and endovascular stenting is 6%. Despite these improvements in perioperative deaths, the risks of stroke and paraplegia remain with endovascular treatment (combined outcome risk 4%). The pathophysiology of each aspect of AAS is described. The best imaging techniques and the evolving role of endovascular techniques in the definitive management of AAS are discussed incorporating strategies to reduce perioperative morbidity.

  10. Fluid dynamics of aortic valve stenosis

    NASA Astrophysics Data System (ADS)

    Keshavarz-Motamed, Zahra; Maftoon, Nima

    2009-11-01

    Aortic valve stenosis, which causes considerable constriction of the flow passage, is one of the most frequent cardiovascular diseases and is the most common cause of the valvular replacements which take place for around 100,000 per year in North America. Furthermore, it is considered as the most frequent cardiac disease after arterial hypertension and coronary artery disease. The objective of this study is to develop an analytical model considering the coupling effect between fluid flow and elastic deformation with reasonable boundary conditions to describe the effect of AS on the left ventricle and the aorta. The pulsatile and Newtonian blood flow through aortic stenosis with vascular wall deformability is analyzed and its effects are discussed in terms of flow parameters such as velocity, resistance to flow, shear stress distribution and pressure loss. Meanwhile we developed analytical expressions to improve the comprehension of the transvalvular hemodynamics and the aortic stenosis hemodynamics which is of great interest because of one main reason. To medical scientists, an accurate knowledge of the mechanical properties of whole blood flow in the aorta can suggest a new diagnostic tool.

  11. Pentacuspid aortic valve diagnosed by transoesophageal echocardiography

    PubMed Central

    Cemri, M; Cengel, A; Timurkaynak, T

    2000-01-01

    Congenital aortic valve anomalies are quite a rare finding in echocardiographic examinations. A case of a 19 year old man with a pentacuspid aortic valve without aortic stenosis and regurgitation, detected by transoesophageal echocardiography, is presented.


Keywords: pentacuspid aortic valve; echocardiography PMID:10995427

  12. [Aortic valve replacement for the small aortic annulus].

    PubMed

    Oshima, H; Usui, A; Akita, T; Ueda, Y

    2006-04-01

    Aortic valve surgery for the small aortic annulus is still challenging for surgeons. Recently, the new types of high performance prosthesis have been developed and the chance of an aortic root enlargement (ARE) is decreasing. In this study, we propose the ideal strategy of the aortic surgery for the small aortic annulus. We analyzed the clinical records of 158 patients who underwent aortic valve replacement from August 1999 to October 2005 in our institution. The small aortic annulus was observed in 38 patients (24%). Fourteen patients of this group underwent ARE. Patient-prosthesis mismatch (PPM) was less frequently observed in patients with ARE compared to those without ARE. The additional time required for ARE was not considerable, and neither ischemic time nor cardiopulmonary bypass time was significantly prolonged by ARE. In conclusion, we have to select a prosthesis with sufficient orifice area to avoid PPM, otherwise we should choose an option of ARE. For this consideration, we definitely need the chart that demonstrates the relationship between the nominal size of various types of prostheses and the size of a patient's annulus that those prostheses actually fit.

  13. Aortic biomechanics in hypertrophic cardiomyopathy

    PubMed Central

    Badran, Hala Mahfouz; Soltan, Ghada; Faheem, Nagla; Elnoamany, Mohamed Fahmy; Tawfik, Mohamed; Yacoub, Magdi

    2015-01-01

    Background: Ventricular-vascular coupling is an important phenomenon in many cardiovascular diseases. The association between aortic mechanical dysfunction and left ventricular (LV) dysfunction is well characterized in many disease entities, but no data are available on how these changes are related in hypertrophic cardiomyopathy (HCM). Aim of the work: This study examined whether HCM alone is associated with an impaired aortic mechanical function in patients without cardiovascular risk factors and the relation of these changes, if any, to LV deformation and cardiac phenotype. Methods: 141 patients with HCM were recruited and compared to 66 age- and sex-matched healthy subjects as control group. Pulse pressure, aortic strain, stiffness and distensibility were calculated from the aortic diameters measured by M-mode echocardiography and blood pressure obtained by sphygmomanometer. Aortic wall systolic and diastolic velocities were measured using pulsed wave Doppler tissue imaging (DTI). Cardiac assessment included geometric parameters and myocardial deformation (strain and strain rate) and mechanical dyssynchrony. Results: The pulsatile change in the aortic diameter, distensibility and aortic wall systolic velocity (AWS') were significantly decreased and aortic stiffness index was increased in HCM compared to control (P < .001) In HCM AWS' was inversely correlated to age(r = − .32, P < .0001), MWT (r = − .22, P < .008), LVMI (r = − .20, P < .02), E/Ea (r = − .16, P < .03) LVOT gradient (r = − 19, P < .02) and severity of mitral regurg (r = − .18, P < .03) but not to the concealed LV deformation abnormalities or mechanical dyssynchrony. On multivariate analysis, the key determinant of aortic stiffness was LV mass index and LVOT obstruction while the role LV dysfunction in aortic stiffness is not evident in this population. Conclusion: HCM is associated with abnormal aortic mechanical properties. The severity of cardiac

  14. Prosthesis-preserving aortic root repair after aortic valve replacement.

    PubMed

    Hamamoto, Masaki; Kobayashi, Taira; Kodama, Hiroshi

    2015-07-01

    We describe a new technique of prosthesis-preserving aortic root replacement for patients who have previously undergone aortic valve replacement. With preservation of the mechanical prosthesis, we implant a Gelweave Valsalva graft using double suture lines. The first suture line is made between the sewing cuff of the mechanical valve and the graft, with mattress sutures of 2/0 braided polyester with pledgets. After the first sutures are tied, the second suture line is created between the graft collar and the aortic root remnant with continuous 4/0 polypropylene sutures.

  15. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Siebenmann, R; Schneider, K; von Segesser, L; Turina, M

    1988-06-11

    348 cases of abdominal aortic aneurysm were reviewed for typical features of inflammatory aneurysm (IAAA) (marked thickening of aneurysm wall, retroperitoneal fibrosis and rigid adherence of adjacent structures). IAAA was present in 15 cases (14 male, 1 female). When compared with patients who had ordinary aneurysms, significantly more patients complained of back or abdominal pain (p less than 0.01). Erythrocyte sedimentation rate was highly elevated. Diagnosis was established in 7 of 10 computed tomographies. 2 patients underwent emergency repair for ruptured aneurysm. Unilateral ureteral obstruction was present in 4 cases and bilateral in 1. Repair of IAAA was performed by a modified technique. Histological examination revealed thickening of the aortic wall, mainly of the adventitial layer, infiltrated by plasma cells and lymphocytes. One 71-year-old patient operated on for rupture of IAAA died early, and another 78-year-old patient after 5 1/2 months. Control computed tomographies revealed spontaneous regression of inflammatory infiltration after repair. Equally, hydronephrosis due to ureteral obstruction could be shown to disappear or at least to decrease. IAAA can be diagnosed by computed tomography with high sensitivity. Repair involves low risk, but modification of technique is necessary. The etiology of IAAA remains unclear.

  16. The excluder aortic endograft.

    PubMed

    Alterman, Daniel M; Stevens, Scott L

    2008-06-01

    Since its introduction, more than 59000 patients have been treated with Gore Excluder endoprosthesis (GORE) for abdominal aortic aneurysm (AAA) in the past 11 years. It has become clearer that differences in device delivery and design provide certain advantages that may favor one anatomical milieu over another. Behavior of the aneurysm sac also seems to be graft dependent as more long-term data become available. The currently available low-permeability GORE seems to have addressed the problem of endotension noted with previous designs. Cumulative data are reviewed, and the data demonstrate very low perioperative morbidity and mortality and excellent protection from aneurysm-related complications with the GORE device. Superior ease of use, excellent trackability, and rare failures requiring acute open conversion characterize the GORE device. By addressing clinical demands of aortic endografting, Gore has eclipsed other endografts in the industry to now dominate the US market. The aim of this review is to describe the history, experience, advantages, and future goals with the GORE for the treatment of AAA.

  17. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity

    SciTech Connect

    Weber, Martina; Baker, Meredith B.; Moore, Jeffrey P.; Searles, Charles D.

    2010-03-19

    Mechanical forces associated with blood flow play an important role in regulating vascular signaling and gene expression in endothelial cells (ECs). MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. miRNAs are known to have an important role in modulating EC biology, but their expression and functions in cells subjected to shear stress conditions are unknown. We sought to determine the miRNA expression profile in human ECs subjected to unidirectional shear stress and define the role of miR-21 in shear stress-induced changes in EC function. TLDA array and qRT-PCR analysis performed on HUVECs exposed to prolonged unidirectional shear stress (USS, 24 h, 15 dynes/cm{sup 2}) identified 13 miRNAs whose expression was significantly upregulated (p < 0.05). The miRNA with the greatest change was miR-21; it was increased 5.2-fold (p = 0.002) in USS-treated versus control cells. Western analysis demonstrated that PTEN, a known target of miR-21, was downregulated in HUVECs exposed to USS or transfected with pre-miR-21. Importantly, HUVECs overexpressing miR-21 had decreased apoptosis and increased eNOS phosphorylation and nitric oxide (NO{sup {center_dot}}) production. These data demonstrate that shear stress forces regulate the expression of miRNAs in ECs, and that miR-21 influences endothelial biology by decreasing apoptosis and activating the NO{sup {center_dot}} pathway. These studies advance our understanding of the mechanisms by which shear stress forces modulate vascular homeostasis.

  18. Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

    PubMed Central

    Abedat, Suzan; Beeri, Ronen; Valitsky, Michael; Daher, Sameh; Kott-Gutkowski, Miriam; Gal-Moscovici, Anca; Sosna, Jacob; Rajamannan, Nalini M.; Lotan, Chaim

    2011-01-01

    Renal failure is associated with aortic valve calcification. Using our rat model of uremia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n = 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n = 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosis-related genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. PMID:21335463

  19. Minimally invasive aortic valve surgery

    PubMed Central

    Castrovinci, Sebastiano; Emmanuel, Sam; Moscarelli, Marco; Murana, Giacomo; Caccamo, Giuseppa; Bertolino, Emanuela Clara; Nasso, Giuseppe; Speziale, Giuseppe; Fattouch, Khalil

    2016-01-01

    Aortic valve disease is a prevalent disorder that affects approximately 2% of the general adult population. Surgical aortic valve replacement is the gold standard treatment for symptomatic patients. This treatment has demonstrably proven to be both safe and effective. Over the last few decades, in an attempt to reduce surgical trauma, different minimally invasive approaches for aortic valve replacement have been developed and are now being increasingly utilized. A narrative review of the literature was carried out to describe the surgical techniques for minimally invasive aortic valve surgery and report the results from different experienced centers. Minimally invasive aortic valve replacement is associated with low perioperative morbidity, mortality and a low conversion rate to full sternotomy. Long-term survival appears to be at least comparable to that reported for conventional full sternotomy. Minimally invasive aortic valve surgery, either with a partial upper sternotomy or a right anterior minithoracotomy provides early- and long-term benefits. Given these benefits, it may be considered the standard of care for isolated aortic valve disease. PMID:27582764

  20. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis

    PubMed Central

    Moran, Corey S.; Seto, Sai-Wang; Krishna, Smriti M.; Sharma, Surabhi; Jose, Roby J.; Biros, Erik; Wang, Yutang; Morton, Susan K.; Golledge, Jonathan

    2017-01-01

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE−/− mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm. PMID:28220880

  1. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.

    PubMed

    Moran, Corey S; Seto, Sai-Wang; Krishna, Smriti M; Sharma, Surabhi; Jose, Roby J; Biros, Erik; Wang, Yutang; Morton, Susan K; Golledge, Jonathan

    2017-02-21

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE(-/-) mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

  2. Diesel exhaust exposure enhances venoconstriction via uncoupling of eNOS

    SciTech Connect

    Knuckles, Travis L.; Lund, Amie K.; Lucas, Selita N.; Campen, Matthew J.

    2008-08-01

    Environmental air pollution is associated with adverse cardiovascular events, including increased hospital admissions due to heart failure and myocardial infarction. The exact mechanism(s) by which air pollution affects the heart and vasculature is currently unknown. Recent studies have found that exposure to air pollution enhances arterial vasoconstriction in humans and animal models. Work in our laboratory has shown that diesel emissions (DE) enhance vasoconstriction of mouse coronary arteries. Thus, we hypothesized that DE could enhance vasoconstriction in arteries and veins through uncoupling of endothelial nitric oxide synthase (eNOS). To test this hypothesis, we first bubbled DE through a physiological saline solution and exposed isolated mesenteric veins. Second, we exposed animals, whole body, to DE at 350 {mu}g/m{sup 3} for 4 h, after which mesenteric arteries and veins were isolated. Results from these experiments show that saline bubbled with DE as well as inhaled DE enhances vasoconstriction in veins but not arteries. Exposure to several representative volatile organic compounds found in the DE-exposed saline did not enhance arterial constriction. L-nitro-arginine-methyl-ester (L-NAME), an eNOS inhibitor, normalized the control vessels to the DE-exposed vessels implicating an uncoupling of eNOS as a mechanism for enhanced vasoconstriction. The principal conclusions of this research are 1) veins exhibit endothelial dysfunction following in vivo and ex vivo exposures to DE, 2) veins appear to be more sensitive to DE effects than arteries, and 3) DE components most likely induce endothelial dysfunction through the uncoupling of eNOS.

  3. eNOS gene polymorphisms modify the association of PM(10) with oxidative stress.

    PubMed

    Kim, Jin Hee; Choi, Yoon-Hyeong; Bae, Sanghyuk; Park, Hye-Yin; Hong, Yun-Chul

    2012-11-15

    Previous studies have suggested that air pollution increases various health outcomes through oxidative stress and oxidative stress-related genes modify the relationship between air pollution and health outcomes. Therefore, we evaluated the effect of PM(10) on the levels of malondialdehyde (MDA), oxidative stress biomarker, and the effect modification by genetic polymorphisms of eNOS, oxidative stress-related gene, in the 560 Korean elderly. We obtained urine samples repeatedly from participants during five medical examinations between 2008 and 2010 and all ambient air pollutant concentration data from the Korea National Institute of Environmental Research air quality monitoring system. We measured urinary levels of MDA to assess oxidative stress and genotyped eNOS (rs1799983, rs2853796, and rs7830). Mixed-effect model was used to estimate the effect of PM(10) on the level of oxidative stress biomarker and their modification by genotypes. PM(10) showed apparent positive effect on MDA level after adjusting for age, sex, BMI, cotinine level, temperature, dew point, levels of SO(2), O(3), NO(2), and CO, and season (p=0.0133). Moreover, the association of PM(10) with MDA was found only in participants with eNOS GG genotype for rs1799983 (p=0.0107), TT genotype for rs2853796 (p=0.0289), or GT genotype for rs7830 (p=0.0158) and in participants with a set of risky haplotypes (GTT, GTG, GGT, and TGT) (p=0.0093). Our results suggest that PM(10) affect oxidative stress in the elderly and eNOS genotype affect the oxidative stress level in regard of exposure to PM(10).

  4. Apoptosis in testicular tissue of rats after vasectomy: evaluation of eNOS, iNOS immunoreactivities and the effects of ozone therapy

    PubMed Central

    Alpcan, Serhan; Başar, Halil; Aydos, Tolga Reşat; Kul, Oğuz; Kısa, Üçler; Başar, Murad Mehmet

    2014-01-01

    Objective: We aimed to investigate the changes in endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) expression and apoptotic index in rat testicular tissue, as well as serum and seminal plasma sex hormone levels after vasectomy, and the effect of ozone therapy (OT). Material and methods: Adult male Wistar rats were used (n=6 per group). Control (G1), sham for 4 weeks (G2) or 6 weeks (G3), orchiectomy at the 4th (G4) or 6th (G5) week after left vasectomy, orchiectomy at the 4th (G6) or 6th (G7) week after bilateral vasectomy, orchiectomy after 6 weeks OT following left (G8) or bilateral (G9) vasectomy, orchiectomy after 6 weeks OT (G10). Results: In the left testes, while there were increases in eNOS and iNOS immunoreactivity and apoptotic indexes in G4 and G5, no changes were observed in contralateral testis. These values increased in G6 and G7, while OT inhibited these parameters in the left testis of G8 and both testes of G9. Sex hormone levels did not show any changes after vasectomy and ozone therapy. Conclusion: While OT was found to be protective against some parameters mentioned above under stress conditions, it seemed to cause some harmful effects when used in healthy conditions. PMID:26328178

  5. Some Aspects of Essentially Nonoscillatory (ENO) Formulations for the Euler Equations, Part 3

    NASA Technical Reports Server (NTRS)

    Chakravarthy, Sukumar R.

    1990-01-01

    An essentially nonoscillatory (ENO) formulation is described for hyperbolic systems of conservation laws. ENO approaches are based on smart interpolation to avoid spurious numerical oscillations. ENO schemes are a superset of Total Variation Diminishing (TVD) schemes. In the recent past, TVD formulations were used to construct shock capturing finite difference methods. At extremum points of the solution, TVD schemes automatically reduce to being first-order accurate discretizations locally, while away from extrema they can be constructed to be of higher order accuracy. The new framework helps construct essentially non-oscillatory finite difference methods without recourse to local reductions of accuracy to first order. Thus arbitrarily high orders of accuracy can be obtained. The basic general ideas of the new approach can be specialized in several ways and one specific implementation is described based on: (1) the integral form of the conservation laws; (2) reconstruction based on the primitive functions; (3) extension to multiple dimensions in a tensor product fashion; and (4) Runge-Kutta time integration. The resulting method is fourth-order accurate in time and space and is applicable to uniform Cartesian grids. The construction of such schemes for scalar equations and systems in one and two space dimensions is described along with several examples which illustrate interesting aspects of the new approach.

  6. Green tea polyphenols down-regulate caveolin-1 expression via ERK1/2 and p38MAPK in endothelial cells.

    PubMed

    Li, Yanrong; Ying, Chenjiang; Zuo, Xuezhi; Yi, Haiwei; Yi, Weijie; Meng, Yi; Ikeda, Katsumi; Ye, Xiaolei; Yamori, Yukio; Sun, Xiufa

    2009-12-01

    Caveolin-1 (Cav-1), a negative regulator of endothelial nitric oxide synthase (eNOS), influences various aspects of the cardiovascular functions. We had reported that a high-fat diet up-regulated aortic Cav-1 expressions in rats. In this study, we investigated the effects of green tea polyphenols (GTPs) on endothelial Cav-1 expression and phosphorylation in vitro. Bovine aortic endothelial cells (BAECs) were treated with 4 microg/ml GTPs for 0, 4, 8, 12, 16 and 24 h, and with 0, 0.04, 0.4, 4 and 40 microg/ml GTPs for 16 h, respectively. Cav-1 protein and mRNA were detected using Western blot and reverse transcriptase polymerase chain reaction. Cav-1 protein expression was down-regulated after treatment of BAECs with 4 microg/ml GTPs for 12, 16 and 24 h. And decrease in the level of Cav-1 mRNA was observed after GTP treatment for 4 and 8 h. GTPs (0.04-4 microg/ml) down-regulate Cav-1 protein expressions and mRNA levels dose dependently. PD98059, an inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2), up-regulated Cav-1 expression in BAECs alone and abolished the down-regulation effects of GTPs in BAECs while pretreatment with it. Inhibition of p38 mitogen-activated protein kinase (p38MAPK) with SB203580, which down-regulates Cav-1 expression in BAECs alone, deteriorated the Cav-1 down-regulating effects by GTPs. In addition to the effects on expression of Cav-1, GTP treatment inhibited phosphorylation of Cav-1 [tyrosine 14 (Tyr14)]. These data indicate that GTPs down-regulate gene expression of Cav-1 time- and dose- dependently via activating ERK1/2 and inhibiting p38MAPK signaling.

  7. Screening for Abdominal Aortic Aneurysm

    MedlinePlus

    ... signs or symptoms of an abdominal aortic aneurysm (AAA). The final recommendation statement summarizes what the Task ... the potential benefits and harms of screening for AAA: (1) Men ages 65 to 75 who smoke ...

  8. Evaluation of regional aortic distensibility using color kinesis.

    PubMed

    Kato, Yoshimasa; Kotoh, Keiju; Yamashita, Akio; Furuta, Hidetoshi; Shimazu, Chikasi; Misaki, Takurou

    2003-01-01

    Regional aortic stiffness cannot be evaluated by conventional methods. Regional aortic wall velocity during systole in the descending aorta was evaluated by using transesophageal echocardiography with color kinesis. The authors defined regional aortic distensibility (RAD) by considering pulse pressure, with RAD (microm/s/mm Hg) = (regional aortic wall velocity)/(pulse pressure). RAD was evaluated in 38 patients who had coronary artery disease (CAD) and 10 who did not. RAD decreased depending on aging (partial regression coefficient was -5.39 x 10(-1), p<0.001), and RAD was lower in the CAD group than that in the no-CAD group (p<0.05). In the CAD group, 19 patients had a single fixed plaque (4 calcified and 15 noncalcified plaques). RAD in the calcified plaque was lower than that in the noncalcified plaque (p<0.01), and RAD was lower in the noncalcified plaque than that in the no-plaque region (p<0.05). In noncalcified plaques, the relation between RAD and maximum intimal thickness had a significant correlation, r=0.7, p<0.001. The residual of RAD from the regression line was significantly larger in the calcified plaque than that in the noncalcified plaque (p<0.001). In conclusion, RAD can express increasing regional aortic wall stiffness brought about by arteriosclerosis quantitatively. Color kinesis provides information on characteristic difference between calcified and noncalcified plaque.

  9. Thoracic Aortic Aneurysm: Reading the Enemy’s Playbook

    PubMed Central

    Elefteriades, John A.

    2008-01-01

    Background: At the Yale University Center for Thoracic Aortic Disease, we have been using our clinical experience and laboratory investigations to shed light on the pathophysiology of thoracic aortic aneurysm (TAA), the clinical behavior of thoracic aortic aneurysm, and the optimal clinical management. Materials and Methods: The Yale database contains information on 3,000 patients with thoracic aortic aneurysm, with 9,000 patient-years of follow-up and 9,000 imaging studies. Advanced statistical techniques were applied to this information. Results: Analysis yielded the following Yale-generated observations: (1) TAA is a genetic disease with a predominantly autosomal dominant mode of inheritance; (2) matrix metalloproteinase (MMP) enzymes are activated in the pathogenesis of TAA; (3) wall tension in TAA approaches the tensile limits of aortic tissue at a diameter of 6 cm; (4) by the time a TAA reaches a clinical diameter of 6 cm, 34 percent of affected patients have suffered dissection or rupture; (5) extreme physical exertion or severe emotion often precipitate acute dissection; and (6) single nucleotide polymorphisms (SNPs) and RNA expression profile changes are being identified that predispose a patient to TAA and can serve as biomarkers for screening for this virulent disease. Conclusions: The “playbook” of TAA is gradually being read, with the help of scientific investigations, positioning practitioners to combat this lethal disease more effectively than ever before. PMID:19099048

  10. [New aspects in aortic valve disease].

    PubMed

    Tornos, P

    2001-01-01

    Renewed interest for aortic valve disease has evolved in recent years. Aortic valve replacement has become the second most frequent cause of cardiac surgery, following coronary bypass surgery. In addition, the etiologic and physiopathologic knowledge of this disorder has improved. In the present paper we analyze three aspects of the disease which are, at present, the subject of study and controversy: first, we discuss the possible relationship between degenerative aortic stenosis and atherosclerosis; second, the involvement of the aortic root in cases of bicuspid aortic valve; and third, the surgical indications in asymptomatic patients with either aortic stenosis or regurgitation.

  11. Rare or unusual causes of chronic, isolated, pure aortic regurgitation

    SciTech Connect

    Waller, B.F.; Taliercio, C.P.; Dickos, D.K.; Howard, J.; Adlam, J.H.; Jolly, W. )

    1990-08-01

    Six patients undergoing aortic valve replacement had rare or unusual causes of isolated, pure aortic regurgitation. Two patients had congenitally bicuspid aortic valves with a false commissure (raphe) displaced to the aortic wall (tethered bicuspid aortic valve), two had floppy aortic valves, one had a congenital quadricuspid valve, and one had radiation-induced valve damage.

  12. Coronary Flow Impacts Aortic Leaflet Mechanics and Aortic Sinus Hemodynamics.

    PubMed

    Moore, Brandon L; Dasi, Lakshmi Prasad

    2015-09-01

    Mechanical stresses on aortic valve leaflets are well-known mediators for initiating processes leading to calcific aortic valve disease. Given that non-coronary leaflets calcify first, it may be hypothesized that coronary flow originating from the ostia significantly influences aortic leaflet mechanics and sinus hemodynamics. High resolution time-resolved particle image velocimetry (PIV) measurements were conducted to map the spatiotemporal characteristics of aortic sinus blood flow and leaflet motion with and without physiological coronary flow in a well-controlled in vitro setup. The in vitro setup consists of a porcine aortic valve mounted in a physiological aorta sinus chamber with dynamically controlled coronary resistance to emulate physiological coronary flow. Results were analyzed using qualitative streak plots illustrating the spatiotemporal complexity of blood flow patterns, and quantitative velocity vector and shear stress contour plots to show differences in the mechanical environments between the coronary and non-coronary sinuses. It is shown that the presence of coronary flow pulls the classical sinus vorticity deeper into the sinus and increases flow velocity near the leaflet base. This creates a beneficial increase in shear stress and washout near the leaflet that is not seen in the non-coronary sinus. Further, leaflet opens approximately 10% farther into the sinus with coronary flow case indicating superior valve opening area. The presence of coronary flow significantly improves leaflet mechanics and sinus hemodynamics in a manner that would reduce low wall shear stress conditions while improving washout at the base of the leaflet.

  13. Aortic root replacement with a valve-sparing technique for quadricuspid aortic valve.

    PubMed

    Yamanaka, Katsuhiro; Okada, Kenji; Okita, Yutaka

    2015-04-01

    A 67-year old man with ascending aortic aneurysm was referred because of a quadricuspid aortic valve. He underwent aortic root replacement with a valve-sparing technique. Under deep hypothermic circulatory arrest, replacement of the ascending aorta was successfully performed. The postoperative course was uneventful without recurrence of aortic regurgitation.

  14. Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms

    PubMed Central

    Malashicheva, Anna; Kostina, Daria; Kostina, Aleksandra; Irtyuga, Olga; Voronkina, Irina; Smagina, Larisa; Ignatieva, Elena; Gavriliuk, Natalia; Uspensky, Vladimir; Moiseeva, Olga; Vaage, Jarle; Kostareva, Anna

    2016-01-01

    Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis. PMID:26904289

  15. Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms.

    PubMed

    Malashicheva, Anna; Kostina, Daria; Kostina, Aleksandra; Irtyuga, Olga; Voronkina, Irina; Smagina, Larisa; Ignatieva, Elena; Gavriliuk, Natalia; Uspensky, Vladimir; Moiseeva, Olga; Vaage, Jarle; Kostareva, Anna

    2016-01-01

    Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.

  16. COX2 Inhibition Reduces Aortic Valve Calcification In Vivo

    PubMed Central

    Wirrig, Elaine E.; Gomez, M. Victoria; Hinton, Robert B.; Yutzey, Katherine E.

    2016-01-01

    Objective Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects approximately 1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild type mice, increased expression of the gene encoding cyclooxygenase 2/COX2 (Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed. Approach and Results In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression. Conclusions COX2 expression is upregulated in CAVD and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo. PMID:25722432

  17. Aortic Arch Interruption and Persistent Fifth Aortic Arch in Phace Syndrome: Prenatal Diagnosis and Postnatal Course.

    PubMed

    Chiappa, Enrico; Greco, Antonella; Fainardi, Valentina; Passantino, Silvia; Serranti, Daniele; Favilli, Silvia

    2015-09-01

    PHACE is a rare congenital neurocutaneous syndrome where posterior fossa malformations, hemangiomas, cerebrovascular anomalies, aortic arch anomalies, cardiac defects, and eye abnormalities are variably associated. We describe the prenatal detection and the postnatal course of a child with PHACE syndrome with a unique type of aortic arch anomaly consisting of proximal interruption of the aortic arch and persistence of the fifth aortic arch. The fifth aortic arch represented in this case a vital systemic-to-systemic connection between the ascending aorta and the transverse portion of the aortic arch allowing adequate forward flow through the aortic arch without surgical treatment.

  18. Abdominal aortic aneurysm repair - open - discharge

    MedlinePlus

    ... aortic aneurysm repair - open Aortic angiography Chest MRI Hardening of the ... Center-Shreveport, Shreveport, LA. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla ...

  19. Aortic valve orifice equation independent of valvular flow intervals: application to aortic valve area computation in aortic stenosis and comparison with the Gorlin formula.

    PubMed

    Seitz, W; Oppenheimer, L; McIlroy, M; Nelson, D; Operschall, J

    1986-12-01

    An orifice equation is derived relating the effective aortic valve area, A, the average aortic valve pressure gradient, dP, the stroke volume, SV, and the heart frequency, FH, through considerations of momentum conservation across the aortic valve. This leads to a formula consistent with Newton's second law of motion. The form of the new equation is A = (7.5 X 10(-5)) SV FH2/Pd, where A, VS, FH and Pd are expressed in cm2, ml, s-1 and mmHg, respectively. Aortic valve areas computed with the new orifice equation are found to correlate with those computed by the Gorlin formula in conditions of resting haemodynamic states at a level of r = 0.86, SE = 0.25 cm2, N = 120. The results suggest that the new formula may be considered as an independent orifice equation having a similar domain of validity as the Gorlin formula. The new equation offers the possibility of deriving additional useful haemodynamic relationships through combination with established cardiological formulas and applying it in a noninvasive Doppler ultrasonic or echocardiographic context.

  20. Management of bicuspid aortic valve with or without involvement of ascending aorta and aortic root.

    PubMed

    Neragi-Miandoab, S

    2014-06-01

    Patients with a bicuspid aortic valve (BAV) constitute a heterogeneous population with variable clinical presentation and complications. More than 50% of the patients who require aortic valve replacement have a BAV, a condition that may be associated with dilation of ascending aorta and aortic insufficiency caused by cusp disease or aortic root pathology. Of the potential BAV-related complications, dilation of the aortic root and ascending aorta are among the most serious. The dilation of ascending aorta and aortic root have been the subject of controversy. Whereas some surgeons believe that the dilation of the aorta is caused by the hemodynamic properties of the BAV, others believe that the dilation of the aortic root is secondary to genetic defects associated with the BAV. Management of a BAV should be tailored to each patient's clinical condition. The surgical approach varies from aortic valve replacement to combined aortic valve and root replacement to aortic-valve-sparing root replacement.

  1. Abdominal aortic feminism.

    PubMed

    Mortimer, Alice Emily

    2014-11-14

    A 79-year-old woman presented to a private medical practice 2 years previously for an elective ultrasound screening scan. This imaging provided the evidence for a diagnosis of an abdominal aortic aneurysm (AAA) to be made. Despite having a number of recognised risk factors for an AAA, her general practitioner at the time did not follow the guidance set out by the private medical professional, that is, to refer the patient to a vascular specialist to be entered into a surveillance programme and surgically evaluated. The patient became symptomatic with her AAA, was admitted to hospital and found to have a tender, symptomatic, 6 cm leaking AAA. She consented for an emergency open AAA repair within a few hours of being admitted to hospital, despite the 50% perioperative mortality risk. The patient spent 4 days in intensive care where she recovered well. She was discharged after a 12 day hospital stay but unfortunately passed away shortly after her discharge from a previously undiagnosed gastric cancer.

  2. Proteomic Analysis of Bovine Axonemes Exposed to Acute Alcohol: Role of eNOS and HSP90 in Cilia Stimulation

    PubMed Central

    Simet, Samantha M.; Pavlik, Jacqueline A.; Sisson, Joseph H.

    2012-01-01

    Background Cilia are fingerlike motor-driven organelles, which propel inhaled particles and mucus from the lung and airways. We have previously shown that brief alcohol exposure stimulates ciliary motility through an endothelial nitric oxide (eNOS)-dependent pathway localized in the ciliary metabolon. However, the signaling molecules of the ciliary metabolon involved in alcohol-triggered cilia beat frequency (CBF) stimulation upstream of eNOS activation are unknown. Methods and Results We hypothesized that brief alcohol exposure alters threonine and serine phosphorylation of proteins involved in stimulating ciliary beat frequency. Two-dimensional electrophoresis indicated both increases and deceases in the serine and threonine phosphorylation states of several proteins. One of the proteins identified was heat shock protein 90 (HSP90), which undergoes increased threonine phosphorylation after brief alcohol exposure. Because HSP90 has been shown to associate with eNOS in lung tissue, we hypothesized that HSP90 is a key component in alcohol-triggered eNOS activation and that these two proteins co-localize within the ciliary metabolon. Immunofluorescence experiments demonstrate that eNOS and HSP90 co-localize within basal bodies of the ciliary metabolon and partially translocate to the axoneme upon brief alcohol exposure. Pretreatment with geldanamycin, which disrupts HSP90 chaperone functions, prevented eNOS-HSP90 association and prevented the translocation of eNOS from the ciliary metabolon to the axoneme. Functional cilia motility studies revealed that geldanamycin blocked alcohol-stimulated ciliary motility in bovine bronchial epithelial cells and mouse tracheal rings. Conclusions Based on the HSP90 localization with eNOS, alcohol activation of HSP90 phosphorylation, and geldanamycin’s ability inhibit HSP90-eNOS association, prevent eNOS translocation to the axoneme, and block alcohol-stimulated ciliary motility, we conclude that alcohol-induced cilia stimulation

  3. ET-1 Stimulates Superoxide Production by eNOS Following Exposure of Vascular Endothelial Cells to Endotoxin.

    PubMed

    Gopalakrishna, Deepak; Pennington, Samantha; Karaa, Amel; Clemens, Mark G

    2016-07-01

    It has been shown that microcirculation is hypersensitized to endothelin1 (ET-1) following endotoxin (lipopolysaccharide [LPS]) treatment leading to an increased vasopressor response. This may be related in part to decreased activation of endothelial nitric oxide synthase (eNOS) by ET-1. eNOS can also be uncoupled to produce superoxide (O2). This aberrant eNOS activity could further contribute to the hyperconstriction and injury caused by ET-1 following LPS. We therefore tested whether LPS affects ROS production by vascular endothelial cells and whether and how this effect is altered by ET-1. Human umbilical vein endothelial cells (HUVEC) or human microvascular endothelial cells (HMEC) were subjected to a 6-h treatment with LPS (250 ng/mL) or LPS and sepiapterin (100 μM) followed by a 30-min treatment with 100 μM L-Iminoethyl Ornithine (L-NIO) an irreversible eNOS inhibitor and 30-min treatment with ET-1 (10 nM). Conversion of [H]L-arginine to [H]L-citrulline was used to measure eNOS activity. Superoxide dismutase (SOD) inhibitable reduction of Cytochrome-C, dihydro carboxy fluorescein (DCF), and Mitosox was used to estimate ROS. LT-SDS PAGE was used to assess the degree of monomerization of the eNOS homodimer. Stimulation of HUVECs with ET-1 significantly increased NO synthesis by 1.4-fold (P < 0.05). ET-1 stimulation of LPS-treated HUVECs failed to increase NO production. Western blot for eNOS protein showed no change in eNOS protein levels. LPS alone resulted in an insignificant increase in ROS production as measured by cytochrome C that was increased 4.6-fold by ET-1 stimulation (P < 0.05). L-NIO significantly decreased ET-1-induced ROS production (P < 0.05). Sepiapterin significantly decreased ROS production in both; unstimulated and ET-1-stimulated LPS-treated groups, but did not restore NO production. DCF experiments confirmed intracellular ROS while Mitosox suggested a non-mitochondrial source. ET-1 treatment following a chronic LPS stress

  4. Thoracic Aortic Aneurysm from Chronic Antiestrogen Therapy.

    PubMed

    Tripathi, Rishi; Sainathan, Sandeep; Ziganshin, Bulat A; Elefteriades, John A

    2017-03-01

    Aortic aneurysms are a common but often undetected pathology prevalent in the population. They are often detected as incidental findings on imaging studies performed for unrelated pathologies. Estrogens have been shown to exert a protective influence on aortic tissue. Pharmacological agents blocking the actions of estrogens may thus be implicated in causing aortic pathologies. We present the case of an elderly woman with breast carcinoma treated for 18 years with antiestrogen therapy who subsequently developed acute thoracic aortic deterioration (enlargement and wall disruption).

  5. Association of eNOS Gene Polymorphisms G894T and T-786C with Risk of Hepatorenal Syndrome

    PubMed Central

    Yigit, Ali; Yesilada, Elif; Gulbay, Gonca; Bılgıc, Yılmaz; Yildirim, Oguzhan; Turkoz, Yusuf; Aksungur, Zeynep

    2016-01-01

    Background. There are no studies investigating the relationship between endothelial nitric oxide synthase (eNOS) gene polymorphisms and hepatorenal syndrome (HRS). Aim. The purpose of this study is to elucidate whether eNOS gene polymorphisms (G894T and T-786C) play a role in the development of type-2 HRS. Methods. This study was carried out in a group of 92 patients with cirrhosis (44 patients with type-2 HRS and 48 without HRS) and 50 healthy controls. Polymorphisms were determined by polymerase chain reaction (PCR) and melting curve analysis. Results. We did not find any significant difference in allele and genotype distributions of the eNOS -T-786C polymorphism among the groups (p = 0.440). However, the frequency of GT (40.9%) and TT (13.6%) genotypes and mutant allele T (34.1%) for the eNOS G894T polymorphism were significantly higher (p < 0.001 and p < 0.001, resp.) in the HRS group than in both the stable cirrhosis (14.6%, 4.2%, and 11.5%, resp.) and the control (22.0%, 2.0%, and 13.0%, resp.) groups. Conclusion. The occurrence of mutant genotypes (GT/TT) and mutant allele T in eNOS -G894T polymorphisms should be considered as a potential risk factor in cirrhotic patients with HRS. PMID:27594880

  6. Chronic treatment with qiliqiangxin ameliorates aortic endothelial cell dysfunction in diabetic rats.

    PubMed

    Chen, Fei; Wu, Jia-Le; Fu, Guo-Sheng; Mou, Yun; Hu, Shen-Jiang

    2015-03-01

    Qiliqiangxin (QL), a traditional Chinese medicine, has been shown to be beneficial for chronic heart failure. However, whether QL can also improve endothelial cell function in diabetic rats remains unknown. Here, we investigated the effect of QL treatment on endothelial dysfunction by comparing the effect of QL to that of benazepril (Ben) in diabetic Sprague-Dawley rats for 8 weeks. Cardiac function was evaluated by echocardiography and catheterization. Assays for acetylcholine-induced, endothelium-dependent relaxation (EDR), sodium nitroprusside-induced endothelium-independent relaxation, serum nitric oxide (NO), and nitric oxide synthase (NOS) as well as histological analyses were performed to assess endothelial function. Diabetic rats showed significantly inhibited cardiac function and EDR, decreased expression of serum NO and phosphorylation at Ser(1177) on endothelial NOS (eNOS), and impaired endothelial integrity after 8 weeks. Chronic treatment for 8 weeks with either QL or Ben prevented the inhibition of cardiac function and EDR and the decrease in serum NO and eNOS phosphorylation caused by diabetes. Moreover, either QL or Ben suppressed inducible NOS (iNOS) protein levels as well as endothelial necrosis compared with the diabetic rats. Additionally, QL prevented the increase in angiotensin-converting enzyme 1 and angiotensin II receptor type 1 in diabetes. Thus, chronic administration of QL improved serum NO production, EDR, and endothelial integrity in diabetic rat aortas, possibly through balancing eNOS and iNOS activity and decreasing renin-angiotensin system expression.

  7. Surgical Repair of Retrograde Type A Aortic Dissection after Thoracic Endovascular Aortic Repair

    PubMed Central

    Kim, Chang-Young; Kim, Yeon Soo; Ryoo, Ji Yoon

    2014-01-01

    It is expected that the stent graft will become an alternative method for treating aortic diseases or reducing the extent of surgery; therefore, thoracic endovascular aortic repair has widened its indications. However, it can have rare but serious complications such as paraplegia and retrograde type A aortic dissection. Here, we report a surgical repair of retrograde type A aortic dissection that was performed after thoracic endovascular aortic repair. PMID:24570865

  8. Aortic or Mitral Valve Replacement With the Biocor and Biocor Supra

    ClinicalTrials.gov

    2016-03-09

    Aortic Valve Insufficiency; Aortic Valve Regurgitation; Aortic Valve Stenosis; Aortic Valve Incompetence; Mitral Valve Insufficiency; Mitral Valve Regurgitation; Mitral Valve Stenosis; Mitral Valve Incompetence

  9. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections.

    PubMed

    Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay; Nickerson, Deborah A; Guo, Dong-chuan

    2014-02-01

    Thoracic aortic aneurysms involving the aortic root and/or ascending aorta can lead to acute aortic dissections. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of the disease, referred to as familial TAAD (FTAAD) that can be inherited in an autosomal dominant manner with variable expression with respect to disease presentation, age of onset and associated features. Whole exome sequencing (WES) has been used to identify causative mutations in novel genes for TAAD. The strategy used to reduce the large number of rare variants identified using WES is to sequence distant relatives with TAAD and filter for heterozygous rare variants that are shared between the relatives, predicted to disrupt protein function and segregate with the TAAD phenotype in other family members. Putative genes are validated by identifying additional families with a causative mutation in the genes. This approach has successfully identified novel genes for FTAAD.

  10. Successes and Challenges of Using Whole Exome Sequencing to Identify Novel Genes Underlying an Inherited Predisposition for Thoracic Aortic Aneurysms and Acute Aortic Dissections

    PubMed Central

    Milewicz, Dianna M.; Regalado, Ellen; Shendure, Jay; Nickerson, Deborah A.; Guo, Dongchuan

    2013-01-01

    Thoracic aortic aneurysms involving the aortic root and/or ascending aorta can lead to acute aortic dissections. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of the disease, referred to as familial TAAD (FTAAD), which can be inherited in an autosomal dominant manner with variable expression with respect to disease presentation, age of onset and associated features. Whole exome sequencing (WES) has been used to identify causative mutations in novel genes for TAAD. The strategy used to reduce the large number of rare variants identified using WES is to sequence distant relatives with TAAD and filter for heterozygous rare variants that are shared between the relatives, predicted to disrupt protein function and segregate with the TAAD phenotype in other family members. Further validation of putative genes by sequencing of additional families with TAAD has successfully identified novel genes for FTAAD. PMID:23953976

  11. Balloon aortic valvuloplasty as a bridge to aortic valve replacement in a patient with severe calcific aortic stenosis

    PubMed Central

    Swinkels, B.M.; Jaarsma, W.; Wely, L. Relik-van; van Swieten, H.A.; Ernst, J.M.P.G.; Plokker, H.W.M.

    2003-01-01

    This case report describes a patient with severe calcific aortic stenosis who was initially considered inoperable because of a very poor left ventricular function and severe pulmonary hypertension. After balloon aortic valvuloplasty, the clinical and haemodynamic status of the patient improved to such an extent that subsequent aortic valve replacement was considered possible and eventually proved to be successful. Balloon aortic valvuloplasty has value as a potential bridge to aortic valve replacement when the risks for surgery are considered to be too high. ImagesFigure 1 PMID:25696195

  12. [MINIMALLY INVASIVE AORTIC VALVE REPLACEMENT].

    PubMed

    Tabata, Minoru

    2016-03-01

    Minimally invasive aortic valve replacement (MIAVR) is defined as aortic valve replacement avoiding full sternotomy. Common approaches include a partial sternotomy right thoracotomy, and a parasternal approach. MIAVR has been shown to have advantages over conventional AVR such as shorter length of stay and smaller amount of blood transfusion and better cosmesis. However, it is also known to have disadvantages such as longer cardiopulmonary bypass and aortic cross-clamp times and potential complications related to peripheral cannulation. Appropriate patient selection is very important. Since the procedure is more complex than conventional AVR, more intensive teamwork in the operating room is essential. Additionally, a team approach during postoperative management is critical to maximize the benefits of MIAVR.

  13. Pseudoaneurysm of the aortic arch

    PubMed Central

    Lu, Yuan-Qiang; Yao, Feng; Shang, An-Dong; Pan, Jian

    2016-01-01

    Abstract Background: Pseudoaneurysm of the aortic arch is uncommonly associated with cancer, and is extremely rare in pulmonary cancer. Here, we report an unusual and successfully treated case of aortic arch pseudoaneurysm in a male patient with lung squamous cell carcinoma. Methods: A 64-year-old male patient was admitted to the Emergency Department, presenting with massive hemoptysis (>500 mL blood during the 12 hours prior to treatment). The diagnosis of aortic arch pseudoaneurysm was confirmed after inspection of computed tomographic angiography and three-dimensional reconstruction. We processed the immediate endovascular stent-grafting for this patient. Results: This patient recovered with no filling or enlargement of the pseudoaneurysm, no episodes of hemoptysis, and no neurological complications during the 4-week follow-up period. Conclusion: Herein, we compare our case with other cancer-related pseudoaneurysms in the medical literature and summarize the clinical features and treatment of this unusual case. PMID:27495079

  14. eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study

    PubMed Central

    Faloppi, Luca; Scarpi, Emanuela; Foschi, Francesco Giuseppe; Iavarone, Massimo; Lauletta, Gianfranco; Corbelli, Jody; Valgiusti, Martina; Facchetti, Floriana; Corte, Cristina della; Neri, Luca Maria; Tamberi, Stefano; Cascinu, Stefano; Scartozzi, Mario; Amadori, Dino; Nanni, Oriana; Tenti, Elena

    2016-01-01

    Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib. PMID:27058899

  15. eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study.

    PubMed

    Casadei Gardini, Andrea; Marisi, Giorgia; Faloppi, Luca; Scarpi, Emanuela; Foschi, Francesco Giuseppe; Iavarone, Massimo; Lauletta, Gianfranco; Corbelli, Jody; Valgiusti, Martina; Facchetti, Floriana; Della Corte, Cristina; Neri, Luca Maria; Tamberi, Stefano; Cascinu, Stefano; Scartozzi, Mario; Amadori, Dino; Nanni, Oriana; Tenti, Elena; Ulivi, Paola; Frassineti, Giovanni Luca

    2016-05-10

    Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.

  16. Singleton Merten Syndrome: A Rare Cause of Early Onset Aortic Stenosis

    PubMed Central

    Mungee, Sudhir

    2017-01-01

    Singleton Merten syndrome (SMS) is a rare autosomal dominant genetic disorder with variable expression. Its characteristic features include abnormal aortic calcification, abnormal ossification of extremities, and dental anomalies. We present a young man with dyspnea who was noted to have aortic stenosis in the background of glaucoma, psoriasis, dental anomalies, hand and foot deformities, Achilles tendinitis, osteopenia, and nephrolithiasis. The conglomeration of features led to the diagnosis of SMS. His mother had a very similar phenotype. PMID:28321341

  17. Severe aortic stenosis: forgotten associations.

    PubMed

    Godinho, Ana Rita; Amorim, Sandra; Campelo, Manuel; Martins, Elisabete; Lopez Rodriguez, Elisa; Coelho, Rosa; Macedo, Guilherme; Maciel, Maria Júlia

    2014-09-01

    The authors present the case of a 68-year-old man with predominantly right heart failure in the context of severe aortic stenosis associated with pulmonary hypertension. Anemia was diagnosed which, after endoscopic study, was considered to be secondary to angiodysplasia and a diagnosis of Heyde syndrome was made. After valve replacement surgery the patient's heart failure improved and hemoglobin levels stabilized. We present this case to show the need to recognize less common associations of severe aortic stenosis, in order to provide immediate and appropriate treatment.

  18. Acute aortic dissection at two extreme ages.

    PubMed

    Ramzisham, A R M; Arief, H; Ngoo, K S; Zamrin, D M; Joanna, O S M

    2011-01-01

    Acute aortic dissection is a life-threatening condition, warranting prompt diagnosis and treatment. Management of which incorporates multidisciplinary expertise from the medical, surgical and intensive care. If left untreated, the mortality rate of acute aortic disease exceeds 50% within 48 hours and 80% within two weeks, with a 5-year survival rate of 19%. The most common cause of death in untreated acute aortic dissection, regardless of aetiology, is aortic rupture. We would like to share our successful experience of cases at the two extreme ages of acute aortic dissection. Literature review with their pathogenesis are discussed.

  19. L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats

    SciTech Connect

    Ramprasath, Tharmarajan; Hamenth Kumar, Palani; Syed Mohamed Puhari, Shanavas; Senthil Murugan, Ponniah; Vasudevan, Varadaraj; Selvam, Govindan Sadasivam

    2012-11-23

    Highlights: Black-Right-Pointing-Pointer L-Arginine treatment reduced the metabolic disturbances in diabetic animals. Black-Right-Pointing-Pointer Antioxidant marker proteins were found high in myocardium by L-arginine treatment. Black-Right-Pointing-Pointer Elevated antioxidant status, mediates the reduced TBA-reactivity in left ventricle. Black-Right-Pointing-Pointer L-Arginine treatment enhanced the Nrf2 and eNOS signaling in left ventricle. Black-Right-Pointing-Pointer Improved cell survival signaling by arginine, offers a novel tactic for targeting. -- Abstract: Hyperglycemia is independently related with excessive morbidity and mortality in cardiovascular disorders. L-Arginine-nitric oxide (NO) pathway and the involvement of NO in modulating nuclear factor-E2-related factor-2 (Nrf2) signaling were well established. In the present study we investigated, whether L-arginine supplementation would improve the myocardial antioxidant defense under hyperglycemia through activation of Nrf2 signaling. Diabetes was induced by alloxan monohydrate (90 mg kg{sup -1} body weight) in rats. Both non-diabetic and diabetic group of rats were divided into three subgroups and they were administered either with L-arginine (2.25%) or L-NAME (0.01%) in drinking water for 12 days. Results showed that L-arginine treatment reduced the metabolic disturbances in diabetic rats. Antioxidant enzymes and glutathione levels were found to be increased in heart left ventricles, thereby reduction of lipid peroxidation by L-arginine treatment. Heart histopathological analysis further validates the reversal of typical diabetic characteristics consisting of alterations in myofibers and myofibrillary degeneration. qRT-PCR studies revealed that L-arginine treatment upregulated the transcription of Akt and downregulated NF-{kappa}B. Notably, transcription of eNOS and Nrf2 target genes was also upregulated, which were accompanied by enhanced expression of Nrf2 in left ventricular tissue from diabetic

  20. eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

    PubMed Central

    Li, Feng; Hagaman, John R.; Kim, Hyung-Suk; Maeda, Nobuyo; Jennette, J. Charles; Faber, James E.; Karumanchi, S. Ananth; Smithies, Oliver

    2012-01-01

    Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia–like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia–like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467±74 versus 174±23 μg/d), lower creatinine clearance (126±29 versus 452±63 μl/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ETA receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ETA receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia–like phenotype through activation of the endothelin system. PMID:22282588

  1. MMP-2 Isoforms in Aortic Tissue and Serum of Patients with Ascending Aortic Aneurysms and Aortic Root Aneurysms

    PubMed Central

    Tscheuschler, Anke; Meffert, Philipp; Beyersdorf, Friedhelm; Heilmann, Claudia; Kocher, Nadja; Uffelmann, Xenia; Discher, Philipp; Siepe, Matthias; Kari, Fabian A.

    2016-01-01

    Objective The need for biological markers of aortic wall stress and risk of rupture or dissection of ascending aortic aneurysms is obvious. To date, wall stress cannot be related to a certain biological marker. We analyzed aortic tissue and serum for the presence of different MMP-2 isoforms to find a connection between serum and tissue MMP-2 and to evaluate the potential of different MMP-2 isoforms as markers of high wall stress. Methods Serum and aortic tissue from n = 24 patients and serum from n = 19 healthy controls was analyzed by ELISA and gelatin zymography. 24 patients had ascending aortic aneurysms, 10 of them also had aortic root aneurysms. Three patients had normally functioning valves, 12 had regurgitation alone, eight had regurgitation and stenosis and one had only stenosis. Patients had bicuspid and tricuspid aortic valves (9/15). Serum samples were taken preoperatively, and the aortic wall specimen collected during surgical aortic repair. Results Pro-MMP-2 was identified in all serum and tissue samples. Pro-MMP-2 was detected in all tissue and serum samples from patients with ascending aortic/aortic root aneurysms, irrespective of valve morphology or other clinical parameters and in serum from healthy controls. We also identified active MMP-2 in all tissue samples from patients with ascending aortic/aortic root aneurysms. None of the analyzed serum samples revealed signals relatable to active MMP-2. No correlation between aortic tissue total MMP-2 or tissue pro-MMP-2 or tissue active MMP-2 and serum MMP-2 was found and tissue MMP-2/pro-MMP-2/active MMP-2 did not correlate with aortic diameter. This evidence shows that pro-MMP-2 is the predominant MMP-2 species in serum of patients and healthy individuals and in aneurysmatic aortic tissue, irrespective of aortic valve configuration. Active MMP-2 species are either not released into systemic circulation or not detectable in serum. There is no reliable connection between aortic tissue—and serum MMP-2

  2. Bicuspid aortic valve hemodynamics does not promote remodeling in porcine aortic wall concavity

    PubMed Central

    Atkins, Samantha K; Moore, Alison N; Sucosky, Philippe

    2016-01-01

    AIM: To investigate the role of type-I left-right bicuspid aortic valve (LR-BAV) hemodynamic stresses in the remodeling of the thoracic ascending aorta (AA) concavity, in the absence of underlying genetic or structural defects. METHODS: Transient wall shear stress (WSS) profiles in the concavity of tricuspid aortic valve (TAV) and LR-BAV AAs were obtained computationally. Tissue specimens excised from the concavity of normal (non-dilated) porcine AAs were subjected for 48 h to those stress environments using a shear stress bioreactor. Tissue remodeling was characterized in terms of matrix metalloproteinase (MMP) expression and activity via immunostaining and gelatin zymography. RESULTS: Immunostaining semi-quantification results indicated no significant difference in MMP-2 and MMP-9 expression between the tissue groups exposed to TAV and LR-BAV AA WSS (P = 0.80 and P = 0.19, respectively). Zymography densitometry revealed no difference in MMP-2 activity (total activity, active form and latent form) between the groups subjected to TAV AA and LR-BAV AA WSS (P = 0.08, P = 0.15 and P = 0.59, respectively). CONCLUSION: The hemodynamic stress environment present in the concavity of type-I LR-BAV AA does not cause any significant change in proteolytic enzyme expression and activity as compared to that present in the TAV AA. PMID:26839660

  3. A family of high-order targeted ENO schemes for compressible-fluid simulations

    NASA Astrophysics Data System (ADS)

    Fu, Lin; Hu, Xiangyu Y.; Adams, Nikolaus A.

    2016-01-01

    Although classical WENO schemes have achieved great success and are widely accepted, they exhibit several shortcomings. They are too dissipative for direct simulations of turbulence and lack robustness when very-high-order versions are applied to complex flows. In this paper, we propose a family of high-order targeted ENO schemes which are applicable for compressible-fluid simulations involving a wide range of flow scales. In order to increase the numerical robustness as compared to very-high-order classical WENO schemes, the reconstruction dynamically assembles a set of low-order candidate stencils with incrementally increasing width. While discontinuities and small-scale fluctuations are efficiently separated, the numerical dissipation is significantly diminished by an ENO-like stencil selection, which either applies a candidate stencil with its original linear weight, or removes its contribution when it is crossed by a discontinuity. The background linear scheme is optimized under the constraint of preserving an approximate dispersion-dissipation relation. By means of quasi-linear analyses and practical numerical experiments, a set of case-independent parameters is determined. The general formulation of arbitrarily high-order schemes is presented in a straightforward way. A variety of benchmark-test problems, including broadband waves, strong shock and contact discontinuities are studied. Compared to well-established classical WENO schemes, the present schemes exhibit significantly improved robustness, low numerical dissipation and sharp discontinuity capturing. They are particularly suitable for DNS and LES of shock-turbulence interactions.

  4. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

    PubMed Central

    Zeng, Qingchun; Song, Rui; Fullerton, David A.; Ao, Lihua; Zhai, Yufeng; Li, Suzhao; Ballak, Dov B.; Cleveland, Joseph C.; Reece, T. Brett; McKinsey, Timothy A.; Xu, Dingli; Dinarello, Charles A.; Meng, Xianzhong

    2017-01-01

    Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease. PMID:28137840

  5. Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes

    PubMed Central

    Raaz, Uwe; Schellinger, Isabel N.; Chernogubova, Ekaterina; Warnecke, Christina; Kayama, Yosuke; Penov, Kiril; Hennigs, Jan K.; Salomons, Florian; Eken, Suzanne; Emrich, Fabian C.; Zheng, Wei H.; Adam, Matti; Jagger, Ann; Nakagami, Futoshi; Toh, Ryuji; Toyama, Kensuke; Deng, Alicia; Buerke, Michael; Maegdefessel, Lars; Hasenfuß, Gerd; Spin, Joshua M.; Tsao, Philip S.

    2015-01-01

    Rationale Accelerated arterial stiffening is a major complication of diabetes with no specific therapy available up to date. Objective The present study investigates the role of the osteogenic transcription factor Runx2 as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes. Methods and Results Using a murine model of type 2 diabetes (db/db mice) we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae as well as in thoracic aortic samples from type 2 diabetic patients. Vascular smooth muscle-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that Runx2 expression in diabetes is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter. Conclusion In conclusion this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes, promoting arterial stiffness irrespective of calcification. PMID:26208651

  6. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor γ dependent Hsp90-eNOS signaling and nitric oxide production

    SciTech Connect

    Bi, Rui; Bao, Chunrong; Jiang, Lianyong; Liu, Hao; Yang, Yang; Mei, Ju; Ding, Fangbao

    2015-05-01

    Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-γ, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAH associated right ventricular hypertrophy and systolic pressure in rats. PPARγ was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH. - Highlights: • miR-27b plays a role in endothelial function and NO release. • miR-27b inhibition ameliorates MCT-induced endothelial dysfunction and PAH. • miR-27b targets PPARγ in HPAECs. • miR-27b regulates PPARγ dependent Hsp90-eNOS and NO signaling.

  7. Notch-dependent EMT is attenuated in patients with aortic aneurysm and bicuspid aortic valve.

    PubMed

    Kostina, Aleksandra S; Uspensky, Vladimir Е; Irtyuga, Olga B; Ignatieva, Elena V; Freylikhman, Olga; Gavriliuk, Natalia D; Moiseeva, Olga M; Zhuk, Sergey; Tomilin, Alexey; Kostareva, Аnna А; Malashicheva, Anna B

    2016-04-01

    Bicuspid aortic valve is the most common congenital heart malformation and the reasons for the aortopathies associated with bicuspid aortic valve remain unclear. NOTCH1 mutations are associated with bicuspid aortic valve and have been found in individuals with various left ventricular outflow tract abnormalities. Notch is a key signaling during cardiac valve formation that promotes the endothelial-to-mesenchymal transition. We address the role of Notch signaling in human aortic endothelial cells from patients with bicuspid aortic valve and aortic aneurysm. Aortic endothelial cells were isolated from tissue fragments of bicuspid aortic valve-associated thoracic aortic aneurysm patients and from healthy donors. Endothelial-to-mesenchymal transition was induced by activation of Notch signaling. Effectiveness of the transition was estimated by loss of endothelial and gain of mesenchymal markers by immunocytochemistry and qPCR. We show that aortic endothelial cells from the patients with aortic aneurysm and bicuspid aortic valve have down regulated Notch signaling and fail to activate Notch-dependent endothelial-to-mesenchymal transition in response to its stimulation by different Notch ligands. Our findings support the idea that bicuspid aortic valve and associated aortic aneurysm is associated with dysregulation of the entire Notch signaling pathway independently on the specific gene mutation.

  8. Aortic Root Enlargement or Sutureless Valve Implantation?

    PubMed Central

    Baikoussis, Nikolaos G.; Dedeilias, Panagiotis; Argiriou, Michalis

    2016-01-01

    Aortic valve replacement (AVR) in patients with a small aortic annulus is a challenging issue. The importance of prosthesis–patient mismatch (PPM) post aortic valve replacement (AVR) is controversial but has to be avoided. Many studies support the fact that PPM has a negative impact on short and long term survival. In order to avoid PPM, aortic root enlargement may be performed. Alternatively and keeping in mind that often some comorbidities are present in old patients with small aortic root, the Perceval S suturelles valve implantation could be a perfect solution. The Perceval sutureless bioprosthesis provides reasonable hemodynamic performance avoiding the PPM and providing the maximum of aortic orifice area. We would like to see in the near future the role of the aortic root enlargement techniques in the era of surgical implantation of the sutureless valve (SAVR) and the transcatheter valve implantation (TAVI). PMID:28028424

  9. Genetic and Epigenetic Regulation of Aortic Aneurysms

    PubMed Central

    Kim, Ha Won

    2017-01-01

    Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture. PMID:28116311

  10. Aortic Wall Injury Related to Endovascular Therapy for Aortic Coarctation.

    PubMed

    Tretter, Justin T; Jones, Thomas K; McElhinney, Doff B

    2015-09-01

    Aortic wall complications can occur in unrepaired aortic coarctation (CoA) and after surgical repair or endovascular treatment. This review summarizes the available literature and current understanding of aortic wall injury (AWI) surrounding the management of CoA, focusing specifically on acute and follow-up AWI after endovascular treatment. There have been 23 reported cases of aortic rupture after endovascular treatment for CoA, including angioplasty alone, bare metal stenting, and primary covered stent therapy. Even if these published cases represent only a minority of ruptures that have actually occurred, the incidence is substantially <1%. The incidence of acute aneurysm formation was 0% to 13% after angioplasty, 0% to 5% after bare metal stent placement, and <1% after covered stent placement. The reported incidence and natural history of both acute and new AWI during follow-up after endovascular therapy for CoA varies considerably, likely secondary to ascertainment and reporting biases and inconsistent definitions. Although important AWI after endovascular treatment of CoA seems to be declining in frequency with increasing experience and improving technology, it remains one of the most important potential adverse outcomes. Long-term surveillance for new AWI and monitoring of existing AWI is mandatory, with institution of appropriate treatment when necessary. A central research focus in this population should be determination of the appropriate treatment for both native and recurrent CoA across various ages with regard to limiting recurrent CoA and preventing associated aortic wall complications, in addition to determining the appropriate treatment of various AWI. Consistent definitions and reporting are necessary to truly understand the incidence of, risk factors for, and measures protective against AWI after angioplasty or stent implantation for CoA.

  11. Visceral Infarction Following Aortic Surgery

    PubMed Central

    Johnson, Willard C.; Nabseth, Donald C.

    1974-01-01

    An experience with aortic surgery is reported which reveals that visceral ischemia is more frequent than expected and significantly contributes to operative mortality. Two of five deaths among 84 patients who had aorto-iliac occlusive disease and four of 40 deaths among 103 aneurysmectomies (both ruptured and elective) were related to visceral ischemia. A review of the literature reveals 99 cases of colonic ischemia in more than 6,100 cases of aortic surgery, an incidence of 1.5%. Only 10 cases of small bowel ischemia were recorded. The present experience with 9 cases of colon ischemia and one of small bowel ischemia is presented particularly with reference to pathophysiology and prevention. It is concluded that patients should be identified by appropriate angiography if considered a risk for visceral infarction, and, if present, visceral arterial reconstruction should be performed in addition to aortic reconstructive surgery. Colon infarction following aortic aneurysmal surgery is directly related to ligation of a patent IMA. Thus re-implantation of the patent IMA should be considered. ImagesFig. 1a. PMID:4277757

  12. Critical aortic stenosis and acute ascending aortic penetrating ulcer managed utilizing transapical TAVR and TEVAR.

    PubMed

    Allen, Keith B; Davis, J Russell; Cohen, David J

    2015-10-01

    Thoracic endovascular aortic repair (TEVAR) of acute ascending aortic pathology is feasible; however, the unique features of this aortic segment in addition to access challenges restricts its use to a select, high-risk subset of patients. With the advent of TAVR, large device delivery using transapical access has become a well-defined technique. We report a patient with critical aortic stenosis and an acute ascending aortic penetrating ulcer with tamponade managed successfully utilizing transapical TAVR and TEVAR. To our knowledge, this is the first reported case of a hybrid single-stage TAVR and ascending aortic TEVAR using transapical access.

  13. Identification of Reference Genes for Quantitative Real Time PCR Assays in Aortic Tissue of Syrian Hamsters with Bicuspid Aortic Valve

    PubMed Central

    Rueda-Martínez, Carmen; Fernández, M. Carmen; Soto-Navarrete, María Teresa; Jiménez-Navarro, Manuel; Durán, Ana Carmen; Fernández, Borja

    2016-01-01

    Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation in humans, and appears frequently associated with dilatation of the ascending aorta. This association is likely the result of a common aetiology. Currently, a Syrian hamster strain with a relatively high (∼40%) incidence of BAV constitutes the only spontaneous animal model of BAV disease. The characterization of molecular alterations in the aorta of hamsters with BAV may serve to identify pathophysiological mechanisms and molecular markers of disease in humans. In this report, we evaluate the expression of ten candidate reference genes in aortic tissue of hamsters in order to identify housekeeping genes for normalization using quantitative real time PCR (RT-qPCR) assays. A total of 51 adult (180–240 days old) and 56 old (300–440 days old) animals were used. They belonged to a control strain of hamsters with normal, tricuspid aortic valve (TAV; n = 30), or to the affected strain of hamsters with TAV (n = 45) or BAV (n = 32). The expression stability of the candidate reference genes was determined by RT-qPCR using three statistical algorithms, GeNorm, NormFinder and Bestkeeper. The expression analyses showed that the most stable reference genes for the three algorithms employed were Cdkn1β, G3pdh and Polr2a. We propose the use of Cdkn1β, or both Cdkn1β and G3pdh as reference genes for mRNA expression analyses in Syrian hamster aorta. PMID:27711171

  14. TGFB2 loss of function mutations cause familial thoracic aortic aneurysms and acute aortic dissections associated with mild systemic features of the Marfan syndrome

    PubMed Central

    Boileau, Catherine; Guo, Dong-Chuan; Hanna, Nadine; Regalado, Ellen S.; Detaint, Delphine; Gong, Limin; Varret, Mathilde; Prakash, Siddharth; Li, Alexander H.; d’Indy, Hyacintha; Braverman, Alan C.; Grandchamp, Bernard; Kwartler, Callie S.; Gouya, Laurent; Santos-Cortez, Regie Lyn P.; Abifadel, Marianne; Leal, Suzanne M.; Muti, Christine; Shendure, Jay; Gross, Marie-Sylvie; Rieder, Mark J.; Vahanian, Alec; Nickerson, Deborah A.; Michel, Jean Baptiste; Jondeau, Guillaume; Milewicz, Dianna M.

    2014-01-01

    A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease, followed by whole exome sequencing of affected relatives, identified causative mutations in TGFB2. These mutations, a frameshift mutation in exon 6 and a nonsense mutation in exon 4, segregated with disease with a combined LOD score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified two additional TGFB2 mutations. TGFB2 encodes the transforming growth factor beta-2 (TGF-β2) and the mutations are predicted to cause haploinsufficiency for TGFB2, but aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency of TGFB2 predisposes to thoracic aortic disease, suggesting the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta. PMID:22772371

  15. Nicotinamide Phosphoribosyltransferase in Smooth Muscle Cells Maintains Genome Integrity, Resists Aortic Medial Degeneration and Is Suppressed in Human Thoracic Aortic Aneurysm Disease.

    PubMed

    Watson, Alanna; Nong, Zengxuan; Yin, Hao; O'Neil, Caroline; Fox, Stephanie; Balint, Brittany; Guo, Ray; Leo, Oberdan; Chu, Michael W; Gros, Robert; Pickering, J G

    2017-03-29

    Rationale: The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage but their capacities decline with age and stress. Recently, cellular production of NAD(+) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown. Objective: To determine if a Nampt-NAD(+) control system exists within the aortic media and is required for aortic health. Methods and Results: Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine if a Nampt-NAD(+)control system in SMCs impacts aortic integrity, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD(+) in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed SA-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible upon re-supplying NAD(+) with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. NAMPT promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with NAMPT expression. Conclusions: The aortic media depends on an intrinsic NAD(+) fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.

  16. Single nucleotide polymorphism (SNP) of the endothelial nitric oxide synthase (eNOS) gene (Glu298Asp variant) in infertile men with asthenozoospermia.

    PubMed

    Buldreghini, Eddi; Mahfouz, Reda Z; Vignini, Arianna; Mazzanti, Laura; Ricciardo-Lamonica, Giuseppe; Lenzi, Andrea; Agarwal, Ashok; Balercia, Giancarlo

    2010-01-01

    The objective of this study was to elucidate the missense Glu298Asp polymorphism within exon 7 of the endothelial nitric oxide synthase (eNOS) gene in infertile men with asthenozoospermia and its potential role in sperm motility. In this prospective controlled study conducted in our andrology unit, we investigated the frequency of the 894G>T polymorphism (Glu298Asp variant) within exon 7 of the eNOS gene in 70 infertile men and 60 healthy men. Sperm motion kinetics were assessed with computer-assisted semen analysis. The presence of G>T, a single nucleotide polymorphism (SNP) in exon 7 of the eNOS gene (NCBI SNP cluster rs1799983; GenBank accession number NG_011992; protein accession number NP_000594) was determined by allelespecific polymerase chain reaction followed by restriction fragment length polymorphism analysis. Sequencing analysis was used to confirm the specific genotype. The 894G>T eNOS allele (T) was found at a higher frequency in the patients with asthenozoospermia (60% vs 22.5% in the control group; P = .02). The percentage of progressive motile sperm (grade a + b) was lower in the asthenozoospermic infertile men with the homozygous eNOS (TT) genotype than in the wild-type eNOS (GG) (P = .02) and heterozygous eNOS (GT) genotypes (P = .01). However, the percentage of progressive motile sperm (grade a + b) was higher in the wild-type vs mutant eNOS (TT) (P = .03) and heterozygous eNOS (GT) genotypes (P = .04). Our findings suggest that the T allele encoding for aspartic acid of the eNOS (Glu298Asp) gene may contribute to poor sperm motility.

  17. Human leucocytes in asthenozoospermic patients: endothelial nitric oxide synthase expression.

    PubMed

    Buldreghini, E; Hamada, A; Macrì, M L; Amoroso, S; Boscaro, M; Lenzi, A; Agarwal, A; Balercia, G

    2014-12-01

    In a basic study at the Andrology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy, we evaluated the pattern of mRNA endothelial nitric oxide synthase (eNOS) expression in human blood leucocytes isolated from normozoospermic fertile and asthenozoospermic infertile men to elucidate any pathogenic involvement in sperm cell motility. Forty infertile men with idiopathic asthenozoospermia and 45 normozoospermic fertile donors, age-matched, were included. Semen parameters were evaluated, and expression analysis of mRNA was performed in human leucocytes using reverse transcription polymerase chain reaction. Sperm volume, count, motility and morphology were determined, and eNOS expression and Western blotting analyses were performed. A positive correlation was observed between the concentrations of NO and the percentage of immotile spermatozoa. The mRNA of eNOS was more expressed in peripheral blood leucocytes isolated from asthenozoospermic infertile men versus those of fertile normozoospermic men (7.46 ± 0.38 versus 7.06 ± 0.56, P = 0.0355). A significant up-regulation of eNOS gene in peripheral blood leucocytes was 1.52-fold higher than that of fertile donors. It is concluded that eNOS expression and activity are enhanced in blood leucocytes in men with idiopathic asthenozoospermia.

  18. iTRAQ proteomic analysis of extracellular matrix remodeling in aortic valve disease

    PubMed Central

    Martin-Rojas, Tatiana; Mourino-Alvarez, Laura; Alonso-Orgaz, Sergio; Rosello-Lleti, Esther; Calvo, Enrique; Lopez-Almodovar, Luis Fernando; Rivera, Miguel; Padial, Luis R.; Lopez, Juan Antonio; Cuesta, Fernando de la; Barderas, Maria G.

    2015-01-01

    Degenerative aortic stenosis (AS) is the most common worldwide cause of valve replacement. The aortic valve is a thin, complex, layered connective tissue with compartmentalized extracellular matrix (ECM) produced by specialized cell types, which directs blood flow in one direction through the heart. There is evidence suggesting remodeling of such ECM during aortic stenosis development. Thus, a better characterization of the role of ECM proteins in this disease would increase our understanding of the underlying molecular mechanisms. Aortic valve samples were collected from 18 patients which underwent aortic valve replacement (50% males, mean age of 74 years) and 18 normal control valves were obtained from necropsies (40% males, mean age of 69 years). The proteome of the samples was analyzed by 2D-LC MS/MS iTRAQ methodology. The results showed an altered expression of 13 ECM proteins of which 3 (biglycan, periostin, prolargin) were validated by Western blotting and/or SRM analyses. These findings are substantiated by our previous results demonstrating differential ECM protein expression. The present study has demonstrated a differential ECM protein pattern in individuals with AS, therefore supporting previous evidence of a dynamic ECM remodeling in human aortic valves during AS development. PMID:26620461

  19. Early molecular changes in irradiated aortic endothelium.

    PubMed

    Gajdusek, C; Onoda, K; London, S; Johnson, M; Morrison, R; Mayberg, M

    2001-07-01

    Irradiated aortic endothelial cells (EC) exhibit distinct morphological, functional, and physiological responses to ionizing radiation (IR). However, the molecular basis for these responses has not been fully characterized. Cultured bovine and rat aortic endothelial cells were exposed to single fraction doses (0-30 Gy) of gamma radiation. IR caused dose-dependent DNA strand breaks which were repaired to near baseline levels within 30 min. A dose-dependent inhibition of cell growth was noted for IR greater than 1 Gy. At doses greater than 2.5 Gy, morphologic changes consistent with apoptosis and loss of cell viability were present beginning 12-16 h after radiation, with subsequent detachment of EC from the cell monolayer. By Western blot analysis, expression of p53, gadd45, p21, and bax protein increased in a time-and dose-dependent manner; p53 expression was maximal at 3 h after IR, and gadd45, bax and p21 levels peaked at 6 h. By Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), levels of p53 mRNA were not significantly increased after IR, whereas gadd45 exhibited time- and dose-dependent increase in mRNA synthesis after IR. Activation of intracellular caspases, manifest by proteolytic poly (ADP-ribose) polymerase (PARP) and lamin B cleavage, was maximal at 15 h after IR, concident with other indices of EC apoptosis, including oligonucleosomal DNA degradation, TUNEL immunostaining, and morphologic changes. The tripeptide protease inhibitor z-Val-Ala-Asp (zVAD) prevented PARP and lamin cleavage, DNA fragmentation, morphological changes, and cell detachment in irradiated EC. The combined data suggested that gamma radiation induces a dose- and time-dependent sequence of early events in cultured EC with modulate growth arrest, apoptosis, and possibly premature senescence in surviving cells.

  20. Mutations in Myosin Light Chain Kinase Cause Familial Aortic Dissections

    PubMed Central

    Wang, Li; Guo, Dong-chuan; Cao, Jiumei; Gong, Limin; Kamm, Kristine E.; Regalado, Ellen; Li, Li; Shete, Sanjay; He, Wei-Qi; Zhu, Min-Sheng; Offermanns, Stephan; Gilchrist, Dawna; Elefteriades, John; Stull, James T.; Milewicz, Dianna M.

    2010-01-01

    Mutations in smooth muscle cell (SMC)-specific isoforms of α-actin and β-myosin heavy chain, two major components of the SMC contractile unit, cause familial thoracic aortic aneurysms leading to acute aortic dissections (FTAAD). To investigate whether mutations in the kinase that controls SMC contractile function (myosin light chain kinase [MYLK]) cause FTAAD, we sequenced MYLK by using DNA from 193 affected probands from unrelated FTAAD families. One nonsense and four missense variants were identified in MYLK and were not present in matched controls. Two variants, p.R1480X (c.4438C>T) and p.S1759P (c.5275T>C), segregated with aortic dissections in two families with a maximum LOD score of 2.1, providing evidence of linkage of these rare variants to the disease (p = 0.0009). Both families demonstrated a similar phenotype characterized by presentation with an acute aortic dissection with little to no enlargement of the aorta. The p.R1480X mutation leads to a truncated protein lacking the kinase and calmodulin binding domains, and p.S1759P alters amino acids in the α-helix of the calmodulin binding sequence, which disrupts kinase binding to calmodulin and reduces kinase activity in vitro. Furthermore, mice with SMC-specific knockdown of Mylk demonstrate altered gene expression and pathology consistent with medial degeneration of the aorta. Thus, genetic and functional studies support the conclusion that heterozygous loss-of-function mutations in MYLK are associated with aortic dissections. PMID:21055718

  1. Development of confocal immunofluorescence FRET microscopy to Investigate eNOS and GSNOR localization and interaction in pulmonary endothelial cells

    NASA Astrophysics Data System (ADS)

    Rehman, Shagufta; Brown-Steinke, Kathleen; Palmer, Lisa; Periasamy, Ammasi

    2015-03-01

    Confocal FRET microscopy is a widely used technique for studying protein-protein interactions in live or fixed cells. Endothelial nitric oxide synthase (eNOS) and S-nitrosoglutathione reductase (GSNOR) are enzymes involved in regulating the bioavailability of S-nitrosothiols (SNOs) in the pulmonary endothelium and have roles in the development of pulmonary arterial hypertension. Labeling of endogenous proteins to better understand a disease process can be challenging. We have used immunofluorescence to detect endogenous eNOS and GSNOR in primary pulmonary endothelial cells to co-localize these proteins as well as to study their interaction by FRET. The challenge has been in selecting the right immunofluorescence labeling condition, right antibody, the right blocking reagent, the right FRET pair and eliminating cross-reactivity of secondary antibodies. We have used Alexa488 and Alexa568 as a FRET pair. After a series of optimizations, the data from Confocal Laser Scanning Microscopy (CLSM) demonstrate co-localization of eNOS and GSNOR in the perinuclear region of the pulmonary endothelial cell primarily within the cis-Golgi with lower levels of co-localization seen within the trans-Golgi. FRET studies demonstrate, for the first time, interaction between eNOS and GSNOR in both murine and bovine pulmonary endothelial cells. Further characterization of eNOSGSNOR interaction and the subcellular location of this interaction will provide mechanistic insight into the importance of S-nitrosothiol signaling in pulmonary biology, physiology and pathology.

  2. Pretreatment with β-Boswellic Acid Improves Blood Stasis Induced Endothelial Dysfunction: Role of eNOS Activation

    PubMed Central

    Wang, Mingming; Chen, Minchun; Ding, Yi; Zhu, Zhihui; Zhang, Yikai; Wei, Peifeng; Wang, Jingwen; Qiao, Yi; Li, Liang; Li, Yuwen; Wen, Aidong

    2015-01-01

    Vascular endothelial cells play an important role in modulating anti-thrombus and maintaining the natural function of vascular by secreting many active substances. β-boswellic acid (β-BA) is an active triterpenoid compound from the extract of boswellia serrate. In this study, it is demonstrated that β-BA ameliorates plasma coagulation parameters, protects endothelium from blood stasis induced injury and prevents blood stasis induced impairment of endothelium-dependent vasodilatation. Moreover, it is found that β-BA significantly increases nitric oxide (NO) and cyclic guanosine 3’, 5’-monophosphate (cGMP) levels in carotid aortas of blood stasis rats. To stimulate blood stasis-like conditions in vitro, human umbilical vein endothelial cells (HUVECs) were exposed to transient oxygen and glucose deprivation (OGD). Treatment of β-BA significantly increased intracellular NO level. Western blot and immunofluorescence as well as immunohistochemistry reveal that β-BA increases phosphorylation of enzyme nitric oxide synthase (eNOS) at Ser1177. In addition, β-BA mediated endothelium-dependent vasodilatation can be markedly blocked by eNOS inhibitor L-NAME in blood stasis rats. In OGD treated HUEVCs, the protective effect of β-BA is attenuated by knockdown of eNOS. In conclusion, the above findings provide convincing evidence for the protective effects of β-BA on blood stasis induced endothelial dysfunction by eNOS signaling pathway. PMID:26482008

  3. Impact of Lifestyle Intervention on HDL-Induced eNOS Activation and Cholesterol Efflux Capacity in Obese Adolescent

    PubMed Central

    Wesnigk, Jenny; De Guchtenaere, Ann; Fischer, Tina; Schuler, Gerhard; Vrints, Christiaan J.

    2016-01-01

    Background. Endothelial dysfunction occurs in obese children and adolescent and is regarded as a key step in the development of atherosclerosis. Important components for the development of endothelial dysfunction are reduced activity of endothelial nitric oxide synthase (eNOS) and an increase in cholesterol deposition in the vessel wall, due to reduced reverse cholesterol transport (RCT) activity. High density lipoprotein (HDL) exhibits antiatherosclerotic properties including modulation of eNOS activity and cholesterol efflux capacity. Lifestyle intervention programs can modify endothelial dysfunction in obese adolescents, but their impact on HDL-mediated eNOS activation and RCT is unknown so far. Methods. Obese adolescents (15 ± 1 years, BMI > 35 kg/m2) where randomized either to an intervention group (IG, n = 8; restricted diet and exercise) or to a usual care group (UC, n = 8). At the beginning and after 10 months of treatment HDL-mediated eNOS phosphorylation and cholesterol efflux capacity were evaluated. Results. Ten months of treatment resulted in a substantial weight loss (−31%), an improvement of endothelial function, and an increase in HDL-mediated eNOS-Ser1177 phosphorylation and RCT. A correlation between change in eNOS-Ser1177 phosphorylation or RCT and change in endothelial function was noted. Conclusion. A structured lifestyle intervention program improves antiatherosclerotic HDL functions, thereby positively influencing endothelial function. PMID:27965912

  4. Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke

    PubMed Central

    Shyu, Hann-Yeh; Chen, Ming-Hua; Hsieh, Yi-Hsien; Shieh, Jia-Ching; Yen, Ling-Rong; Wang, Hsiao-Wei; Cheng, Chun-Wen

    2017-01-01

    Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09–2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16–2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06–2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan. PMID:28346478

  5. Hypertensive Emergency in Aortic Dissection and Thoracic Aortic Aneurysm—A Review of Management

    PubMed Central

    Gupta, Prateek K.; Gupta, Himani; Khoynezhad, Ali

    2009-01-01

    Over the last few decades, treatment for aortic dissection and thoracic aortic aneurysms has evolved significantly with improvement in outcomes. Treatment paradigms include medical, endovascular and surgical options. As aortic dissection presents as a hypertensive emergency, diligent control of BP is of utmost importance in order to reduce the progression of dissection with possible aortic branch malperfusion. Treatment should begin on arrival to the emergency department and continues in the intensive care unit, endovascular suite or the operating room. Novel antihypertensive medications with improved pharmacological profile and improved surgical techniques, have improved the prognosis of patients with aortic aneurysm and/or aortic dissection. Nevertheless, morbidity and mortality remain high and hypertensive emergency poses a significant challenge in aortic dissection and thoracic aortic aneurysms. PMID:27713224

  6. [Surgical technique of aortic valve replacement for small aortic annulus in elderly patients].

    PubMed

    Hata, T; Fujiwara, K; Furukawa, H; Tsushima, Y; Yoshitaka, H; Kuinose, M; Minami, H; Ishida, A; Tamura, K; Totsugawa, T; Kanemitsu, H; Ozawa, M

    2006-04-01

    Recent reports have shown that aortic valve replacement in elderly patients over 65 years with atherosclerotic aortic stenosis and a small aortic annulus is possible by using a small sized bioprosthesis (Carpentier-Edwards pericardial valve). Here we present out surgical technique. Firstly, the native calcified aortic valve was removed completely to gain total exposure of the surrounding aortic root and sinus of Valsalva like Bentall procedure. Secondly, a small sized bioprosthesis was implanted with intermittent noneverting mattress 2-0 sutures with spaghetti and small polytetrafluoroethylene (PTFE) felt. Aortic annulus is the dilated by inserting Hegar dilator sizing from 25 to 27 mm. Therefore, aortic valve replacement for small aortic annulus in intra- or supra-annular position should be easily accomplished. Good surgical results and hemodynamic state were achieved in 25 consecutive cases using this technique.

  7. The Relationship between Tension and Length of the Aortic Adventitia Resected from the Aortic Wall of Acute Aortic Dissection

    PubMed Central

    Kitano, Mitsuru; Teranishi, Hiroo; Kudo, Masahumi; Matsuura, Makoto

    2014-01-01

    Objective: To our knowledge, no previous study has described the measurement of the tensile strength of the human aortic adventitia. In the present study, we examined the relationship between the tension and length of the aortic adventitia resected from the aortic wall of patients with acute aortic dissection. Methods: We obtained rectangular specimens from the aortic adventitia that was resected in patients with acute aortic dissection during surgery. The specimens were placed on a tension meter (Digital Force Gauge FGS-10, SHIMPO, Kyoto, Japan) within 15 min after resection and stretched until they were pulled apart, and the tension and length were recorded. Results: We obtained 18 specimens during surgery from 11 cases of acute aortic dissection. When the specimen was being pulled apart, the mean tension recorded was 10.2 ± 4.9 N/cm specimen width, whereas the mean elongated length recorded was 4.2 ± 1.1 mm/cm specimen length. Discussion: We determined that the aortic adventitia is elastic and expandable up to 140% of its original length. This indicates that dilation of the aorta to >4.2 cm in diameter may result in a rupture if the original aortic diameter prior to dissection was 3 cm. (*English translation of J Jpn Coll Angiol 2013; 53: 77-81) PMID:25298826

  8. Severe Aortic Stenosis Associated with Unicommissural Unicuspid Aortic Valve in a Middle Aged Male

    PubMed Central

    Kwon, Hee-Jin; Kim, Song Soo; Sun, Byung Joo; Jin, Sun Ah; Kim, Jun-Hyung; Lee, Jae-Hwan; Choi, Siwan; Jeong, Jin-Ok; Seong, In-Whan

    2016-01-01

    Unicuspid aortic valve (UAV) is an extremely rare form of congenital aortic valvular abnormality. Although UAV shows similar clinical characteristics to bicuspid aortic valve, the clinical symptoms develop at earlier age and progress at a faster pace in UAV. In this report, we are presenting a 42-year-old male with severe aortic stenosis associated with unicommissural UAV. The patients underwent a successful Bentall operation. PMID:27721957

  9. The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

    PubMed Central

    Gonzalez, Carmen; Rosas-Hernandez, Hector; Jurado-manzano, Brenda; Ramirez-Lee, Manuel Alejandro; Salazar-Garcia, Samuel; Martinez-Cuevas, Pedro Pablo; Velarde-salcedo, Aída Jimena; Morales-Loredo, Humberto; Espinosa-Tanguma, Ricardo; Ali, Syed F; Rubio, Rafael

    2015-01-01

    Aim: Prolactin family hormones include growth hormone, placental lactogen and prolactin, which are able to regulate angiogenesis via NO and prostaglandins. However, their effects on vascular tone are not fully understood. The aim of this study was to evaluate the effects of prolactin family hormones on rat vascular tone in vitro. Methods: Aortic rings were prepared from adult male rats and precontracted with phenylephrine, then treated with the hormones and drugs. The tension was measured with isometric force displacement transducer connected to a polygraph. NO production and prostacyclin release in physiological solution was determined. Cultured rat aortic endothelial cells (RAECs) were treated with the hormones and drugs, and the phosphorylation of eNOS at serine 1177 was assessed using Western bolt analysis. Results: Administration of growth hormone or placental lactogen (0.01–100 nmol/L) induced endothelium-dependent vasodilation. Both the hormones significantly increased the phosphorylation of eNOS in RAECs and NO level in physiological solution. Preincubation with L-NAME blocked growth hormone- or placental lactogen-induced vasodilation and NO production. Preincubation with an antibody against growth hormone receptors blocked growth hormone- and placental lactogen-induced vasodilation. Addition of a single dose of prolactin (0.01 nmol/L) induced sustained vessel relaxation, whereas multiple doses of prolactin induced a biphasic contraction-relaxation effect. The vascular effects of prolactin depended on endothelium. Prolactin significantly increased the level of prostacyclin I2 in physiological solution. Preincubation with indomethacin or an antibody against prolactin receptors blocked prolactin-induced vasodilation. Conclusion: The prolactin family hormones regulate rat vascular tone, selectively promoting either relaxation or contraction of vascular smooth muscle via activation of either growth hormone receptors or prolactin receptors within the

  10. Aortic Stenosis: Pathophysiology, Diagnosis, and Therapy.

    PubMed

    Joseph, Jessica; Naqvi, Syed Yaseen; Giri, Jay; Goldberg, Sheldon

    2017-03-01

    The incidence of aortic stenosis increases with age, affecting up to 10% of the population by the eighth decade. Once symptoms develop, aortic stenosis is rapidly fatal. Proper management requires an understanding of the physiology and criteria used to define disease severity. There is no effective pharmacologic treatment. Surgical aortic valve replacement has been the gold standard treatment for decades. However, over the last 10 years transcatheter aortic valve replacement has emerged as an attractive, less-invasive option for appropriately selected patients. Refinements in valve design and delivery systems have led to widespread use of this breakthrough technology in selected patients. We review the pathophysiology, criteria for valve replacement, and the results of the trials comparing transcatheter aortic valve replacement with surgical aortic valve replacement.

  11. Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension

    PubMed Central

    Zhou, Ning; Lee, Jia-Jye; Stoll, Shaunrick; Ma, Ben; Wiener, Robert; Wang, Charles; Costa, Kevin D.; Qiu, Hongyu

    2017-01-01

    Aims Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway. Methods and results Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame. Conclusions SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness. PMID:28003268

  12. Transcatheter aortic valve replacement for bicuspid aortic stenosis 13years post heart transplant.

    PubMed

    Julien, Maureen B; Desai, Nimesh; Brozena, Susan; Herrmann, Howard C

    2016-12-16

    Despite the widespread use of transcatheter aortic valve replacement (TAVR) for moderate and high-risk patients with severe aortic stenosis, it is utilized less frequently in patients with bicuspid aortic valves (BAV). Orthotopic heart transplant (OHT) donors tend to be younger and may have undiagnosed BAV. We present a case of successful TAVR in a patient with BAV thirteen years after OHT.

  13. Traumatic aortic incompetence following road traffic accident

    PubMed Central

    Irving, J. B.

    1974-01-01

    This case report describes the presentation and treatment of a case of aortic incompetence, resulting from a road traffic accident. The relevant literature is briefly reviewed. Aortic incompetence due to trauma has been described following non-penetrating chest injuries, such as kicks from horses (Barie, 1881), falls from heights and crushing accidents (Kissane, Koons and Clark, 1948; Levine, Roberts and Morrow, 1962). Despite the frequency of road traffic accidents, there have been no recent reports of traumatic aortic valve damage. PMID:4467876

  14. Low-gradient aortic stenosis.

    PubMed

    Clavel, Marie-Annick; Magne, Julien; Pibarot, Philippe

    2016-09-07

    An important proportion of patients with aortic stenosis (AS) have a 'low-gradient' AS, i.e. a small aortic valve area (AVA <1.0 cm(2)) consistent with severe AS but a low mean transvalvular gradient (<40 mmHg) consistent with non-severe AS. The management of this subset of patients is particularly challenging because the AVA-gradient discrepancy raises uncertainty about the actual stenosis severity and thus about the indication for aortic valve replacement (AVR) if the patient has symptoms and/or left ventricular (LV) systolic dysfunction. The most frequent cause of low-gradient (LG) AS is the presence of a low LV outflow state, which may occur with reduced left ventricular ejection fraction (LVEF), i.e. classical low-flow, low-gradient (LF-LG), or preserved LVEF, i.e. paradoxical LF-LG. Furthermore, a substantial proportion of patients with AS may have a normal-flow, low-gradient (NF-LG) AS: i.e. a small AVA-low-gradient combination but with a normal flow. One of the most important clinical challenges in these three categories of patients with LG AS (classical LF-LG, paradoxical LF-LG, and NF-LG) is to differentiate a true-severe AS that generally benefits from AVR vs. a pseudo-severe AS that should be managed conservatively. A low-dose dobutamine stress echocardiography may be used for this purpose in patients with classical LF-LG AS, whereas aortic valve calcium scoring by multi-detector computed tomography is the preferred modality in those with paradoxical LF-LG or NF-LG AS. Although patients with LF-LG severe AS have worse outcomes than those with high-gradient AS following AVR, they nonetheless display an important survival benefit with this intervention. Some studies suggest that transcatheter AVR may be superior to surgical AVR in patients with LF-LG AS.

  15. Cocking of a poppet-disc prosthesis in the aortic position. A cause of intermittent aortic regurgitation.

    PubMed

    Hammer, W J; Hearne, M J; Roberts, W C

    1976-02-01

    Intermittent aortic regurgitation due to cocking is described for the first time after replacement of the aortic valve with a poppet-disc prosthesis. A combination of disc grooving and strut thrombus produced the cocking with resultant aortic regurgitation.

  16. Bacillus licheniformis prosthetic aortic valve endocarditis.

    PubMed Central

    Santini, F; Borghetti, V; Amalfitano, G; Mazzucco, A

    1995-01-01

    A 73-year old man developed an acute prosthetic aortic valve dehiscence for which emergent operation was undertaken. The intraoperative evidence of an aortic annular disruption and of a subannular abscess led to the hypothesis that an endocarditis process was involved. The aortic valve was replaced with a stentless porcine bioprosthesis. Cultures taken intraoperatively from the aortic area had a pure growth of aerobic, spore-forming, gram-positive bacilli identified as Bacillus licheniformis. The patient responded to specific antibiotic therapy with no relapse at a 20-month follow-up. The potentiality of B. licheniformis as a pathogen should be reconsidered. PMID:8576381

  17. Aortic Aneurysm: Etiopathogenesis and Clinicopathologic Correlations

    PubMed Central

    2016-01-01

    Aortic aneurysm (AA) is one of the life-threatening aortic diseases, leading to aortic rupture of any cause including atherosclerotic and non-atherosclerotic diseases. AA is diagnosed in a variable proportion of patients with dilated aorta by imaging modality. The etiopathogenesis of AA remains unclear in many aortic diseases. Furthermore, although it may be difficult to explain all phenotypes of patients even if genetic mutation could be identified in some proteins such as smooth muscle cell α-actin (ACTA2), myosin heavy chain 11 (MYH11) or SMAD3, individualized consideration of these factors in each patient is essential on the basis of clinicopathological characteristics. PMID:27375798

  18. Hypoplasia of the aortic root 1

    PubMed Central

    Nicks, Rowan; Cartmill, T.; Bernstein, L.

    1970-01-01

    We report a technique for the enlargement of a hypoplastic aortic root by an operation whereby the hypoplastic aortic root has been so enlarged by the insertion of a Dacron fabric gusset that it will accommodate a size 9A or larger Starr-Edwards prosthesis. Our experience in five patients is described. No matter what type of valve is used for replacement of a diseased aortic valve, and no matter what improved designs of valvular prosthesis are ultimately developed, it will be necessary (in the particular group described) to enlarge the aortic ring to accommodate a size which will function correctly without causing left ventricular outflow obstruction. Images PMID:5452289

  19. Aortic dilatation in children with systemic hypertension.

    PubMed

    Gupta-Malhotra, Monesha; Devereux, Richard B; Dave, Archana; Bell, Cynthia; Portman, Ronald; Milewicz, Diana

    2014-04-01

    The aim of the study was to determine the presence of aortic dilatation in hypertensive children, the prevalence of which is 4% to 10% in hypertensive adults. Prospectively enrolled multiethnic children, untreated for their hypertension, underwent an echocardiogram to exclude congenital heart disease and evaluate for end-organ damage and aortic size. The aorta was measured in the parasternal long-axis view at three levels: the sinus of Valsalva, supra-tubular junction, and the ascending aorta. Aortic dilatation was determined by z-score >2 at any one of the levels measured. Hypertension was defined as blood pressure above the 95th percentile based on the Fourth Working Group criteria confirmed by 24-hour ambulatory blood pressure monitoring. Among 142 consecutive hypertensive children (median age, 14 years; 45% females) aortic dilatation was detected in 2.8% (95% confidence interval, 1%-7%; median age, 16 years; 100% females). Children with aortic dilatation, when compared with those without, had significantly more aortic valve insufficiency (P = .005) and left ventricular hypertrophy (P = .018). Prevalence of aortic dilatation was 2.8% and was associated with significantly more aortic insufficiency and left ventricular hypertrophy in comparison to those without aortic dilatation.

  20. Aortic Dilatation in Children with Systemic Hypertension

    PubMed Central

    Gupta-Malhotra, Monesha; Devereux, Richard B.; Dave, Archana; Bell, Cynthia; Portman, Ronald; Milewicz, Diana

    2014-01-01

    Background The aim of the study was to determine presence of aortic dilatation in hypertensive children, the prevalence of which is 4–10% in hypertensive adults. Methods Prospectively enrolled multiethnic children untreated for their hypertension, underwent an echocardiogram to exclude congenital heart disease and evaluate for end-organ damage and aortic size. The aorta was measured in the parasternal long-axis view at 3 levels: the sinus of Valsalva, supra-tubular junction and the ascending aorta. Aortic dilatation was determined by z-score > 2 at any 1 of the levels measured. Hypertension was defined as blood pressure above the 95th percentile based on the Fourth Working Group criteria confirmed by 24-hour ambulatory blood pressure monitoring. Results Among 142 consecutive hypertensive children (median age 14 years, 45% females) aortic dilatation was detected in 2.8% (95% CI 1% to 7%, median age 16 years, 100% females). Children with aortic dilatation, when compared to those without, had significantly more aortic valve insufficiency (p = 0.005) and left ventricular hypertrophy (p = 0.018). Conclusions Prevalence of aortic dilatation was 2.8% and was associated with significantly more aortic insufficiency and left ventricular hypertrophy in comparison to those without aortic dilatation. PMID:24507486

  1. Aortic Stenosis: Changing Disease Concepts

    PubMed Central

    Rashedi, Nina

    2015-01-01

    Aortic stenosis (AS) occurs in almost 10% of adults over age 80 years with a mortality about 50% at 2 years unless outflow obstruction is relieved by aortic valve replacement (AVR). Development of AS is associated with anatomic, clinical and genetic risk factors including a bicuspid valve in 50%; clinical factors that include older age, hypertension, smoking, diabetes and elevated serum lipoprotein(a) [Lp(a)] levels; and genetic factors such as a polymorphism in the Lp(a) locus. Early stages of AS are characterized by focal areas of leaflet thickening and calcification. The rate of hemodynamic progression is variable but eventual severe AS is inevitable once even mild valve obstruction is present. There is no specific medical therapy to prevent leaflet calcification. Basic principles of medical therapy for asymptomatic AS are patient education, periodic echocardiographic and clinical monitoring, standard cardiac risk factor evaluation and modification and treatment of hypertension or other comorbid conditions. When severe AS is present, a careful evaluation for symptoms is needed, often with an exercise test to document symptom status and cardiac reserve. In symptomatic patients with severe AS, AVR improves survival and relieves symptoms. In asymptomatic patients with severe AS, AVR also is appropriate if ejection fraction is < 50%, disease progression is rapid or AS is very severe (aortic velocity > 5 m/s). The choice of surgical or transcatheter AVR depends on the estimated surgical risk plus other factors such as frailty, other organ system disease and procedural specific impediments. PMID:26140146

  2. Development of the human aortic arch system captured in an interactive three-dimensional reference model.

    PubMed

    Rana, M Sameer; Sizarov, Aleksander; Christoffels, Vincent M; Moorman, Antoon F M

    2014-06-01

    Variations and mutations in the human genome, such as 22q11.2 microdeletion, can increase the risk for congenital defects, including aortic arch malformations. Animal models are increasingly expanding our molecular and genetic insights into aortic arch development. However, in order to justify animal-to-human extrapolations, a human morphological, and molecular reference model would be of great value, but is currently lacking. Here, we present interactive three-dimensional reconstructions of the developing human aortic arch system, supplemented with the protein distribution of developmental markers for patterning and growth, including T-box transcription factor TBX1, a major candidate for the phenotypes found in patients with the 22q11.2 microdeletion. These reconstructions and expression data facilitate unbiased interpretations, and reveal previously unappreciated aspects of human aortic arch development. Based on our reconstructions and on reported congenital anomalies of the pulmonary trunk and tributaries, we postulate that the pulmonary arteries originate from the aortic sac, rather than from the sixth pharyngeal arch arteries. Similar to mouse, TBX1 is expressed in pharyngeal mesenchyme and epithelia. The endothelium of the pharyngeal arch arteries is largely negative for TBX1 and family member TBX2 but expresses neural crest marker AP2α, which gradually decreases with ongoing development of vascular smooth muscle. At early stages, the pharyngeal arch arteries, aortic sac, and the dorsal aortae in particular were largely negative for proliferation marker Ki67, potentially an important parameter during aortic arch system remodeling. Together, our data support current animal-to-human extrapolations and future genetic and molecular analyses using animal models of congenital heart disease. © 2013 Wiley Periodicals, Inc.

  3. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease

    PubMed Central

    Bosse, Authors: Kevin; Hans, Chetan P.; Zhao, Ning; Koenig, Sara N.; Huang, Nianyuan; Guggilam, Anuradha; LaHaye, Stephanie; Tao, Ge; Lucchesi, Pamela A.; Lincoln, Joy; Lilly, Brenda; Garg, Vidu

    2013-01-01

    The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease. PMID:23583836

  4. Aortic valve replacement for aortic stenosis with a small aortic annulus in a patient having Werner's syndrome and liver cirrhosis.

    PubMed

    Sogawa, M; Kasuya, S; Yamamoto, K; Koshika, M; Oguma, F; Hayashi, J

    2001-12-01

    Werner's syndrome is a rare genetic disease characterized by premature aging and scleroderma-like involvement of the skin. We report a case of aortic valve replacement for severely calcified aortic valve stenosis with a small annulus in a patient suffering from Werner's syndrome and liver cirrhosis

  5. Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

    PubMed Central

    Cooper, Leroy L.; Mitchell, Gary F.

    2016-01-01

    Background Aortic stiffness is associated with cardiovascular and cerebrovascular events and cognitive decline. This mini-review focuses on relations of aortic stiffness with microvascular dysfunction and discusses the contribution of abnormal pulsatile hemodynamics to cerebrovascular damage and cognitive decline. We also provide a rationale for considering aortic stiffness as a putative and important contributor to memory impairment in older individuals. Summary Aging is associated with stiffening of the aorta but not the muscular arteries, which reduces wave reflection and increases the transmission of pulsatility into the periphery. Aortic stiffening thereby impairs a protective mechanism that shields the peripheral microcirculation from excessive pulsatility within downstream target organs. Beyond midlife, aortic stiffness increases rapidly and exposes the cerebral microcirculation to abnormal pulsatile mechanical forces that are associated with microvascular damage and remodeling in the brain. Aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain; however, a mechanistic link between aortic stiffness and memory has not been established. We showed that in a community-based sample of older individuals, cerebrovascular resistance and white matter hyperintensities - markers of cerebrovascular remodeling and damage - mediated the relation between higher aortic stiffness and lower performance on memory function tests. These data suggest that microvascular and white matter damage associated with excessive aortic stiffness contribute to impaired memory function with advancing age. Key Messages Increasing evidence suggests that vascular etiologies - including aortic stiffness and microvascular damage - contribute to memory impairment and the pathogenesis of dementia, including Alzheimer's disease. Interventions that reduce aortic stiffness may delay memory decline among older individuals. PMID:27752478

  6. [Unicuspid Aortic Valve Stenosis Combined with Aortic Coarctation;Report of a Case].

    PubMed

    Kubota, Takehiro; Wakasa, Satoru; Shingu, Yasushige; Matsui, Yoshiro

    2016-06-01

    Unicuspid aortic valve in an adult is extremely rare. In addition, 90% of the patients with aortic coarctation are reported to die before the age 50. A 60-year-old woman was admitted to our hospital for further examination of exertional dyspnea which had begun one year before. She had been under medical treatment for hypertension since early thirties, and had been also diagnosed with moderate aortic stenosis at 50 years of age. She was at 1st diagnosed with aortic coarctation combined with bicuspid aortic valve stenosis. The aortic valve was then found unicuspid and was replaced under cardiopulmonary bypass with perfusion to both the ascending aorta and the femoral artery. Repair of aortic coarctation was performed 3 months later through left thoracotomy without extracorporeal circulation due to the rich collateral circulation. She had no postoperative complications, and hypertension as well as ankle-brachial index improved to the normal levels.

  7. Aortic annuloplasty with aortic root reconstruction to prevent patient-prosthesis mismatch.

    PubMed

    Hopkins, Richard A

    2006-07-01

    Part of the ongoing argument concerning patient-prosthesis mismatch (PPM) following aortic valve replacement (AVR) is due to the perception that aortic annulus enlargement procedures increase the risk and technical difficulty of aortic valve surgery. Here, an aortic root reconstruction that involves enlargement of the annulus and tailoring of the aortic root to accommodate larger stented prostheses is presented that has been personally performed in 196 patients with no technique-related surgical deaths or complications, and thus can be carried out without additional risk. This aortic root enlargement aortoplasty and annuloplasty method can be calibrated to all AVRs involving stented manufactured prostheses when these are deemed the prosthesis of choice for the patient with a relatively small annulus and/or aortic root, severe left ventricular hypertrophy, compromised LV function or a very active lifestyle, to achieve predicted EOA values > or = 1.00 cm2/m2.

  8. Mitral and aortic regurgitation following transcatheter aortic valve replacement

    PubMed Central

    Szymański, Piotr; Hryniewiecki, Tomasz; Dąbrowski, Maciej; Sorysz, Danuta; Kochman, Janusz; Jastrzębski, Jan; Kukulski, Tomasz; Zembala, Marian

    2016-01-01

    Objective To analyse the impact of postprocedural mitral regurgitation (MR), in an interaction with aortic regurgitation (AR), on mortality following transcatheter aortic valve implantation (TAVI). Methods To assess the interaction between MR and AR, we compared the survival rate of patients (i) without both significant MR and AR versus (ii) those with either significant MR or significant AR versus (iii) with significant MR and AR, all postprocedure. 381 participants of the Polish Transcatheter Aortic Valve Implantation Registry (166 males (43.6%) and 215 females (56.4%), age 78.8±7.4 years) were analysed. Follow-up was 94.1±96.5 days. Results Inhospital and midterm mortality were 6.6% and 10.2%, respectively. Significant MR and AR were present in 16% and 8.1% patients, including 3.1% patients with both significant MR and AR. Patients with significant versus insignificant AR differed with respect to mortality (log rank p=0.009). This difference was not apparent in a subgroup of patients without significant MR (log rank p=0.80). In a subgroup of patients without significant AR, there were no significant differences in mortality between individuals with versus without significant MR (log rank p=0.44). Significant MR and AR had a significant impact on mortality only when associated with each other (log rank p<0.0001). At multivariate Cox regression modelling concomitant significant MR and AR were independently associated with mortality (OR 3.2, 95% CI 1.54 to 5.71, p=0.002). Conclusions Significant MR or AR postprocedure, when isolated, had no impact on survival. Combined MR and AR had a significant impact on a patient's prognosis. PMID:26908096

  9. Relative Reduction of Endothelial Nitric-Oxide Synthase Expression and Transcription in Atherosclerosis-Prone Regions of the Mouse Aorta and in an in Vitro Model of Disturbed Flow

    PubMed Central

    Won, Doyon; Zhu, Su-Ning; Chen, Mian; Teichert, Anouk-Martine; Fish, Jason E.; Matouk, Charles C.; Bonert, Michael; Ojha, Matadial; Marsden, Philip A.; Cybulsky, Myron I.

    2007-01-01

    Atherosclerosis develops in distinct regions of the arterial tree. Defining patterns and mechanisms of endothelial cell gene expression in different regions of normal arteries is key to understanding the initial molecular events in atherogenesis. In this study, we demonstrated that the expression of endothelial nitric-oxide synthase (eNOS), an atheroprotective gene, and its phosphorylation on Ser1177, a marker of activity, were lower in regions of the normal mouse aorta that are predisposed to atherosclerosis. The same expression pattern was observed in mouse strains that are both susceptible and resistant to atherosclerosis, and the topography of eNOS expression was inverse to p65, the main nuclear factor-κB subunit. Modeling of disturbed and uniform laminar flow in vitro reproduced the expression patterns of eNOS and p65 that were found in vivo. Heterogeneous nuclear RNA expression and RNA polymerase II chromosome immunoprecipitation studies demonstrated that regulation of transcription contributed to increased eNOS expression in response to shear stress. In vivo, the transcription of eNOS was reduced in regions of the mouse aorta predisposed to atherosclerosis, as defined by reporter gene expression in eNOS promoter-β-galactosidase reporter transgenic mice. These data suggest that disturbed hemodynamic patterns found at arterial branches and curvatures uniquely modulate endothelial cell gene expression by regulating transcription, potentially explaining why these regions preferentially develop atherosclerosis when risk factors such as hypercholesterolemia are introduced. PMID:17982133

  10. Recent advances in aortic valve replacement for aortic stenosis

    PubMed Central

    Al-Adhami, Ahmed; Al-Attar, Nawwar

    2016-01-01

    Aortic valve replacement is no longer an operation that is approached solely through a median sternotomy. Recent advances in the fields of transcatheter valves have expanded the proportion of patients eligible for intervention. Comparisons between transcatheter valves and conventional surgery have shown non-inferiority of transcatheter valve implants in patients with a high or intermediate pre-operative predictive risk. With advances in our understanding of sutureless valves and their applicability to minimally invasive surgery, the invasiveness and trauma of surgery can be reduced with potential improvements in outcome. The strategy of care has radically changed over the last decade. PMID:27803800

  11. Biomechanical characterization of ascending aortic aneurysm with concomitant bicuspid aortic valve and bovine aortic arch.

    PubMed

    Pham, T; Martin, C; Elefteriades, J; Sun, W

    2013-08-01

    Studies have shown that patients harboring bicuspid aortic valve (BAV) or bovine aortic arch (BAA) are more likely than the general population to develop ascending aortic aneurysm (AsAA). A thorough quantification of the AsAA tissue properties for these patient groups may offer insights into the underlying mechanisms of AsAA development. Thus, the objective of this study was to investigate and compare the mechanical and microstructural properties of aortic tissues from AsAA patients with and without concomitant BAV or BAA. AsAA (n=20), BAV (n=20) and BAA (n=15) human tissues were obtained from patients who underwent elective AsAA surgery. Planar biaxial and uniaxial failure tests were used to characterize the mechanical and failure properties of the tissues, respectively. Histological analysis was performed to detect medial degenerative characteristics of aortic aneurysm. Individual layer thickness and composition were quantified for each patient group. The circumferential stress-strain response of the BAV samples was stiffer than both AsAA (p=0.473) and BAA (p=0.152) tissues at a low load. The BAV samples were nearly isotropic, while AsAA and BAA samples were anisotropic. The areal strain of BAV samples was significantly less than that of AsAA (p=0.041) and BAA (p=0.004) samples at a low load. The BAA samples were similar to the AsAA samples in both mechanical and failure properties. On the microstructural level, all samples displayed moderate medial degeneration, characterized by elastin fragmentation, cell loss, mucoid accumulation and fibrosis. The ultimate tensile strength of BAV and BAA sampleswere also found to decrease with age. Overall, the BAV samples were stiffer than both AsAA and BAA samples, and the BAA samples were similar to the AsAA samples. The BAV samples were thinnest, with less elastin than AsAA and BAA samples, which may be attributed to the loss of extensibility of these tissues at a low load. No apparent difference in failure mechanics among

  12. Aortic Valve Calcification in Mild Primary Hyperparathyroidism

    PubMed Central

    Iwata, Shinichi; Walker, Marcella Donovan; Di Tullio, Marco R.; Hyodo, Eiichi; Jin, Zhezhen; Liu, Rui; Sacco, Ralph L.; Homma, Shunichi

    2012-01-01

    Context: It is unclear whether cardiovascular disease is present in primary hyperparathyroidism (PHPT). Objective: Aortic valve structure and function were compared in PHPT patients and population-based controls. Design: This is a case-control study. Setting: The study was conducted in a university hospital metabolic bone disease unit. Participants: We studied 51 patients with PHPT and 49 controls. Outcome Measures: We measured the aortic valve calcification area and the transaortic pressure gradient. Results: Aortic valve calcification area was significantly higher in PHPT (0.24 ± 0.02 vs. 0.17 ± 0.02 cm2, p<0.01), although there was no difference in the peak transaortic pressure gradient, a functional measure of valvular calcification (5.6 ± 0.3 vs. 6.0 ± 0.3 mm Hg, P = 0.39). Aortic valve calcification area was positively associated with PTH (r = 0.34; P < 0.05) but not with serum calcium, phosphorus, or 25-hydroxyvitamin D levels or with calcium-phosphate product. Serum PTH level remained an independent predictor of aortic valve calcification area after adjustment for age, sex, body mass index, smoking status, history of hypercholesterolemia and hypertension, and estimated glomerular filtration rate. Conclusions: Mild PHPT is associated with subclinical aortic valve calcification. PTH, but not serum calcium concentration, predicted aortic valve calcification. PTH was a more important predictor of aortic valve calcification than well-accepted cardiovascular risk factors. PMID:22031523

  13. Endovascular approach to acute aortic trauma

    PubMed Central

    Karmy-Jones, Riyad; Teso, Desarom; Jackson, Nicole; Ferigno, Lisa; Bloch, Robert

    2009-01-01

    Traumatic thoracic aortic injury remains a major cause of death following motor vehicle accidents. Endovascular approaches have begun to supersede open repair, offering the hope of reduced morbidity and mortality. The available endovascular technology is associated with specific anatomic considerations and complications. This paper will review the current status of endovascular management of traumatic thoracic aortic injuries. PMID:21160721

  14. [Acute aortic syndromes and sleep apnea].

    PubMed

    Baguet, Jean-Philippe

    2016-10-01

    Obstructive sleep apnea (OSA) is a common disease, often present in "cardiovascular or metabolic patients". OSA favours the occurrence of arterial lesions, all the more if severe. There is a strong relationship between OSA and acute aortic syndromes (AAS). This relationship is in part explained by aortic dilatation linked to OSA. The presence of repeated episodes of sudden variation of transmural pressure applied on aortic wall seems to play a major role in this dilatation. All OSA patients should have a search of aortic dilatation by ultrasound (at a thoracic and abdominal level). Also, screening of OSA should be systematically performed in patients with aortic disease. The effect of continuous positive airway pressure in apneic patients with AAS has not been studied.

  15. Valvular and aortic diseases in osteogenesis imperfecta.

    PubMed

    Lamanna, Arvin; Fayers, Trevor; Clarke, Sophie; Parsonage, William

    2013-10-01

    Osteogenesis imperfecta (OI) is an inheritable connective tissue disorder caused by defective collagen synthesis with the principal manifestations of bone fragility. OI has been associated with left sided valvular regurgitation and aortic dilation. Valve and aortic surgery are technically feasible in patients with OI but are inherently high risk due to the underlying connective tissue defect. This report reviews the valvular and aortic pathology associated with OI and their management. We describe two cases of patients with OI who have significant aortic and mitral valve regurgitation, one of whom has been managed conservatively and the other who has undergone successful mitral valve repair and aortic valve replacement. The latter case represents the fifth case of mitral valve repair in a patient with OI reported in the medical literature.

  16. Genetic risk factors for arterial ischemic stroke in children: a possible MTHFR and eNOS gene-gene interplay?

    PubMed

    Djordjevic, Valentina; Stankovic, Marija; Brankovic-Sreckovic, Vesna; Rakicevic, Ljiljana; Radojkovic, Dragica

    2009-07-01

    In order to investigate the influence of genetic factors in childhood stroke, we compared the distributions of mutations/ polymorphisms affecting hemostasis and/or endothelial function (factor V [FV] Leiden, factor II [FII] G20210A, methylenetetrahydrofolate reductase [MTHFR] C677T, angiotensin-converting enzyme [ACE] insertion/deletion [ID], and endothelial nitric oxide synthase [eNOS] G894T) among children with stroke and controls. A total number of 26 children with arterial ischemic stroke and a control group of 50 healthy children were included in the study. No statistically significant differences in allelic and genotypic distribution were detected in comparisons between groups. However, when combined genotypes were analyzed, statistical significance was observed for the association of MTHFR CT and eNOS TT gene variants. The results of our study suggest that this genotype combination represents a risk factor of 7.2 (P = .017) for arterial ischemic stroke in children.

  17. [Modern aortic surgery in Marfan syndrome--2011].

    PubMed

    Kallenbach, K; Schwill, S; Karck, M

    2011-09-01

    Marfan syndrome is a hereditary disease with a prevalence of 2-3 in 10,000 births, leading to a fibrillin connective tissue disorder with manifestations in the skeleton, eye, skin, dura mater and in particular the cardiovascular system. Since other syndromes demonstrate similar vascular manifestations, but therapy may differ significantly, diagnosis should be established using the revised Ghent nosology in combination with genotypic analysis in specialized Marfan centres. The formation of aortic root aneurysms with the subsequent risk of acute aortic dissection type A (AADA) or aortic rupture limits life expectancy in patients with Marfan syndrome. Therefore, prophylactic replacement of the aortic root needs to be performed before the catastrophic event of AADA can occur. The goal of surgery is the complete resection of pathological aortic tissue. This can be achieved with excellent results by using a (mechanically) valved conduit that replaces both the aortic valve and the aortic root (Bentall operation). However, the need for lifelong anticoagulation with Coumadin can be avoided using the aortic valve sparing reimplantation technique according to David. The long-term durability of the reconstructed valve is favourable, and further technical improvements may improve longevity. Although results of prospective randomised long-term studies comparing surgical techniques are lacking, the David operation has become the surgical method of choice for aortic root aneurysms, not only at the Heidelberg Marfan Centre. Replacement of the aneurysmal dilated aortic arch is performed under moderate hypothermic circulatory arrest combined with antegrade cerebral perfusion using a heart-lung machine, which we also use in thoracic or thoracoabdominal aneurysms. Close post-operative follow-up in a Marfan centre is pivotal for the early detection of pathological changes on the diseased aorta.

  18. Diagnostic imaging for aortic dissection.

    PubMed

    Kapustin, Andrew J; Litt, Harold I

    2005-01-01

    Diagnostic imaging for aortic dissection has dramatically changed in recent years. Previously, imaging consisted of conventional X-ray radiography, followed by invasive catheter angiography. Now imaging of dissection is performed primarily with multidetector CT, and to a lesser extent, with ultrasound and MRI. Catheter angiography is used primarily as a means of treating complications. Which modality to choose depends on patient factors, physician preference, and differences in availability of state-of-the-art equipment. All three modalities are highly accurate in experienced hands and have revolutionized the detection and evaluation of this condition.

  19. Abdominal Aortic Surgery: Anesthetic Implications

    PubMed Central

    Cunningham, Anthony J.

    1991-01-01

    The objectives of the review are to highlight the clinical characteristics of the patient population; to assess multivariate risk factor analysis and the invasive/non-invasive techniques available for risk factor identification and management in this high-risk surgical population; to assess the major hemodynamic, metabolic, and regional blood flow changes associated with aortic cross-clamping/unclamping procedures and techniques for their modification or attenuation; and to assess the influence of perioperative anesthetic techniques and management on patient outcome. PMID:1814052

  20. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells.

    PubMed

    Fleming, Ingrid; Fisslthaler, Beate; Dixit, Madhulika; Busse, Rudi

    2005-09-15

    The application of fluid shear stress to endothelial cells elicits the formation of nitric oxide (NO) and phosphorylation of the endothelial NO synthase (eNOS). Shear stress also elicits the enhanced tyrosine phosphorylation of endothelial proteins, especially of those situated in the vicinity of cell-cell contacts. Since a major constituent of these endothelial cell-cell contacts is the platelet endothelial cell adhesion molecule-1 (PECAM-1) we assessed the role of PECAM-1 in the activation of eNOS. In human endothelial cells, shear stress induced the tyrosine phosphorylation of PECAM-1 and enhanced the association of PECAM-1 with eNOS. Endothelial cell stimulation with shear stress elicited the phosphorylation of Akt and eNOS as well as of the AMP-activated protein kinase (AMPK). While the shear-stress-induced tyrosine phosphorylation of PECAM-1 as well as the serine phosphorylation of Akt and eNOS were abolished by the pre-treatment of cells with the tyrosine kinase inhibitor PP1 the phosphorylation of AMPK was unaffected. Down-regulation of PECAM-1 using a siRNA approach attenuated the shear-stress-induced phosphorylation of Akt and eNOS, as well as the shear-stress-induced accumulation of cyclic GMP levels while the shear-stress-induced phosphorylation of AMPK remained intact. A comparable attenuation of Akt and eNOS (but not AMPK) phosphorylation and NO production was also observed in endothelial cells generated from PECAM-1-deficient mice. These data indicate that the shear-stress-induced activation of Akt and eNOS in endothelial cells is modulated by the tyrosine phosphorylation of PECAM-1 whereas the shear-stress-induced phosphorylation of AMPK is controlled by an alternative signaling pathway.

  1. Role of Cardiac CT Before Transcatheter Aortic Valve Implantation (TAVI).

    PubMed

    Marwan, Mohamed; Achenbach, Stephan

    2016-02-01

    Catheter-based aortic valve implantation is increasingly being performed in high-risk patients with symptomatic aortic valve stenosis. For successful planning of the procedure, CT has been shown to provide crucial information concerning the aortic root as well as the peripheral access vessels. This article illustrates the increasing role of CT before transcatheter aortic valve implantation.

  2. Improved technique of transapical aortic valve implantation: "the Berlin addition".

    PubMed

    Pasic, Miralem; Dreysse, Stephan; Drews, Thorsten; Buz, Semih; Unbehaun, Axel; Kukucka, Marian; Mladenow, Alexandar; Hetzer, Roland

    2010-06-01

    Transapical aortic valve implantation carries some degree of uncertainty regarding the definitive valve position. We added angiographic visualization of the aortic root while the prosthetic valve is being slowly deployed. It enables easy correction of the position of the valve so that perfect alignment can be achieved of the relationships between the prosthetic valve, aortic valve annulus, aortic cusps, and the coronary arteries.

  3. Nontraumatic avulsion of aortic valve commissure as a cause of acute aortic valve regurgitation

    PubMed Central

    Chang, Rei-Yeuh; Chen, Chien-Chang; Hsu, Wei-Pang; Hsiao, Pei-Ching; Tsai, Han-Lin; Hsiao, Ping-Gune; Wu, Jiann-Der; Guo, How-Ran

    2016-01-01

    Abstract Background: Avulsion of the aortic valve commissure as a cause of acute aortic valve regurgitation is mostly due to trauma, infective endocarditis, or ascending aortic dissection. Nontraumatic avulsion of the aortic valve commissure is very rare. We reviewed the literature and analyzed potential risk factors of nontraumatic avulsion. Case presentation: An 80-year-old male with hypertension was seen in the emergency department with acute onset dyspnea. Echocardiogram revealed left ventricular hypertrophy with adequate systolic function, prolapse of the noncoronary cusp, and incomplete coaptation of the right coronary and noncoronary cusps with severe aortic valve regurgitation. Surgery revealed an avulsion between the left coronary and noncoronary cusps. Histopathology examination of the aortic valve showed myxoid degeneration, fibrosis, and calcification. Examination of the ascending aorta revealed myxoid degeneration and fragmentation of elastic fibers. Aortic valve replacement was performed, and the patient was alive and well 4 years after surgery. A review of the literature showed that more than three-fourths of the similar cases occurred in males, and about half in patients with hypertension and those 60 years of age or older. Conclusions: In the case of acute aortic regurgitation without a history of trauma, infection, or valvotomy, when 2 prolapsed aortic cusps are observed by echocardiography in the absence of an intimal tear of the ascending aorta, an avulsion of the aortic commissure should be suspected, especially in males with hypertension who are 60 years of age or older. PMID:27749570

  4. AB222. Enolase1 (ENO1) and glucose-6-phosphate isomerase (GPI) are good markers to predict human sperm freezability

    PubMed Central

    Jiang, Xuping; Wang, Shangqian; Wang, Wei; Xu, Yang; Sun, Hongyong; Wang, Zengjun; Zhang, Wei

    2016-01-01

    Objective Sperm cryopreservation is a method to preserve sperm samples for a long period. However, the fertility of sperm decreases markedly after freezing and thawing in a certain amount of samples. The aim of the present study was to find useful and reliable predictive biomarkers of the capacity to withstand the freeze-thawing process in human ejaculates. Methods We chose the two proteins as probable markers of sperm freezing capacity. Ejaculate samples were separated into good freezability ejaculates (GFE) and poor freezability ejaculates (PFE) according to progressive motility of the sperm after thawing. Before starting cryopreservation protocols, the two proteins from each group were compared using western blot analysis and immunofluorescence. Results Results showed that normalized content of enolase1 (ENO1) (P<0.05) and glucose-6-phosphate isomerase (GPI) (P<0.01) were both significantly higher in GFE than in PFE. The association of ENO1 and GPI with post thaw sperm viability and motility was confirmed using Pearson’s linear correlation. Conclusions In conclusion, ENO1 and GPI can be used as markers of human sperm freezability before starting the cryopreservation procedure.

  5. 3D Bioprinting of Heterogeneous Aortic Valve Conduits with Alginate/Gelatin Hydrogels

    PubMed Central

    Duan, Bin; Hockaday, Laura A.; Kang, Kevin H.; Butcher, Jonathan T.

    2013-01-01

    Heart valve disease is a serious and growing public health problem for which prosthetic replacement is most commonly indicated. Current prosthetic devices are inadequate for younger adults and growing children. Tissue engineered living aortic valve conduits have potential for remodeling, regeneration, and growth, but fabricating natural anatomical complexity with cellular heterogeneity remain challenging. In the current study, we implement 3D bioprinting to fabricate living alginate/gelatin hydrogel valve conduits with anatomical architecture and direct incorporation of dual cell types in a regionally constrained manner. Encapsulated aortic root sinus smooth muscle cells (SMC) and aortic valve leaflet interstitial cells (VIC) were viable within alginate/gelatin hydrogel discs over 7 days in culture. Acellular 3D printed hydrogels exhibited reduced modulus, ultimate strength, and peak strain reducing slightly over 7-day culture, while the tensile biomechanics of cell-laden hydrogels were maintained. Aortic valve conduits were successfully bioprinted with direct encapsulation of SMC in the valve root and VIC in the leaflets. Both cell types were viable (81.4±3.4% for SMC and 83.2±4.0% for VIC) within 3D printed tissues. Encapsulated SMC expressed elevated alpha-smooth muscle actin when printed in stiff matrix, while VIC expressed elevated vimentin in soft matrix. These results demonstrate that anatomically complex, heterogeneously encapsulated aortic valve hydrogel conduits can be fabricated with 3D bioprinting. PMID:23015540

  6. Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?

    PubMed

    Gao, Yuan Z; Saphirstein, Robert J; Yamin, Rina; Suki, Bela; Morgan, Kathleen G

    2014-10-15

    Increased aortic stiffness is an early and independent biomarker of cardiovascular disease. Here we tested the hypothesis that vascular smooth muscle cells (VSMCs) contribute significantly to aortic stiffness and investigated the mechanisms involved. The relative contributions of VSMCs, focal adhesions (FAs), and matrix to stiffness in mouse aorta preparations at optimal length and with confirmed VSMC viability were separated by the use of small-molecule inhibitors and activators. Using biomechanical methods designed for minimal perturbation of cellular function, we directly quantified changes with aging in aortic material stiffness. An alpha adrenoceptor agonist, in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME) to remove interference of endothelial nitric oxide, increases stiffness by 90-200% from baseline in both young and old mice. Interestingly, increases are robustly suppressed by the Src kinase inhibitor PP2 in young but not old mice. Phosphotyrosine screening revealed, with aging, a biochemical signature of markedly impaired agonist-induced FA remodeling previously associated with Src signaling. Protein expression measurement confirmed a decrease in Src expression with aging. Thus we report here an additive model for the in vitro biomechanical components of the mouse aortic wall in which 1) VSMCs are a surprisingly large component of aortic stiffness at physiological lengths and 2) regulation of the VSMC component through FA signaling and hence plasticity is impaired with aging, diminishing the aorta's normal shock absorption function in response to stressors.

  7. Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?

    PubMed Central

    Gao, Yuan Z.; Saphirstein, Robert J.; Yamin, Rina; Suki, Bela

    2014-01-01

    Increased aortic stiffness is an early and independent biomarker of cardiovascular disease. Here we tested the hypothesis that vascular smooth muscle cells (VSMCs) contribute significantly to aortic stiffness and investigated the mechanisms involved. The relative contributions of VSMCs, focal adhesions (FAs), and matrix to stiffness in mouse aorta preparations at optimal length and with confirmed VSMC viability were separated by the use of small-molecule inhibitors and activators. Using biomechanical methods designed for minimal perturbation of cellular function, we directly quantified changes with aging in aortic material stiffness. An alpha adrenoceptor agonist, in the presence of NG-nitro-l-arginine methyl ester (l-NAME) to remove interference of endothelial nitric oxide, increases stiffness by 90–200% from baseline in both young and old mice. Interestingly, increases are robustly suppressed by the Src kinase inhibitor PP2 in young but not old mice. Phosphotyrosine screening revealed, with aging, a biochemical signature of markedly impaired agonist-induced FA remodeling previously associated with Src signaling. Protein expression measurement confirmed a decrease in Src expression with aging. Thus we report here an additive model for the in vitro biomechanical components of the mouse aortic wall in which 1) VSMCs are a surprisingly large component of aortic stiffness at physiological lengths and 2) regulation of the VSMC component through FA signaling and hence plasticity is impaired with aging, diminishing the aorta's normal shock absorption function in response to stressors. PMID:25128168

  8. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections

    PubMed Central

    Guo, Dong-chuan; Regalado, Ellen S.; Gong, Limin; Duan, Xueyan; Santos-Cortez, Regie Lyn P.; Arnaud, Pauline; Ren, Zhao; Cai, Bo; Hostetler, Ellen M.; Moran, Rocio; Liang, David; Estrera, Anthony; Safi, Hazim J; Leal, Suzanne M.; Bamshad, Michael J.; Shendure, Jay; Nickerson, Deborah A.; Jondeau, Guillaume; Boileau, Catherine; Milewicz, Dianna M.

    2016-01-01

    Rationale Mutations in several genes have been identified that are responsible for approximately 25% of families with familial thoracic aortic aneurysms and dissections (TAAD). However, the causative gene remains unknown in 75% of families. Objectives To identify the causative mutation in families with autosomal dominant inheritance of TAAD. Methods and Results Exome sequencing was used to identify the mutation responsible for a large family with TAAD. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was performed to investigate mutations in candidate genes in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg had significantly lower lysyl oxidase activity when compared with the wild type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections. Conclusions These data, along with previous studies showing the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease. PMID:26838787

  9. ACTIVATION OF VASCULAR ENDOTHELIAL NITRIC OXIDE SYNTHASE AND HEME OXYGENASE-1 EXPRESSION BY ELECTROPHILIC NITRO-FATTY ACIDS

    PubMed Central

    Khoo, Nicholas K.H.; Rudolph, Volker; Cole, Marsha P.; Golin-Bisello, Franca; Schopfer, Francisco J.; Woodcock, Steven R.; Batthyany, Carlos; Freeman, Bruce A.

    2010-01-01

    Reactive oxygen species mediate a decrease in nitric oxide (NO) bioavailability and endothelial dysfunction, with secondary oxidized and nitrated byproducts of these reactions contributing to the pathogenesis of numerous vascular diseases. While oxidized lipids and lipoproteins exacerbate inflammatory reactions in the vasculature, in stark contrast the nitration of polyunsaturated fatty acids and complex lipids yield electrophilic products that exhibit pluripotent anti-inflammatory signaling capabilities acting via both cGMP-dependent and -independent mechanisms. Herein we report that nitro-oleic acid (OA-NO2) treatment increases expression of endothelial nitric oxide synthase (eNOS) and heme oxygenase 1 (HO-1) in the vasculature, thus transducing vascular protective effects associated with enhanced NO production. Administration of OA-NO2 via osmotic pump results in a significant increase in eNOS and HO-1 mRNA in mouse aortas. Moreover, HPLC-MS/MS analysis showed that NO2-FAs are rapidly metabolized in cultured endothelial cells (ECs) and treatment with NO2-FAs stimulated the phosphorylation of eNOS at Ser1179. These post-translational modifications of eNOS, in concert with elevated eNOS gene expression, contributed to an increase in endothelial NO production. In aggregate, OA-NO2-induced eNOS and HO-1 expression by vascular cells can induce beneficial effects on endothelial function and provide a new strategy for treating various vascular inflammatory and hypertensive disorders. PMID:19857569

  10. Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex.

    PubMed

    Toth, Peter; Tarantini, Stefano; Davila, Antonio; Valcarcel-Ares, M Noa; Tucsek, Zsuzsanna; Varamini, Behzad; Ballabh, Praveen; Sonntag, William E; Baur, Joseph A; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

  11. Serum and tissue biomarkers in aortic stenosis

    PubMed Central

    Kapelouzou, Alkistis; Tsourelis, Loukas; Kaklamanis, Loukas; Degiannis, Dimitrios; Kogerakis, Nektarios; Cokkinos, Dennis V.

    2015-01-01

    Background: Calcific aortic valve stenosis (CAVS) is seen in a large proportion of individuals over 60 years. It is an active process, influenced by lipid accumulation, mechanical stress, inflammation, and abnormal extracellular matrix turnover. Various biomarkers (BMs) are studied, as regards mechanisms, diagnosis and prognosis. Methods: In the calcified valves calcium deposition, elastin fragmentation and disorganization of cellular matrix were assessed, together with expression of OPN, OPG, osteocalcin (OCN) and RL2. We prospectively studied the following serum BMs in 60 patients with CAVS and compared them to 20 healthy controls, free from any cardiac disease: Matrix metalloproteinases (MMP) 2 and 9 and tissue inhibitor of metalloproteinase 1 (TIMP1), which regulate collagen turnover, inflammatory factors, i.e. tumor necrosis factor a (TNFa), interleukin 2 (IL2), transforming growth factor β1 (TGF-β1) which regulates fibrosis, fetuin-A (fet-A), osteopontin (OPN), osteoprotegerin (OPG), sclerostin (SOST), and relaxin-2 (RL2) which positively or negatively regulate calcification. Monocyte chemoattractant protein 1 (MCP-1) which regulates migration and infiltration of monocytes/macrophages was also studied as well as malondialdehyde (MDA) an oxidative marker. Results: Extent of tissue valve calcification (Alizarin Red stain) was negatively correlated with tissue elastin, and RL2, and positively correlated with tissue OCN and serum TIMP1 and MCP-1 and negatively with MMP9. Tissue OCN was positively correlated with OPN and negatively with the elastin. Tissue OPN was negatively correlated with elastin and OPG. Tissue OPN OPG and RL2 were not correlated with serum levels In the serum we found in patients statistically lower TIMP1, fet-A and RL2 levels, while all other BMs were higher compared to the healthy group. Positive correlations between SOST and IL2, OPG and MDA but negative with TNFa and OPN were found; also MMP9 was negatively correlated with TNFa and MCP-1

  12. IL-6-STAT3 signaling mediates aortic dissections induced by angiotensin II via the Th17 lymphocyte-IL17 axis in C57BL/6 Mice

    PubMed Central

    Ju, Xiaoxi; Ijaz, Talha; Sun, Hong; Ray, Sutapa; Lejeune, Wanda; Lee, Chang; Recinos, Adrian; Guo, Dong-Chuan; Milewicz, Dianna M.; Tilton, Ronald G.; Brasier, Allan R.

    2013-01-01

    Objective Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanism(s) by which IL-6 signaling induces leukocyte recruitment remain(s) unknown. T-helper 17lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-STAT3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. Methods and Results Ang II infusion induced aortic dissections and CD4+-interleukin 17A (IL-17A)-expressing, Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6−/− mice. To determine pathological roles of Th17 lymphocytes, we treated Ang II infused mice with IL-17A neutralizing antibody (IL17A NAb), or infused Ang II in genetically deficientIL-17A mice, and found decreased aortic chemokine MCP-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL17ANAb experiment. Application of a cell-permeable STAT3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Lastly, we found that Ang II mediated aortic dissections occurred independent of blood pressure changes. Conclusions Our results indicate that the IL-6-STAT3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections. PMID:23685554

  13. Severe Aortic Coarctation in a 75-Year-Old Woman: Total Simultaneous Repair of Aortic Coarctation and Severe Aortic Stenosis

    PubMed Central

    Park, Ju Hyun; Song, Sung Gook; Kim, Jeong Su; Park, Yong Hyun; Kim, Jun; Choo, Ki Seuk; Kim, June Hong; Lee, Sang Kwon

    2012-01-01

    Aortic coarctation is usually diagnosed and repaired in childhood and early adulthood. Survival of a patient with an uncorrected coarctation to more than 70 years of age is extremely unusual, and management strategies for these cases remain controversial. We present a case of a 75-year-old woman who was first diagnosed with aortic coarctation and severe aortic valve stenosis 5 years ago and who underwent a successful one-stage repair involving valve replacement and insertion of an extra-anatomical bypass graft from the ascending to the descending aorta. PMID:22363387

  14. Possible Dual Role of Decorin in Abdominal Aortic Aneurysm

    PubMed Central

    Ueda, Koshiro; Yoshimura, Koichi; Yamashita, Osamu; Harada, Takasuke; Morikage, Noriyasu; Hamano, Kimikazu

    2015-01-01

    Abdominal aortic aneurysm (AAA) is characterized by chronic inflammation, which leads to pathological remodeling of the extracellular matrix. Decorin, a small leucine-rich repeat proteoglycan, has been suggested to regulate inflammation and stabilize the extracellular matrix. Therefore, the present study investigated the role of decorin in the pathogenesis of AAA. Decorin was localized in the aortic adventitia under normal conditions in both mice and humans. AAA was induced in mice using CaCl2 treatment. Initially, decorin protein levels decreased, but as AAA progressed decorin levels increased in all layers. Local administration of exogenous decorin prevented the development of CaCl2-induced AAA. However, decorin was highly expressed in the degenerative lesions of human AAA walls, and this expression positively correlated with matrix metalloproteinase (MMP)-9 expression. In cell culture experiments, the addition of decorin inhibited secretion of MMP-9 in vascular smooth muscle cells, but had the opposite effect in macrophages. The results suggest that decorin plays a dual role in AAA. Adventitial decorin in normal aorta may protect against the development of AAA, but macrophages expressing decorin in AAA walls may facilitate the progression of AAA by up-regulating MMP-9 secretion. PMID:25781946

  15. Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections

    PubMed Central

    Prakash, Siddharth; Kuang, Shao-Qing; Regalado, Ellen; Guo, Dongchuan; Milewicz, Dianna

    2016-01-01

    Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD. PMID:27092555

  16. Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections.

    PubMed

    Prakash, Siddharth; Kuang, Shao-Qing; Regalado, Ellen; Guo, Dongchuan; Milewicz, Dianna

    2016-01-01

    Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

  17. Repair for acquired aortic valve disease.

    PubMed

    Antunes, M J

    1996-10-01

    The favorable results of mitral valvuloplasty when compared with valve replacement have renewed the interest of many surgeons in aortic valve repair. However, these efforts have, for the most part, been unsuccessful. Also, the results of aortic valve replacement are usually better than those of mitral valve replacement. Yet, some patients appear to derive benefit from a conservative aortic valve procedure. The best examples are mild or moderate aortic valve disease associated with mitral valve or coronary artery disease, which constitute the primary indication for operation, where "prophylactic" aortic valve replacement does not appear justifiable. Other possible indications for aortic valvuloplasty includes patient's lack of compliance or contraindication to anticoagulation in young patients. Senile aortic stenosis, in very old patients with a small annulus, preserved leaflet morphology and nonsignificant commissural fusion should be considered for repair. However, since the procedure is not easily reproducible and the results not uniformly predictable, it cannot be recommended for generalized use. Nonetheless, experienced surgeons should be encouraged to continue these efforts.

  18. Acute Type B Aortic Dissection in a Patient with Previous Endovascular Abdominal Aortic Aneurysm Repair

    PubMed Central

    Park, Sung Hun; Rha, Seung-Woon

    2017-01-01

    Endovascular aortic repair (EVAR) was relatively safe, and became a widely performed procedure. If aortic dissection (AD) occurred in patient with previous EVAR, it could cause fatal complications like endograft collapse. Surgical treatment was limited in this situation for comorbidities and complex anatomies. Here we report a rare case of acute type B AD developed following trans-radial coronary intervention in a patient with previous EVAR of abdominal aortic aneurysm, which was treated with thoracic EVAR. PMID:28377913

  19. Aortic root abscess presenting as alternating bundle branch block: Infective endocarditis of bicuspid aortic valve

    PubMed Central

    Jain, Rakesh; Kader, Muneer; Sajeev, C.G.; Krishnan, M.N.

    2015-01-01

    Bicuspid aortic valve is the most common congenital cardiac malformation, affecting 1%–2% of the population. Among various complications, incidence of infective endocarditis (IE) in the bicuspid aortic valve population is high with higher rate of periannular extension resulting in conduction disturbances. Here we are reporting a rare case of infective endocarditis of bicuspid aortic valve presented with alternating bundle branch block. PMID:26138186

  20. Simulations of Transcatheter Aortic Valve Implantation – Implications for Aortic Root Rupture

    PubMed Central

    Wang, Qian; Kodali, Susheel; Primiano, Charles; Sun, Wei

    2014-01-01

    Objectives Aortic root rupture is one of the most severe complications of transcatheter aortic valve implantation (TAVI). The mechanism of this adverse event remains mostly unknown. The purpose of this study was to obtain a better understanding of the biomechanical interaction between the tissue and stent for patients with a high risk of aortic rupture. Methods We simulated the stent deployment process of three TAVI patients with high aortic rupture risk using finite element method. The first case was a retrospective analysis of an aortic rupture case, while the other two cases were prospective studies, which ended with one cancelled procedure and one successful TAVI. Simulation results were evaluated for the risk of aortic root rupture, as well as coronary artery occlusion, and paravalvular leak. Results For Case 1, the simulated aortic rupture location was the same as clinical observations. From the simulation results, it can be seen that the large calcified spot on the interior of the left coronary sinus between coronary ostium and the aortic annulus was pushed by the stent, causing the aortic rupture. For Case 2 and Case 3, predicated results from the simulations were presented to the clinicians at pre-procedure meetings; and they were in agreement with clinician’s observations and decisions. Conclusions Our results indicated that the engineering analysis could provide additional information to help clinicians evaluate complicated, high risk aortic rupture cases. Since a systematic study of a large patient cohort of aortic rupture is currently not available (due to the low occurrence rate) to clearly understand underlying rupture mechanisms, case by case engineering analysis is recommended for evaluating patient-specific aortic rupture risk. PMID:24736808

  1. Bacillus cereus endocarditis in native aortic valve.

    PubMed

    Ngow, H A; Wan Khairina, W M N

    2013-02-01

    Bacillus cereus endocarditis is rare. It has been implicated in immunocompromised individuals, especially in intravenous drug users as well as in those with a cardiac prosthesis. The patient was a 31-year-old ex-intravenous drug addict with a past history of staphylococcal pulmonary valve endocarditis, who presented with symptoms of decompensated cardiac failure. Echocardiography showed severe aortic regurgitation with an oscillating vegetation seen on the right coronary cusp of the aortic valve. The blood cultures grew Bacillus cereus. We report this as a rare case of Bacillus cereus endocarditis affecting a native aortic valve.

  2. Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition

    PubMed Central

    wu, Min; Tang, Ri-ning; Liu, Hong; Pan, Ming-ming; Liu, Bi-cheng

    2016-01-01

    Aim: Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT. Methods: Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs. Results: In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner. Conclusion: These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT. PMID:27593220

  3. Stent graft implantation in an aortic pseudoaneurysm associated with a fractured Cheatham-Platinum stent in aortic coarctation.

    PubMed

    Kuhelj, Dimitrij; Berden, Pavel; Podnar, Tomaž

    2016-03-01

    We report a case of aortic pseudoaneurysm associated with a fractured bare Cheatham-Platinum stent following stenting for aortic coarctation. These complications were recognised 6 years after the implantation procedure and were successfully managed by percutaneous stent graft implantation. Staged approach for stent dilatation might prevent development of aortic pseudoaneurysms. In addition, careful follow-up is warranted after stenting for aortic coarctation, particularly in patients with recognised aortic wall injury.

  4. Vascular Smooth Muscle Sirtuin-1 Protects Against Aortic Dissection During Angiotensin II–Induced Hypertension

    PubMed Central

    Fry, Jessica L; Shiraishi, Yasunaga; Turcotte, Raphaël; Yu, Xunjie; Gao, Yuan Z; Akiki, Rachid; Bachschmid, Markus; Zhang, Yanhang; Morgan, Kathleen G; Cohen, Richard A; Seta, Francesca

    2015-01-01

    Background Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide+–dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus. Methods and Results Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II–treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II–treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol. Conclusions Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan’s syndrome. PMID:26376991

  5. Microparticle-Induced Coagulation Relates to Coronary Artery Atherosclerosis in Severe Aortic Valve Stenosis

    PubMed Central

    Horn, Patrick; Erkilet, Gülsüm; Veulemans, Verena; Kröpil, Patric; Schurgers, Leon; Zeus, Tobias; Heiss, Christian; Kelm, Malte; Westenfeld, Ralf

    2016-01-01

    Background Circulating microparticles (MPs) derived from endothelial cells and blood cells bear procoagulant activity and promote thrombin generation. Thrombin exerts proinflammatory effects mediating the progression of atherosclerosis. Aortic valve stenosis may represent an atherosclerosis-like process involving both the aortic valve and the vascular system. The aim of this study was to investigate whether MP-induced thrombin generation is related to coronary atherosclerosis and aortic valve calcification. Methods In a cross-sectional study of 55 patients with severe aortic valve stenosis, we assessed the coronary calcification score (CAC) as indicator of total coronary atherosclerosis burden, and aortic valve calcification (AVC) by computed tomography. Thrombin-antithrombin complex (TATc) levels were measured as a marker for thrombin formation. Circulating MPs were characterized by flow cytometry according to the expression of established surface antigens and by measuring MP-induced thrombin generation. Results Patients with CAC score below the median were classified as patients with low CAC, patients with CAC Score above the median as high CAC. In patients with high CAC compared to patients with low CAC we detected higher levels of TATc, platelet-derived MPs (PMPs), endothelial-derived MPs (EMPs) and MP-induced thrombin generation. Increased level of PMPs and MP-induced thrombin generation were independent predictors for the severity of CAC. In contrast, AVC Score did not differ between patients with high and low CAC and did neither correlate with MPs levels nor with MP-induced thrombin generation. Conclusion In patients with severe aortic valve stenosis MP-induced thrombin generation was independently associated with the severity of CAC but not AVC indicating different pathomechanisms involved in coronary artery and aortic valve calcification. PMID:27010400

  6. Pulse Pressure Relation to Aortic and Left Ventricular Structure in Older People in the AGES-Reykjavik Study

    PubMed Central

    Torjesen, Alyssa A; Sigurđsson, Sigurđur; Westenberg, Jos JM; Gotal, John D; Bell, Vanessa; Aspelund, Thor; Launer, Lenore J; de Roos, Albert; Gudnason, Vilmundur; Harris, Tamara B; Mitchell, Gary F

    2014-01-01

    High pulse pressure, a major cardiovascular risk factor, has been attributed to medial elastic fiber degeneration and aortic dilation, which transfers hemodynamic load to stiffer collagen. However, recent studies suggest higher pulse pressure is instead associated with smaller aortic diameter. Thus, we sought to elucidate relations of pulse pressure with aortic stiffness and aortic and cardiac dimensions. We used magnetic resonance imaging to examine relations of pulse pressure with lumen area and wall stiffness and thickness in the thoracic aorta and left ventricular structure in 526 participants (72 to 94 years of age, 295 women) in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study. In a multivariable model that adjusted for age, sex, height, weight, and standard vascular risk factors, central pulse pressure had a negative relation with aortic lumen area (all effects expressed as mm Hg/SD; B=−8.1±1.2, P<0.001) and positive relations with left ventricular end-diastolic volume (B=3.8±1.0, P<0.001), carotid-femoral pulse wave velocity (B=3.6±1.0, P<0.001), and aortic wall area (B=3.0±1.2, P=0.015). Higher pulse pressure in older people is associated with smaller aortic lumen area and greater aortic wall stiffness and thickness and left ventricular volume. Relations of larger ventricular volume and smaller aortic lumen with higher pulse pressure suggest mismatch in hemodynamic load accommodation by the heart and aorta in older people. PMID:25024287

  7. Heparin-Induced-Thrombocytopenia Causing Massive Aortic Thrombosis after Ascending Aortic Replacement for Type A Acute Aortic Dissection

    PubMed Central

    Imoto, Kiyotaka; Uchida, Keiji; Isoda, Susumu; Karube, Norihisa; Yasuda, Shota; Masuda, Munetaka

    2016-01-01

    A 77-year-old woman underwent emergency ascending aortic replacement for type A acute aortic dissection. Fifteen days after the operation, she had motor and sensory disturbances in the lower limbs. Computed tomography revealed multiple aortic thrombi and disrupted blood flow in the right external iliac and left common iliac arteries. She underwent an emergency thrombectomy for acute limb ischemia. Because heparin- induced-thrombocytopenia (HIT) was suspected to have caused the multiple aortic thrombi, we postoperatively changed the anticoagulant therapy from heparin to argatroban. Seventeen days after the first operation, gastrointestinal bleeding developed, and the patient died of mesenteric ischemia caused by HIT. Arterial embolization caused by HIT after cardiovascular surgery is a rare, but fatal event. To avoid fatal complications, early diagnosis and early treatment are essential. Use of a scoring system would probably facilitate early diagnosis. PMID:26780951

  8. Patient-prosthesis mismatch: surgical aortic valve replacement versus transcatheter aortic valve replacement in high risk patients with aortic stenosis

    PubMed Central

    Kron, Irving L.

    2016-01-01

    Patient prosthesis mismatch (PPM) can occur when a prosthetic aortic valve has an effective orifice area (EOA) less than that of a native valve. A recent study by Zorn and colleagues evaluated the incidence and significance of PPM in high risk patients with severe aortic stenosis who were randomized to transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). TAVR is associated with decreased incidence of severe PPM compared to traditional SAVR valves. Severe PPM increases risk for death at 1 year postoperatively in high risk patients. The increased incidence of PPM is largely due to differences in valve design and should encourage development of newer SAVR valves to reduce risk for PPM. In addition more vigorous approaches to root enlargement in small annulus should be performed with SAVR to prevent PPM. PMID:27867654

  9. Patient-prosthesis mismatch: surgical aortic valve replacement versus transcatheter aortic valve replacement in high risk patients with aortic stenosis.

    PubMed

    Ghanta, Ravi K; Kron, Irving L

    2016-10-01

    Patient prosthesis mismatch (PPM) can occur when a prosthetic aortic valve has an effective orifice area (EOA) less than that of a native valve. A recent study by Zorn and colleagues evaluated the incidence and significance of PPM in high risk patients with severe aortic stenosis who were randomized to transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). TAVR is associated with decreased incidence of severe PPM compared to traditional SAVR valves. Severe PPM increases risk for death at 1 year postoperatively in high risk patients. The increased incidence of PPM is largely due to differences in valve design and should encourage development of newer SAVR valves to reduce risk for PPM. In addition more vigorous approaches to root enlargement in small annulus should be performed with SAVR to prevent PPM.

  10. Liverpool Aortic Surgery Symposium V: New Frontiers in Aortic Disease and Surgery

    PubMed Central

    Bashir, Mohamad; Fok, Matthew; Shaw, Matthew; Field, Mark; Kuduvalli, Manoj; Desmond, Michael; Harrington, Deborah; Rashid, Abbas; Oo, Aung

    2014-01-01

    Aortic aneurysm disease is a complex condition that requires a multidisciplinary approach in management. The innovation and collaboration among vascular surgery, cardiothoracic surgery, interventional radiology, and other related specialties is essential for progress in the management of aortic aneurysms. The Fifth Liverpool Aortic Surgery Symposium that was held in May 2013 aimed at bringing national and international experts from across the United Kingdom and the globe to deliver their thoughts, applications, and advances in aortic and vascular surgery. In this report, we present a selected short synopsis of the key topics presented at this symposium. PMID:26798724

  11. Management of concomitant large aortic aneurysm and severe stenosis of aortic arc.

    PubMed

    Ren, Shiyan; Sun, Guang; Yang, Yuguang; Liu, Peng

    2014-01-01

    Primary large saccular aortic aneurysm with high grade stenosis of aortic arc is rare, and no standard therapy is available. We have encountered one case and successfully treated using a hybrid interventional approach. A 59-year-old woman with a 7-day history of headache, dizziness and chest pain, and a 5-year history of hypertension admitted and was diagnosed with transverse aortic aneurysm with sever aortic stenosis, the huge saccular aneurysm was located behind the transverse aortic arc. During surgery, a bypass with graft from ascending aorta to left external iliac artery was made initially in order to ensure the blood supply to the left leg, afterward, a 40 mm × 160 mm covered stent was implanted to cover the orifice of aneurysm and was used as a supporting anchorage in the descending aorta, a second covered stent (20 mm × 100 mm) was implanted to expand the stenosis of aortic arc. Follow-up at 1.5-year after surgery, the patient has been doing well without any surgical complication. A collateral pathway between internal mammary artery and inferior epigastric artery via the superior epigastric artery was found on3-dimensional reconstruction before surgery. Interruption of the compensatory arterial collateral pathway in the patient with severe stenosis of aortic arc should be prevented if possible in order to ensure the satisfactory perfusion of the lower limbs of the body.In conclusion, a patient with transverse aortic aneurysm accompanied with severe aortic stenosis can be treated by hybrid surgery.

  12. Inhaled nitric oxide decreases pulmonary endothelial nitric oxide synthase expression and activity in normal newborn rat lungs.

    PubMed

    Hua-Huy, Thông; Duong-Quy, Sy; Pham, Hoa; Pansiot, Julien; Mercier, Jean-Christophe; Baud, Olivier; Dinh-Xuan, Anh Tuan

    2016-01-01

    Inhaled nitric oxide (iNO) is commonly used in the treatment of very ill pre-term newborns. Previous studies showed that exogenous NO could affect endothelial NO synthase (eNOS) activity and expression in vascular endothelial cell cultures or adult rat models, but this has never been fully described in newborn rat lungs. We therefore aimed to assess the effects of iNO on eNOS expression and activity in newborn rats. Rat pups, post-natal day (P) 0 to P7, and their dams were placed in a chamber containing NO at 5 ppm (iNO-5 ppm group) or 20 ppm (iNO-20 ppm group), or in room air (control group). Rat pups were sacrificed at P7 and P14 for evaluation of lung eNOS expression and activity. At P7, eNOS protein expression in total lung lysates, in bronchial and arterial sections, was significantly decreased in the iNO-20 ppm versus control group. At P14, eNOS expression was comparable among all three groups. The amounts of eNOS mRNA significantly differed at P7 between the iNO-20 ppm and control groups. NOS activity decreased in the iNO-20 ppm group at P7 and returned to normal levels at P14. There was an imbalance between superoxide dismutase and NOS activities in the iNO-20 ppm group at P7. Inhalation of NO at 20 ppm early after birth decreases eNOS gene transcription, protein expression and enzyme activity. This decrease might account for the rebound phenomenon observed in patients treated with iNO.

  13. VASCULAR INFLAMMATION AND ABNORMAL AORTIC HISTOMORPHOMETRY IN PATIENTS FOLLOWING PULSATILE AND CONTINUOUS FLOW LEFT VENTRICULAR ASSIST DEVICE PLACEMENT

    PubMed Central

    Lee, Mike; Akashi, Hirokazu; Kato, Tomoko S.; Takayama, Hiroo; Wu, Christina; Xu, Katherine; Collado, Elias; Weber, Matthew P.; Kennel, Peter J.; Brunjes, Danielle L; Ji, Ruiping; Naka, Yoshifumi; George, Isaac; Mancini, Donna; Farr, Maryjane; Schulze, P. Christian

    2017-01-01

    Objective Left ventricular assist devices are increasingly used in patients with advanced heart failure as both destination therapy and bridge-to-transplantation. We aimed to analyze histomorphometric, structural and inflammatory changes following pulsatile and continuous flow left ventricular assist device placement. Method Clinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by western blot. Results Decellularization of the aortic tunica media was observed in patients receiving continuous flow support. Both device types showed an increased inflammatory response following left ventricular assist device placement with variable T cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall. Conclusion Left ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous flow left ventricular assist and associated with aortic media decellularization. These findings help to explain the progressive aortic root dilation and vascular dysfunction in patients following continuous flow device placement. PMID:26899764

  14. Abdominal aortic aneurysms in women

    PubMed Central

    Lo, Ruby C.; Schermerhorn, Marc L.

    2015-01-01

    Abdominal aortic aneurysm (AAA) has long been recognized as a condition predominantly afflicting males, with sex-associated differences described for almost every aspect of the disease from pathophysiology and epidemiology to morbidity and mortality. Women are generally spared from AAA formation by the immunomodulating effects of estrogen but once they develop, the natural history of AAAs in women appears to be more aggressive, with more rapid expansion, a higher tendency to rupture at smaller diameters, and higher mortality following rupture. However, simply repairing AAA at smaller diameters in women is a debatable solution, as even elective endovascular AAA repair (EVAR) is fraught with higher morbidity and mortality in women compared to men. The goal of this review is to summarize what is currently known about the effect of gender on AAA presentation, treatment, and outcomes. Additionally, we aim to review current controversies over screening recommendations and threshold for repair in women. PMID:26747679

  15. Understanding the pathogenesis of abdominal aortic aneurysms

    PubMed Central

    Kuivaniemi, Helena; Ryer, Evan J.; Elmore, James R.; Tromp, Gerard

    2016-01-01

    Summary An aortic aneurysm is a dilatation in which the aortic diameter is ≥ 3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the forces of the luminal blood pressure resulting in progressive dilatation and rupture, a catastrophic event associated with a mortality of 50 – 80%. Smoking and positive family history are important risk factors for the development of abdominal aortic aneurysms (AAA). Several genetic risk factors have also been identified. On the histological level, visible hallmarks of AAA pathogenesis include inflammation, smooth muscle cell apoptosis, extracellular matrix degradation, and oxidative stress. We expect that large genetic, genomic, epigenetic, proteomic and metabolomic studies will be undertaken by international consortia to identify additional risk factors and biomarkers, and to enhance our understanding of the pathobiology of AAA. Collaboration between different research groups will be important in overcoming the challenges to develop pharmacological treatments for AAA. PMID:26308600

  16. Valve selection in aortic valve endocarditis

    PubMed Central

    Zubrytska, Yana

    2016-01-01

    Aortic prosthetic valve endocarditis (PVE) is a potentially life-threatening disease. Mortality and incidence of infective endocarditis have been reduced in the past 30 years. Medical treatment of aortic PVE may be successful in patients who have a prompt response after antibiotic treatment and who do not have prosthetic dysfunction. In advanced stages, antibiotic therapy alone is insufficient to control the disease, and surgical intervention is necessary. Surgical treatment may be lifesaving, but it is still associated with considerable morbidity and mortality. The aim of surgery is to perform a radical excision of all infected and necrotic tissue, reconstruction of the left ventricle outflow tract, and replacement of the aortic valve. There is no unanimous consensus on which is the optimal prosthesis to implant in this context, and several surgical techniques have been suggested. We aim to analyze the efficacy of the surgical treatment and discuss the issue of valve selection in patients with aortic valve endocarditis. PMID:27785132

  17. Computational analysis of an aortic valve jet

    NASA Astrophysics Data System (ADS)

    Shadden, Shawn C.; Astorino, Matteo; Gerbeau, Jean-Frédéric

    2009-11-01

    In this work we employ a coupled FSI scheme using an immersed boundary method to simulate flow through a realistic deformable, 3D aortic valve model. This data was used to compute Lagrangian coherent structures, which revealed flow separation from the valve leaflets during systole, and correspondingly, the boundary between the jet of ejected fluid and the regions of separated, recirculating flow. Advantages of computing LCS in multi-dimensional FSI models of the aortic valve are twofold. For one, the quality and effectiveness of existing clinical indices used to measure aortic jet size can be tested by taking advantage of the accurate measure of the jet area derived from LCS. Secondly, as an ultimate goal, a reliable computational framework for the assessment of the aortic valve stenosis could be developed.

  18. Activation of Endocannabinoid System Is Associated with Persistent Inflammation in Human Aortic Aneurysm

    PubMed Central

    Gestrich, Christopher; Duerr, Georg D.; Heinemann, Jan C.; Meertz, Anne; Probst, Chris; Roell, Wilhelm; Schiller, Wolfgang; Zimmer, Andreas; Bindila, Laura; Lutz, Beat; Welz, Armin; Dewald, Oliver

    2015-01-01

    Human aortic aneurysms have been associated with inflammation and vascular remodeling. Since the endocannabinoid system modulates inflammation and tissue remodeling, we investigated its components in human aortic aneurysms. We obtained anterior aortic wall samples from patients undergoing elective surgery for aortic aneurysm or coronary artery disease as controls. Histological and molecular analysis (RT-qPCR) was performed, and endocannabinoid concentration was determined using LC-MRM. Patient characteristics were comparable between the groups except for a higher incidence of arterial hypertension and diabetes in the control group. mRNA level of cannabinoid receptors was significantly higher in aneurysms than in controls. Concentration of the endocannabinoid 2-arachidonoylglycerol was significantly higher, while the second endocannabinoid anandamide and its metabolite arachidonic acid and palmitoylethanolamide were significantly lower in aneurysms. Histology revealed persistent infiltration of newly recruited leukocytes and significantly higher mononuclear cell density in adventitia of the aneurysms. Proinflammatory environment in aneurysms was shown by significant upregulation of M-CSF and PPARγ but associated with downregulation of chemokines. We found comparable collagen-stained area between the groups, significantly decreased mRNA level of CTGF, osteopontin-1, and MMP-2, and increased TIMP-4 expression in aneurysms. Our data provides evidence for endocannabinoid system activation in human aortic aneurysms, associated with persistent low-level inflammation and vascular remodeling. PMID:26539497

  19. Identification and refinement of two strong constitutive promoters for gene expression system of Schizosaccharomyces pombe.

    PubMed

    Wang, Hongcheng; Wang, Haiyang; Wang, Meng; Zhang, Lei; Wang, Ren; Mei, Yanzhen; Shao, Weilan

    2014-06-01

    Fission yeast Schizosaccharomyces pombe shares various important properties with higher eukaryotes and is now considered a useful host for elevated production of mammalian proteins for medicinal applications. The full-length nmt1 promoter has been widely used as a strong promoter in S. pombe expression system. In the present study, the promoters of the eno101 and gpd3 genes in S. pombe were identified as strong constitutive promoters. For convenient applications in the plasmids of S. pombe, these promoters were refined to 276-bp eno and 273-bp gpd promoters by deleting undesired sequences and examining the expression of reporter genes including lacZ and xynA. Both the refined eno and gpd promoters provided approximately 1.5-fold higher expression of LacZ than nmt1 promoter. Furthermore, gene expression under the control of the eno or gpd promoter was not repressed by the components of YES medium while nmt1 promoter was inhibited by thiamine in yeast extract. Therefore, both eno and gpd promoters offer opportunities for efficient production of recombinant proteins by S. pombe in high cell-density fermentation.

  20. Puerarin protects endothelial cells from oxidized low density lipoprotein induced injuries via the suppression of LOX-1 and induction of eNOS.

    PubMed

    Bao, Mei-hua; Zhang, Yi-wen; Lou, Xiao-ya; Xiao, Yan; Cheng, Yu; Zhou, Hong-hao

    2014-04-01

    Oxidized low density lipoprotein (oxLDL) induced injury of endothelial cells is considered to be the first step in the pathogenesis of atherosclerosis. This study aimed to investigate some of the effects and mechanisms of puerarin on oxLDL-induced endothelial injuries. We measured cell viability, and the release of lactate dehydrogenase (LDH), nitric oxide (NO), and interleukin-8 (IL-8) to evaluate the protective effects of puerarin. Intracellular reactive oxygen species (ROS) were detected using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The expression of lectin-like low-density lipoprotein receptor-1 (LOX-1), endothelial nitric oxide synthase (eNOS), cyclooxygenase 2 (COX-2), p38MAPK, and protein kinase B (PKB) phosphorylation, nuclear factor-κB (NF-κB) nuclear translocation, and inhibitor of κB (IκB) degradation were detected using quantitative real-time PCR or Western blot. The results showed that oxLDL significantly decreased cell viability, increased LDH and IL-8 release, inhibited NO production, and induced COX-2 expression. Pretreatment with puerarin led to a strong inhibition of these effects. OxLDL stimulated the expression of LOX-1, the overproduction of ROS, the phosphorylation of p38MAPK, the dephosphorylation of PKB, activation of NF-κB, and the degradation of IκB. These oxLDL-induced effects were suppressed after puerarin pretreatment. These results suggest that puerarin inhibits oxLDL-induced endothelial cell injuries, at least in part, via inhibition of the LOX-1-mediated p38MAPK-NF-κB inflammatory and the PKB-eNOS signaling pathways.

  1. [Mechanism of losartan suppressing vascular calcification in rat aortic artery].

    PubMed

    Shao, Juan; Wu, Panfeng; Wu, Jiliang; Li, Mincai

    2016-08-01

    Objective To investigate the effect of the angiotensin II receptor 1 (AT1R) blocker losartan on vascular calcification in rat aortic artery and explore the underlying mechanisms. Methods SD rats were divided randomly into control group, vascular calcification model group and treatment group. Vascular calcification models were made by subcutaneous injection of warfarin plus vitamin K1 for two weeks. Rats in the treatment group were subcutaneously injected with losartan (10 mg/kg) at the end of the first week and consecutively for one week. We observed the morphological changes by HE staining and the calcium deposition by Alizarin red staining in the artery vascular wall. The mRNA expressions of bone morphogenetic protein 2 (BMP2) and Runt-related transcription factor 2 (RUNX2) were analyzed by reverse transcription PCR. The BMP2 and RUNX2 protein expressions were determined by Western blotting. The apoptosis of smooth muscle cells (SMCs) were detected by TUNEL. The AT1R expression was tested by fluorescent immunohistochemistry. Results The aortic vascular calcification was induced by warfarin and vitamin K1. Compared with the vascular calcification model group, the mRNA and protein expressions of BMP2 and RUNX2 were significantly downregulated in the aorta in the losartan treatment group. Furthermore, the apoptosis of SMCs and the AT1R expression obviously decreased. Conclusion AT1R blocker losartan inhibits the apoptosis of SMCs and reduces AT1R expression; it downregulates the BMP2 and RUNX2 expressions in the vascular calcification process.

  2. Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2.

    PubMed

    Chen, Jianglei; Lin, Yi; Sun, Zhongjie

    2016-10-01

    Fibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti-aging Klotho gene (KL) promotes high-fat-diet-induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho-deficient (KL(+/-) ) mice and WT littermates were fed with a high-fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL(+/-) mice than of WT mice, indicating that Klotho deficiency promotes HFD-induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL(+/-) mice fed with a HFD. Treatment with AICAR markedly attenuated HFD-induced AVF in KL(+/-) mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL(+/-) mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho-deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol-induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD-induced fibrosis in aortic valves, likely through the AMPKα-RUNX2 pathway.

  3. Aortic coarctation repair in the adult.

    PubMed

    Cardoso, Goncalo; Abecasis, Miguel; Anjos, Rui; Marques, Marta; Koukoulis, Giovanna; Aguiar, Carlos; Neves, José Pedro

    2014-07-01

    Aortic coarctation can be repaired surgically or percutaneously. The decision should be made according to the anatomy and location of the coarctation, age of the patient, presence of other cardiac lesions, and other anatomic determinants (extensive collaterals or aortic calcification). This article reviews the different therapeutic options available, explaining the differences between children and adults, describing different approaches to the same disease, exemplified by three cases of nonclassic surgical approach and one percutaneous treatment.

  4. Regional aortic distensibility and its relationship with age and aortic stenosis: a computed tomography study.

    PubMed

    Wong, Dennis T L; Narayan, Om; Leong, Darryl P; Bertaso, Angela G; Maia, Murilo G; Ko, Brian S H; Baillie, Timothy; Seneviratne, Sujith K; Worthley, Matthew I; Meredith, Ian T; Cameron, James D

    2015-06-01

    Aortic distensibility (AD) decreases with age and increased aortic stiffness is independently associated with adverse cardiovascular outcomes. The association of severe aortic stenosis (AS) with AD in different aortic regions has not been evaluated. Elderly subjects with severe AS and a cohort of patients without AS of similar age were studied. Proximal aortic cross-sectional-area changes during the cardiac cycle were determined using retrospective-ECG-gating on 128-detector row computed-tomography. Using oscillometric-brachial-blood-pressure measurements, the AD at the ascending-aorta (AA), proximal-descending-aorta (PDA) and distal-descending-aorta (DDA) was determined. Linear mixed effects modelling was used to determine the association of age and aortic stenosis on regional AD. 102 patients were evaluated: 36 AS patients (70-85 years), 24 AS patients (>85 years) and 42 patients without AS (9 patients <50 years, 20 patients between 51-70 years and 13 patients 70-85 years). When comparing patients 70-85 years, AA distensibility was significantly lower in those with AS compared to those without AS (0.9 ± 0.9 vs. 1.4 ± 1.1, P = 0.03) while there was no difference in the PDA (1.0 ± 1.1 vs. 1.0 ± 1.2, P = 0.26) and DDA (1.1 ± 1.2 vs. 1.2 ± 0.8, P = 0.97). In patients without AS, AD decreased with age in all aortic regions (P < 0.001). The AA in patients <50 years were the most distensible compared to other aortic regions. There is regional variation in aortic distensibility with aging. Patients with aortic stenosis demonstrated regional differences in aortic distensibility with lower distensibility demonstrated in the proximal ascending aorta compared to an age-matched cohort.

  5. Expression of the nuclear factor-kappaB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke.

    PubMed

    Altura, Burton M; Kostellow, Adele B; Zhang, Aimin; Li, Wenyan; Morrill, Gene A; Gupta, Raj K; Altura, Bella T

    2003-09-01

    Proto-oncogene (c-fos, c-jun) and nuclear factor-kappa B (NF-kappaB) expression, as well as DNA synthesis, in aortic and cerebral vascular smooth muscle cells (VSMCs) were upregulated by a decrease in extracellular magnesium ions ([Mg2+]o). Upregulation of these transcriptional factors was inversely proportional to the [Mg2+]o and occurred over the pathophysiologic range of serum Mg2+ found in patients presenting with hypertension, ischemic heart disease, and stroke. Removal of extracellular Ca2+ ([Ca2+]o), use of nifedipine or protein kinase C (PKC) inhibitors prevented the upregulation of the proto-oncogenes and DNA synthesis in VSMCs. These data show that [Mg2+]o may be an important, heretofore, overlooked natural modulator of proto-oncogene and NF-kappaB expression in VSMCs and that Ca2+ and PKC may play critical roles in induction of c-fos and c-jun in VSMCs induced by a decrease in [Mg2+]o. These results point to a role for low serum Mg2+ in potential development of hypertension, atherogenesis, vascular disease, and stroke.

  6. Gender Differences in Abdominal Aortic Aneurysms

    PubMed Central

    Hannawa, Kevin K.; Eliason, Jonathan L.; Upchurch, Gilbert R.

    2010-01-01

    Abdominal aortic aneurysms (AAAs) comprise the 10th leading cause of death in Caucasian males 65–74 years of age, and accounted for nearly 16,000 deaths overall in the year 2000. Therefore, understanding the pathophysiology of AAAs is an important undertaking. Clinically, multiple risk factors are associated with the development of AAAs, including increasing age, positive smoking history, and hypertension. Male gender is also a well-established risk factor for the development of an AAA with a 4:1 male to female ratio. The reason for this gender disparity is unknown. The pathogenesis of AAAs formation is complex and multifactorial. Histologically, AAAs are characterized by early chemokine driven leukocyte infiltration into the aortic wall. Subsequent destruction of elastin and collagen in the media and adventitia ensues due to excessive local production of matrix degrading enzymes, and is accompanied by smooth muscle cell loss and thinning of the aortic wall. At present, there are no medical therapies available to treat patients with aortic aneurysms, using only the crude measurement of aortic diameter as a threshold for which patients must undergo life-threatening and costly surgery. Defining the early mechanisms underlying gender-related differences in AAA formation are critical, as understanding differences in disease patterns based on gender may allow us to develop new translational approaches to the prevention and treatment of patients with aortic aneurysms. PMID:19426607

  7. Quantification of abdominal aortic deformation after EVAR

    NASA Astrophysics Data System (ADS)

    Demirci, Stefanie; Manstad-Hulaas, Frode; Navab, Nassir

    2009-02-01

    Quantification of abdominal aortic deformation is an important requirement for the evaluation of endovascular stenting procedures and the further refinement of stent graft design. During endovascular aortic repair (EVAR) treatment, the aortic shape is subject to severe deformation that is imposed by medical instruments such as guide wires, catheters, and, the stent graft. This deformation can affect the flow characteristics and morphology of the aorta which have been shown to be elicitors for stent graft failures and be reason for reappearance of aneurysms. We present a method for quantifying the deformation of an aneurysmatic aorta imposed by an inserted stent graft device. The outline of the procedure includes initial rigid alignment of the two abdominal scans, segmentation of abdominal vessel trees, and automatic reduction of their centerline structures to one specified region of interest around the aorta. This is accomplished by preprocessing and remodeling of the pre- and postoperative aortic shapes before performing a non-rigid registration. We further narrow the resulting displacement fields to only include local non-rigid deformation and therefore, eliminate all remaining global rigid transformations. Finally, deformations for specified locations can be calculated from the resulting displacement fields. In order to evaluate our method, experiments for the extraction of aortic deformation fields are conducted on 15 patient datasets from endovascular aortic repair (EVAR) treatment. A visual assessment of the registration results and evaluation of the usage of deformation quantification were performed by two vascular surgeons and one interventional radiologist who are all experts in EVAR procedures.

  8. Characterization of Porcine Aortic Valvular Interstitial Cell ‘Calcified’ Nodules

    PubMed Central

    Cloyd, Kristy L.; El-Hamamsy, Ismail; Boonrungsiman, Suwimon; Hedegaard, Martin; Gentleman, Eileen; Sarathchandra, Padmini; Colazzo, Francesca; Gentleman, Molly M.; Yacoub, Magdi H.; Chester, Adrian H.; Stevens, Molly M.

    2012-01-01

    Valve interstitial cells populate aortic valve cusps and have been implicated in aortic valve calcification. Here we investigate a common in vitro model for aortic valve calcification by characterizing nodule formation in porcine aortic valve interstitial cells (PAVICs) cultured in osteogenic (OST) medium supplemented with transforming growth factor beta 1 (TGF-β1). Using a combination of materials science and biological techniques, we investigate the relevance of PAVICs nodules in modeling the mineralised material produced in calcified aortic valve disease. PAVICs were grown in OST medium supplemented with TGF-β1 (OST+TGF-β1) or basal (CTL) medium for up to 21 days. Murine calvarial osteoblasts (MOBs) were grown in OST medium for 28 days as a known mineralizing model for comparison. PAVICs grown in OST+TGF-β1 produced nodular structures staining positive for calcium content; however, micro-Raman spectroscopy allowed live, noninvasive imaging that showed an absence of mineralized material, which was readily identified in nodules formed by MOBs and has been identified in human valves. Gene expression analysis, immunostaining, and transmission electron microscopy imaging revealed that PAVICs grown in OST+TGF-β1 medium produced abundant extracellular matrix via the upregulation of the gene for Type I Collagen. PAVICs, nevertheless, did not appear to further transdifferentiate to osteoblasts. Our results demonstrate that ‘calcified’ nodules formed from PAVICs grown in OST+TGF-β1 medium do not mineralize after 21 days in culture, but rather they express a myofibroblast-like phenotype and produce a collagen-rich extracellular matrix. This study clarifies further the role of PAVICs as a model of calcification of the human aortic valve. PMID:23110195

  9. H2S regulates endothelial nitric oxide synthase protein stability by promoting microRNA-455-3p expression

    PubMed Central

    Li, Xing-Hui; Xue, Wen-Long; Wang, Ming-Jie; Zhou, Yu; Zhang, Cai-Cai; Sun, Chen; Zhu, Lei; Liang, Kun; Chen, Ying; Tao, Bei-Bei; Tan, Bo; Yu, Bo; Zhu, Yi-Chun

    2017-01-01

    The aims of the present study are to determine whether hydrogen sulfide (H2S) is involved in the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, and to identify the role of microRNA-455-3p (miR-455-3p) during those processes. In cultured human umbilical vein endothelial cells (HUVECs), the expression of miR-455-3p, eNOS protein and the NO production was detected after administration with 50 μM NaHS. The results indicated that H2S could augment the expression of miR-455-3p and eNOS protein, leading to the increase of NO level. We also found that overexpression of miR-455-3p in HUVECs increased the protein levels of eNOS whereas inhibition of miR-455-3p decreased it. Moreover, H2S and miR-455-3p could no longer increase the protein level of eNOS in the presence of proteasome inhibitor, MG-132. In vivo, miR-455-3p and eNOS expression were considerably increased in C57BL/6 mouse aorta, muscle and heart after administration with 50 μmol/kg/day NaHS for 7 days. We also identified that H2S levels and miR-455-3p expression increased in human atherosclerosis plaque while H2S levels decreased in plasma of atherosclerosis patients. Our data suggest that the stability of eNOS protein and the NO production could be regulated by H2S through miR-455-3p. PMID:28322298

  10. Immune response induced by oral delivery of Bacillus subtilis spores expressing enolase of Clonorchis sinensis in grass carps (Ctenopharyngodon idellus).

    PubMed

    Jiang, Hongye; Chen, Tingjin; Sun, Hengchang; Tang, Zeli; Yu, Jinyun; Lin, Zhipeng; Ren, Pengli; Zhou, Xinyi; Huang, Yan; Li, Xuerong; Yu, Xinbing

    2017-01-01

    Clonorchiasis, caused by the consumption of raw or undercooked freshwater fish containing infective metacercariae of Clonorchis sinensisis (C.sinensis), remains a common public health problem. New effective prevention strategies are still urgent to control this food-borne infectious disease. The previous studies suggested Bacillus subtilis (B. subtilis) spores was an ideal vaccines delivery system, and the C.sinensis enolase (CsENO) was a potential vaccine candidate against clonorchiasis. In the current study, we detected CsENO-specific IgM levels by ELISA in sera, intestinal mucus and skin mucus in grass carps (Ctenopharyngodon idella) through oral administration with B. subtilis spores surface expressing CsENO. In addition, immune-related genes expression was also measured by qRT-PCR. Grass carps orally treated with B. subtilis spores or normal forages were used as controls. The results of ELISA manifested that specific IgM levels of grass carps in CsENO group in sera, intestine mucus and skin mucus almost significantly increased from week 4 post the first oral administration when compared to the two control groups. The levels of specific IgM reached its peak in intestine mucus firstly, then in sera, and last in skin mucus. qRT-PCR results showed that 5 immune-related genes expression had different degree of rising trend in CsENO group when compared to the two control groups. Our study demonstrated that orally administrated with B. subtilis spores expressing CsENO induced innate and adaptive immunity, systemic and local mucosal immunity, and humoral and cellular immunity. Our work may pave the way to clarify the exact mechanisms of protective efficacy elicited by B. subtilis spores expressing CsENO and provide new ideas for vaccine development against C. sinensis infection.

  11. Association between increased expression of endothelial isoform of nitric oxide synthase in the human fallopian tube and tubal ectopic pregnancy

    PubMed Central

    Fath Bayati, Leyla; Ghaffari Novin, Marefat; Fadaei Fathabadi, Fatemeh; Piryaei, Abbas; Heidari, Mohammad Hasan; Bandehpour, Mozhgan; Norouzian, Mohsen; Alizadeh Parhizgar, Mahdi; Shakooriyan Fard, Mahmood

    2014-01-01

    Background: Tubal ectopic pregnancy (tEP) is the most common type of extra-uterine pregnancy and the most common cause of maternal mortality. Nitric oxide (NO) is a molecule that incorporates in many physiological processes of female reproductive system. Recent studies have demonstrated the possible role of endothelial isoform of nitric oxide synthase (eNOS) enzyme in the regulation of many reproductive events that occur in the fallopian tube (FT). Objective: The aim of this study was to evaluate the expression of eNOS in the FTs of women with tEP. Materials and Methods: In this case-control study, a total number of 30FTs samples were obtained from three groups including: 10 FTs of women that bearing an EP, 10 FTs from the non-pregnant women at luteal phase of the menstrual cycle, and 10 FTs of healthy pregnant women (n=10). Samples were fixed in 10% buffered formalin and then were evaluated by immunohistochemistry. Results: Localization of eNOS was seen in secretory and ciliated luminal epithelium and vascular endothelium of all groups. However, we did not observed the expression of eNOS in smooth muscle cells of all groups. Expression of eNOS in luminal epithelium of women with EP compared to non-pregnant women at luteal phase of menstrual cycle and healthy pregnant group showed statistically significant increase (p=0.00). Significant difference in expression of eNOS was not observed in luminal epithelium of FTs of women at luteal phase compared to healthy pregnant groups (p=0.78). Conclusion: This study indicates that changes in expression of eNOS in luminal epithelium of FT may lead to development of EP. This article extracted from M.Sc. thesis. (Leyla Fath Bayati) PMID:24799858

  12. CD14 Directs Adventitial Macrophage Precursor Recruitment: Role in Early Abdominal Aortic Aneurysm Formation

    PubMed Central

    Blomkalns, Andra L.; Gavrila, Daniel; Thomas, Manesh; Neltner, Bonnie S.; Blanco, Victor M.; Benjamin, Stephanie B.; McCormick, Michael L.; Stoll, Lynn L.; Denning, Gerene M.; Collins, Sean P.; Qin, Zhenyu; Daugherty, Alan; Cassis, Lisa A.; Thompson, Robert W.; Weiss, Robert M.; Lindower, Paul D.; Pinney, Susan M.; Chatterjee, Tapan; Weintraub, Neal L.

    2013-01-01

    Background Recruitment of macrophage precursors to the adventitia plays a key role in the pathogenesis of abdominal aortic aneurysms (AAAs), but molecular mechanisms remain undefined. The innate immune signaling molecule CD14 was reported to be upregulated in adventitial macrophages in a murine model of AAA and in monocytes cocultured with aortic adventitial fibroblasts (AoAf) in vitro, concurrent with increased interleukin‐6 (IL‐6) expression. We hypothesized that CD14 plays a crucial role in adventitial macrophage precursor recruitment early during AAA formation. Methods and Results CD14−/− mice were resistant to AAA formation induced by 2 different AAA induction models: aortic elastase infusion and systemic angiotensin II (AngII) infusion. CD14 gene deletion led to reduced aortic macrophage infiltration and diminished elastin degradation. Adventitial monocyte binding to AngII‐infused aorta in vitro was dependent on CD14, and incubation of human acute monocytic leukemia cell line‐1 (THP‐1) monocytes with IL‐6 or conditioned medium from perivascular adipose tissue (PVAT) upregulated CD14 expression. Conditioned medium from AoAf and PVAT induced CD14‐dependent monocyte chemotaxis, which was potentiated by IL‐6. CD14 expression in aorta and plasma CD14 levels were increased in AAA patients compared with controls. Conclusions These findings link CD14 innate immune signaling via a novel IL‐6 amplification loop to adventitial macrophage precursor recruitment in the pathogenesis of AAA. PMID:23537804

  13. A doxycycline loaded, controlled-release, biodegradable fiber for the treatment of aortic aneurysms.

    PubMed

    Yamawaki-Ogata, A; Hashizume, R; Satake, M; Kaneko, H; Mizutani, S; Moritan, T; Ueda, Y; Narita, Y

    2010-12-01

    The pathogenesis of aortic aneurysm (AA) is characterized by degradation of extracellular matrix with increased matrix metalloproteinases (MMPs) and inflammatory reaction. Doxycycline (DOXY) has been reported to control the extension of AA by regulation of MMP. However, systemic administration may cause adverse side effects. In this study, we demonstrated the possibility of local administration of DOXY controlled-release biodegradable fiber (DCRBF) for AA in mice. DCRBF was fabricated by biodegradable polymer (polylactic acid; PLA) mixed with DOXY using an electrospinning technique. DCRBF was cocultured with SMCs, macrophages and aortic tissue, and placed on an abdominal aortic aneurysm which induced apolipoprotein E-deficient mice. We evaluated gene and protein expression of proteases, elastin and inflammatory markers. In the presence of DCRBF, MMP-12 was significantly decreased, TGF-β1 and Lox were significantly increased in SMC gene expression, MMP-9 and -12 significantly decreased gene expression of macrophages. The DCRBF preserved elastin content and decreased MMP-2 and -9 in aortic tissue. In addition, IGF-1 and TIMP-1 were significantly increased and IL-6 and TNF-α were significantly decreased with DCRBF in vivo. In conclusion, our results suggested that local administration of DCRBF may become a promising alternative therapeutic strategy for AA.

  14. Valve sparing: aortic root replacement with the reimplantation technique.

    PubMed

    Mastrobuoni, Stefano; Tamer, Sadallah; de Kerchove, Laurent; El Khoury, Gebrine

    2015-01-01

    Aortic valve-sparing procedures are alternative options to aortic valve replacement in patients with aortic root aneurysm and/or severe aortic regurgitation reducing the risk of prosthesis-related complications, such as thromboembolism, and have no need for long-term oral anticoagulation. However, these techniques are technically demanding and long-term results are highly dependent on perfect intraoperative restoration of valve function. We describe a systematic approach to aortic valve-sparing aortic root replacement with the reimplantation technique the way it is currently performed in our institution.

  15. Early aortic valve cusp rupture in relapsing polychondritis.

    PubMed Central

    Marshall, D A; Jackson, R; Rae, A P; Capell, H A

    1992-01-01

    Aortic regurgitation associated with relapsing polychondritis usually occurs late in the disease as a result of aortic root dilatation. A case where aortic regurgitation occurred early and was due to cusp rupture with a normal aortic root is reported. The patient required urgent aortic valve replacement within six weeks of developing a murmur despite apparent control of inflammation with immunosuppressive treatment. The possibility of cusp rupture with sudden haemodynamic deterioration should be considered in patients with relapsing polychondritis who develop aortic regurgitation. Images PMID:1575597

  16. Sodium nitrite exerts an antihypertensive effect and improves endothelial function through activation of eNOS in the SHR

    PubMed Central

    Ling, Wei Chih; Murugan, Dharmani Devi; Lau, Yeh Siang; Vanhoutte, Paul M.; Mustafa, Mohd Rais

    2016-01-01

    Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L−1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS. PMID:27616322

  17. eNOS gene Glu298Asp and 4b/a polymorphisms are associated with renal function parameters in Mexican patients with Fabry disease.

    PubMed

    Marin-Medina, A; Brambila-Tapia, A J L; Picos-Cárdenas, V J; Gallegos-Arreola, M P; Figuera, L E

    2016-10-24

    Fabry disease (FD) is an inherited X-linked lysosomal disease that causes renal failure in a high percentage of affected individuals. The eNOS gene encodes for endothelial nitric oxide synthase, which plays an important role in glomerular hemodynamics. This gene has two main polymorphisms (Glu298Asp and 4b/a) that have been studied in the context of many different diseases, including those involving cardiovascular and renal alterations. Considering the lack of information regarding eNOS variants and FD, we investigated whether there were associations between eNOS genetic variants and renal function parameters in Mexican patients with FD and renal impairment. In total, 15 FD patients with renal alterations were included in the present study, and associations between eNOS polymorphisms and renal function parameters (urea, creatinine, and GFR) were evaluated. The Asp298 and 4a alleles of the eNOS gene were found to be significantly associated with increased levels of urea and creatinine, and a decreased glomerular filtration rate in FD patients, and this association behaved in a co-dominant fashion. Our results coincide with previous reports showing an association between these polymorphisms and kidney disease, and along with other studies regarding their role in the nitric oxide pathway, suggest that these variants affect the severity of nephropathy in patients with FD.

  18. Aortic Dissection in Patients With Bicuspid Aortic Valve–Associated Aneurysms

    PubMed Central

    Wojnarski, Charles M.; Svensson, Lars G.; Roselli, Eric E.; Idrees, Jay J.; Lowry, Ashley M.; Ehrlinger, John; Pettersson, Gösta B.; Gillinov, A. Marc; Johnston, Douglas R.; Soltesz, Edward G.; Navia, Jose L.; Hammer, Donald F.; Griffin, Brian; Thamilarasan, Maran; Kalahasti, Vidyasagar; Sabik, Joseph F.; Blackstone, Eugene H.; Lytle, Bruce W.

    2016-01-01

    Background Data regarding the risk of aortic dissection in patients with bicuspid aortic valve and large ascending aortic diameter are limited, and appropriate timing of prophylactic ascending aortic replacement lacks consensus. Thus our objectives were to determine the risk of aortic dissection based on initial cross-sectional imaging data and clinical variables and to isolate predictors of aortic intervention in those initially prescribed serial surveillance imaging. Methods From January 1995 to January 2014, 1,181 patients with bicuspid aortic valve underwent cross-sectional computed tomography (CT) or magnetic resonance imaging (MRI) to ascertain sinus or tubular ascending aortic diameter greater than or equal to 4.7 cm. Random Forest classification was used to identify risk factors for aortic dissection, and among patients undergoing surveillance, time-related analysis was used to identify risk factors for aortic intervention. Results Prevalence of type A dissection that was detected by imaging or was found at operation or on follow-up was 5.3% (n = 63). Probability of type A dissection increased gradually at a sinus diameter of 5.0 cm—from 4.1% to 13% at 7.2 cm—and then increased steeply at an ascending aortic diameter of 5.3 cm—from 3.8% to 35% at 8.4 cm—corresponding to a cross-sectional area to height ratio of 10 cm2/m for sinuses of Valsalva and 13 cm2/m for the tubular ascending aorta. Cross-sectional area to height ratio was the best predictor of type A dissection (area under the curve [AUC] = 0.73). Conclusions Early prophylactic ascending aortic replacement in patients with bicuspid aortic valve should be considered at high-volume aortic centers to reduce the high risk of preventable type A dissection in those with aortas larger than approximately 5.0 cm or with a cross-sectional area to height ratio greater than approximately 10 cm2/m. PMID:26209494

  19. Aortobronchial Fistula after Thoracic Endovascular Aortic Repair (TEVAR) for Descending Thoracic Aortic Aneurysm.

    PubMed

    Melvan, John Nicholas; DeLaRosa, Jacob; Vasquez, Julio C

    2017-03-07

    Continued enlargement of the aneurysm sac after thoracic endovascular aortic repair (TEVAR) is a known risk after endovascular treatment of thoracic aortic aneurysms. For this reason, periodic outpatient follow-up is required to identify situations that require repair. Here, we describe an aortobronchial fistula (ABF) in a patient lost to follow-up, that presented 3 years after an elective TEVAR done for a primary, descending thoracic aortic aneurysm. Our patient arrived in extremis and suffered massive hemoptysis leading to her demise. Computed tomography (CT) angiogram near the time of her death demonstrated a bleeding ABF immediately distal to her previous TEVAR repair. Aortic aneurysmal disease remains life threatening even after repair. Improved endovascular techniques and devices have resulted in decreased need for reintervention. However, this case demonstrates the risk of thoracic aortic disease progression and highlights the importance of establishing consistent, long-term follow-up after TEVAR.

  20. Percutaneous balloon aortic valvuloplasty in the era of transcatheter aortic valve implantation: a narrative review

    PubMed Central

    Keeble, Thomas R; Khokhar, Arif; Akhtar, Mohammed Majid; Mathur, Anthony; Weerackody, Roshan; Kennon, Simon

    2016-01-01

    The role of percutaneous balloon aortic valvuloplasty (BAV) in the management of severe symptomatic aortic stenosis has come under the spotlight following the development of the transcatheter aortic valve implantation (TAVI) technique. Previous indications for BAV were limited to symptom palliation and as a bridge to definitive therapy for patients undergoing conventional surgical aortic valve replacement (AVR). In the TAVI era, BAV may also be undertaken to assess the ‘therapeutic response’ of a reduction in aortic gradient in borderline patients often with multiple comorbidities, to assess symptomatic improvement prior to consideration of definitive TAVI intervention. This narrative review aims to update the reader on the current indications and practical techniques involved in undertaking a BAV procedure. In addition, a summary of the haemodynamic and clinical outcomes, as well as the frequently encountered procedural complications is presented for BAV procedures conducted during both the pre-TAVI and post-TAVI era. PMID:28008354

  1. Patch annulo-aortoplasty in an adult patient with congenital supravalvular aortic stenosis and a small aortic annulus.

    PubMed

    Morimoto, Naoto; Morimoto, Keisuke; Morimoto, Yoshihisa; Tanaka, Akiko; Sakamoto, Toshihito; Okada, Kenji; Okita, Yutaka

    2011-08-01

    A 39-year-old woman with familial homozygous hypercholesterolemia had supravalvular and valvular aortic stenosis. Modified Nick's procedure and aortic valve replacement was performed to relieve both the supravalvular and annular stenoses. At surgery, the ascending aorta was found to be narrowing at the level of the sinotubular junction, which was compatible with congenital supravalvular aortic stenosis. Histological examination of the aortic cusps showed sclerotic change due to hypercholesterolemia. These findings indicated that familial homozygous hypercholesterolemia caused valvular aortic stenosis and exacerbated congenital supravalvular aortic stenosis.

  2. Repeated thermal therapy upregulates arterial endothelial nitric oxide synthase expression in Syrian golden hamsters.

    PubMed

    Ikeda, Y; Biro, S; Kamogawa, Y; Yoshifuku, S; Eto, H; Orihara, K; Kihara, T; Tei, C

    2001-05-01

    It has been previously reported that sauna therapy, a thermal therapy, improves the hemodynamics and clinical symptoms in patients with chronic heart failure and also improves endothelial function, which is impaired in such patients. The present study investigated whether the improvements observed with sauna therapy are through modulation of arterial endothelial nitric oxide synthase (eNOS) expression. Eight male Syrian golden hamsters underwent sauna therapy, using an experimental far infrared-ray dry sauna system, at 39 degrees C for 15 min followed by 30 degrees C for 20 min daily for 4 weeks. Control group hamsters were placed in the sauna system switched off at room temperature of 24 degrees C for 35 min. Immunohistochemistry found greater amounts of the immunoreactive products of eNOS in the endothelial cells of the aorta and carotid, femoral and coronary arteries in the sauna group than in the control group. Western blot analysis also revealed that 4-week sauna therapy significantly increased eNOS expression in aortas by 50% in 4 series of independent experiments with an identical protocol (p<0.01). In reverse transcription polymerase chain reaction assay, the eNOS mRNA in aortas was greater in the sauna group than in controls, with a peak at 1-week of sauna therapy (approximately 40-fold increase). In conclusion, repeated thermal therapy upregulates eNOS expression in arterial endothelium.

  3. Caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats.

    PubMed

    Ozbek, Emin; Simsek, Abdulmuttalip; Ozbek, Mustafa; Somay, Adnan

    2013-09-26

    Because of the positive corelation between healthy cardiovascular system and sexual life we aimed to evaluate the effect of caloric restriction (CR) on endothelial and neuronal nitric oxide synthase (eNOS, nNOS) expression in cavernousal tissues and eNOS expression in the internal iliac artery in young and aged rats. Young (3 mo, n = 7) and aged (24 mo, n = 7) male Sprague-Dawley rats were subjected to 40% CR and were allowed free access to water for 3 months. Control rats (n = 14) fed ad libitum had free access to food and water at all times. On day 90, rats were sacrificed and internal iliac arteries and penis were removed and parafinized, eNOS and nNOS expression evaluated with immunohistochemistry. Results were evaluated semiquantitatively. eNOS and nNOS expression in cavernousal tis- sue in CR rats were more strong than in control group in both young and old rats. eNOS expression was also higher in the internal iliac arteries of CR rats than in control in young and old rats. As a result of our study we can say that there is a positive link between CR and neurotransmitter of erection in cavernousal tissues and internal iliac arteries. CR has beneficial effect to prevent sexual dysfunction in young and old animals and possible humans.

  4. [New technique of concomitant replacement of the aortic valve and the ascending aorta with enlargement of the aortic annulus for congenital bicuspid aortic valve].

    PubMed

    Takahara, Shingo; Fukasawa, Manabu; Kawahara, Yu; Suzuki, Kotaro; Kobayashi, Yuriko

    2012-12-01

    Congenital bicuspid aortic valve (BAV) is one of the most common congenital heart diseases, with a high incidence of associated valvular lesions and aortic abnormalities including aortic stenosis( AS), aortic regurgitation, aortic dilatation, and aortic dissection. Patients with BAV and AS often have a small aortic annulus. We encountered a case of BAV in which a 51-year-old woman with severe AS having a small aortic annulus and a dilated ascending aorta required surgical intervention. We performed the surgery using new technique that involved concomitant replacement of the aortic valve and the ascending aorta with enlargement of the aortic annulus using a single uniquely-shaped graft to avoid prosthesis patient mismatch. We trimmed the proximal end of the straight graft in shape of 2 teardrops hanging on it to fit the cut annulus. It requires only a single suture line to replace the ascending aorta and enlarge the aortic annulus, which entails a decreased risk of bleeding during surgery. We believe that it could be applicable to many cases requiring concomitant surgery.

  5. Genetically alike Syrian hamsters display both bifoliate and trifoliate aortic valves.

    PubMed

    Sans-Coma, Valentín; Carmen Fernández, M; Fernández, Borja; Durán, Ana C; Anderson, Robert H; Arqué, Josep M

    2012-01-01

    The bifoliate, or bicuspid, aortic valve (BAV) is the most frequent congenital cardiac anomaly in man. It is a heritable defect, but its mode of inheritance remains unclear. Previous studies in Syrian hamsters showed that BAVs with fusion of the right and left coronary leaflets are expressions of a trait, the variation of which takes the form of a phenotypic continuum. It ranges from a trifoliate valve with no fusion of the coronary leaflets to a bifoliate root devoid of any raphe. The intermediate stages are represented by trifoliate valves with fusion of the coronary aortic leaflets, and bifoliate valves with raphes. The aim of this study was to elucidate whether the distinct morphological variants rely on a common genotype, or on different genotypes. We examined the aortic valves from 1 849 Syrian hamsters belonging to a family subjected to systematic inbreeding by full-sib mating. The incidence of the different trifoliate aortic valve (TAV) and bifoliate aortic valve (BAV) morphological variants widely varied in the successive inbred generations. TAVs with extensive fusion of the leaflets, and BAVs, accounted for five-sixths of the patterns found in Syrian hamsters considered to be genetically alike or virtually isogenic, with the probability of homozygosity being 0.999 or higher. The remaining one-sixth hamsters had aortic valves with a tricuspid design, but in most cases the right and left coronary leaflets were slightly fused. Results of crosses between genetically alike hamsters, with the probability of homozygosity being 0.989 or higher, revealed no significant association between the valvar phenotypes in the parents and their offspring. Our findings are consistent with the notion that the BAVs of the Syrian hamster are expressions of a quantitative trait subject to polygenic inheritance. They suggest that the genotype of the virtually isogenic animals produced by systematic inbreeding greatly predisposes to the development of anomalous valves, be they

  6. Role of the CX3C chemokine receptor CX3CR1 in the pathogenesis of atherosclerosis after aortic transplantation

    PubMed Central

    Koeppel, Thomas A.; Sanati, Maryam; Schelzig, Hubert; Jankowski, Joachim; Weber, Christian

    2017-01-01

    Background The CX3C chemokine receptor CX3CR1 is expressed on monocytes as well as tissue resident cells, such as smooth muscle cells (SMCs). Its role in atherosclerotic tissue remodeling of the aorta after transplantation has not been investigated. Methods We here have orthotopically transplanted infrarenal Cx3cr1-/-Apoe-/- and Cx3cr1+/+Apoe-/- aortic segments into Apoe-/-mice, as well as Apoe-/- aortic segments into Cx3cr1-/-Apoe-/- mice. The intimal plaque size and cellular plaque composition of the transplanted aortic segment were analyzed after four weeks of atherogenic diet. Results Transplantation of Cx3cr-/-Apoe-/- aortic segments into Apoe-/- mice resulted in reduced atherosclerotic plaque formation compared to plaque size in Apoe-/- or Cx3cr1-/-Apoe-/- mice after transplantation of Apoe-/- aortas. This reduction in lesion formation was associated with reduced numbers of lesional SMCs but not macrophages within the transplanted Cx3cr-/- Apoe-/- aortic segment. No differences in frequencies of proliferating and apoptotic cells could be observed. Conclusion These results indicate that CX3CR1 on resident vessel wall cells plays a key role in atherosclerotic plaque formation in transplanted aortic grafts. Targeting of vascular CX3CL1/CX3CR1 may therefore be explored as a therapeutic option in vascular transplantation procedures. PMID:28234900

  7. Cardioprotection of exogenous erythropoietin in mice with ligature-induced aortic stenosis: effects on maladaptive cardiac hypertrophy.

    PubMed

    Zheng, L; Xu, J; Qiu, W; Liu, X; Zhao, C-M; Chen, D; Chen, Y

    2010-02-01

    Pre-operative treatment with recombinant human erythropoietin may improve aortic stenosis patients' condition, including anemia and/or cardiac dysfunction, for subjecting to aortic valve replacement. In this study, we tested this hypothesis in a mouse model of aortic stenosis. Adult male mice were subjected to either aortic stenosis created by aortic ligature or sham operation. Aortic stenosis for 4 weeks caused cardiac hypertrophy, pulmonary congestion and left ventricular dysfunction. It was associated with increased levels of tumor necrosis factor-alpha in serum and myocardium, and reduced levels of interleukin-10 in myocardium but not in serum. Myocyte apoptosis rate, level of cleaved caspase 3, activity of nuclear factor-kappaB and expression of p38-MAPK pathway were also elevated. Erythropoietin treatment increased hematocrit but did not prevent the development of cardiac hypertrophy. It, however, reduced the apoptosis, prevented the increases in tumor necrosis factor-alpha, nuclear factor-kappaB activation and phosphorylation of p38, and attenuated the increases in lung weight, the decreases in LVEF and LVFS, and the increases in LVDd and LVDs. In conclusion recombinant human erythropoietin has cardioprotective effects in maladaptive cardiac hypertrophy by inhibiting nuclear factor-kappaB activation, phosphorylation of p38-MAPK pathway, and production of tumor necrosis factor-alpha, together leading to a reduced apoptosis.

  8. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.

    PubMed

    Boileau, Catherine; Guo, Dong-Chuan; Hanna, Nadine; Regalado, Ellen S; Detaint, Delphine; Gong, Limin; Varret, Mathilde; Prakash, Siddharth K; Li, Alexander H; d'Indy, Hyacintha; Braverman, Alan C; Grandchamp, Bernard; Kwartler, Callie S; Gouya, Laurent; Santos-Cortez, Regie Lyn P; Abifadel, Marianne; Leal, Suzanne M; Muti, Christine; Shendure, Jay; Gross, Marie-Sylvie; Rieder, Mark J; Vahanian, Alec; Nickerson, Deborah A; Michel, Jean Baptiste; Jondeau, Guillaume; Milewicz, Dianna M

    2012-07-08

    A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

  9. Regulation of vascular endothelial genes by dietary flavonoids: structure-expression relationship studies and the role of the transcription factor KLF-2.

    PubMed

    Martínez-Fernández, Leyre; Pons, Zara; Margalef, Maria; Arola-Arnal, Anna; Muguerza, Begoña

    2015-03-01

    Physiological concentrations (1 μM) of 15 flavonoids were evaluated in human umbilical vein endothelial cells in the presence of hydrogen peroxide (H₂O₂) for their ability to affect endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression in order to establish the structural basis of their bioactivity. Flavonoid effects on eNOS transcription factor Krüpple like factor-2 (KLF-2) expression were also evaluated. All studied flavonoids appeared to be effective compounds for counteracting the oxidative stress-induced effects on vascular gene expression, indicating that flavonoids are an excellent source of functional endothelial regulator products. Notably, the more effective flavonoids for KLF-2 up-regulation resulted in the highest values for eNOS expression, showing that the increment of eNOS expression would take place through KLF-2 induction. Structure-activity relationship studies showed that the combinations of substructures on flavonoid skeleton that regulate eNOS expression are made up of the following elements: glycosylation and hydroxylation of C-ring, double bond C2=C3 at C-ring, methoxylation and hydroxylation of B-ring, ketone group in C4 at C-ring and glycosylation in C7 of A-ring, while flavonoid features involved in the reduction of vasoconstrictor ET-1 expression are as follows: double bond C2=C3 at C-ring glycosylation in C7 of A-ring and ketone group in C4 of C-ring.

  10. Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms.

    PubMed Central

    Koch, A. E.; Kunkel, S. L.; Pearce, W. H.; Shah, M. R.; Parikh, D.; Evanoff, H. L.; Haines, G. K.; Burdick, M. D.; Strieter, R. M.

    1993-01-01

    Inflammatory leukocytes play a central role in the pathogenesis of human atherosclerotic disease, from early atherogenesis to the late stages of atherosclerosis, such as aneurysm formation. We have shown previously that human abdominal aortic aneurysms are characterized by the presence of numerous chronic inflammatory cells throughout the vessel wall (Am J Pathol 1990, 137: 1199-1213). The signals that attract lymphocytes and monocytes into the aortic wall in aneurysmal disease remain to be precisely defined. We have studied the production of the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by aortic tissues obtained from 47 subjects. We compared the antigenic production of these cytokines by explants of: 1) human abdominal aneurysmal tissue, 2) occlusive (atherosclerotic) aortas, and 3) normal aortas. IL-8, which is chemotactic for neutrophils, lymphocytes, and endothelial cells was liberated in greater quantities by abdominal aortic aneurysms than by occlusive or normal aortas. Using immunohistochemistry, macrophages, and to a lesser degree endothelial cells, were found to be positive for the expression of antigenic IL-8. Similarly, MCP-1, a potent chemotactic cytokine for monocytes/macrophages, was released by explants from abdominal aortic aneurysms in greater quantities than by explants from occlusive or normal aortas. Using immunohistochemistry, the predominant MCP-1 antigen-positive cells were macrophages and to a lesser extent smooth muscle cells. Our results indicate that human abdominal aortic aneurysms produce IL-8 and MCP-1, both of which may serve to recruit additional inflammatory cells into the abdominal aortic wall, hence perpetuating the inflammatory reaction that may result in the pathology of vessel wall destruction and aortic aneurysm formation. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:8494046

  11. Oral administration of diferuloylmethane (curcumin) suppresses proinflammatory cytokines and destructive connective tissue remodeling in experimental abdominal aortic aneurysms.

    PubMed

    Parodi, Federico E; Mao, Dongli; Ennis, Terri L; Pagano, Monica B; Thompson, Robert W

    2006-05-01

    Chronic transmural inflammation and proteolytic destruction of medial elastin are key mechanisms in the development of abdominal aortic aneurysms (AAAs). Diferuloylmethane (curcumin) is a major component of the food additive tumeric, which has been shown to have anti-inflammatory properties. To determine if ingestion of curcumin influences aneurysmal degeneration, C57Bl/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs, followed by daily oral gavage with 100 mg/kg curcumin (n = 36) or water alone (n = 31). By 14 days, mice in the control group developed a mean increase in aortic diameter of 162.8 +/- 4.6% along with a dense mononuclear inflammation and destruction of medial elastin. By comparison, the mean increase in aortic diameter in the curcumin-treated group was only 133.2 +/- 5.2% (p < 0.0001). Although aortic wall inflammation was similar between the groups, the structural integrity of medial elastin was significantly greater in curcumin-treated mice. Curcumin-treated mice also exhibited relative decreases in aortic tissue activator protein-1 and nuclear factor kappaB DNA binding activities and significantly lower aortic tissue concentrations of interleukin-1beta (IL-1beta), IL-6, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 (all p < 0.05). These data demonstrate for the first time that oral administration of curcumin can suppress the development of experimental AAAs, along with structural preservation of medial elastin fibers and reduced aortic wall expression of several cytokines, chemokines, and proteinases known to mediate aneurysmal degeneration. The possibility that dietary ingestion of curcumin may have a beneficial effect in degenerative aortic aneurysms warrants further consideration.

  12. MicroRNAs, fibrotic remodeling, and aortic aneurysms

    PubMed Central

    Milewicz, Dianna M.

    2012-01-01

    Aortic aneurysms are a common clinical condition that can cause death due to aortic dissection or rupture. The association between aortic aneurysm pathogenesis and altered TGF-β signaling has been the subject of numerous investigations. Recently, a TGF-β–responsive microRNA (miR), miR-29, has been identified to play a role in cellular phenotypic modulation during aortic development and aging. In this issue of JCI, Maegdefessel and colleagues demonstrate that decreasing the levels of miR-29b in the aortic wall can attenuate aortic aneurysm progression in two different mouse models of abdominal aortic aneurysms. This study highlights the relevance of miR-29b in aortic disease but also raises questions about its specific role. PMID:22269322

  13. Acute thoracic aortic dissection: how to defuse a time bomb.

    PubMed

    McClarren-Curry, C; Shaughnessy, K

    1999-01-01

    Acute thoracic aortic dissection is frequently misdiagnosed, and even with surgical intervention, the mortality rate is 50%. This article focuses on assessment, interventions, and postoperative care of patients with aortic dissection.

  14. Talk to Your Doctor about Abdominal Aortic Aneurysm

    MedlinePlus

    ... español Talk to Your Doctor about Abdominal Aortic Aneurysm Browse Sections The Basics Overview What is AAA? ... doctor about getting screened (tested) for abdominal aortic aneurysm (AAA). If AAA isn't found and treated ...

  15. Flow in an Aortic Coarctation

    NASA Astrophysics Data System (ADS)

    Loma, Luis; Miller, Paul; Hertzberg, Jean

    2009-11-01

    Coarctation of the aorta is a congenital cardiovascular defect that causes a constriction in the descending thoracic aorta. To gain a better understanding of the cause of post-surgical problems, a rigid glass and a compliant in vitro model of the aortic arch and descending aorta with a coarctation were constructed. Near-physiologic compliance was obtained using a silicone elastomer. Stereoscopic PIV was used to obtain 3D velocity maps. Results show a high speed turbulent jet formed at the exit of the coarctation. Flow in the rigid model was significantly different from in the compliant model. In the rigid model, the jet was symmetric, creating a toroidal recirculation area. In the compliant model, the jet was directed towards the medial wall, inducing flow reversal only at the lateral wall. Peak velocities and turbulence intensities were higher in the rigid model, however shear rate values in the compliant model were significantly above both the rigid model and normal in vivo values at the medial wall. In both models the reattachment region fluctuated, creating oscillatory shear.

  16. Intra-aortic balloon pumps.

    PubMed

    1997-05-01

    Intra-aortic balloon pumps (IABPs) are circulatory assist devices used to treat a number of cardiovascular conditions. IABPs provide temporary circulatory support by reducing the resistance to blood flow out of the heart during systole and by providing added pressure to aid in perfusing the heart during diastole. In this Evaluation, we tested three IABPs from three suppliers. We examined the units' technical performance, safety and monitoring, human factors design, transport operation, and supplier support. Rather than test all the triggering (activation) modes available, we focused our testing on the modes most commonly used on each unit. We also provide information on an IABP currently available only in Japan; although we did not test this unit, we do provide a preliminary judgment based on the information provided to us by the supplier. In the Technology Overview also included in the Evaluation, we describe the basic operation and use of an IABP, as well as review the state of the art of this technology. And in the Selection, Purchasing, and Use Guide at the conclusion of the Evaluation, we discuss such topics as balloon costs and sizing, interfacing IABPs with patient monitors, and the use of IABPs in community hospitals.

  17. Rapid prototyping in aortic surgery.

    PubMed

    Bangeas, Petros; Voulalas, Grigorios; Ktenidis, Kiriakos

    2016-04-01

    3D printing provides the sequential addition of material layers and, thus, the opportunity to print parts and components made of different materials with variable mechanical and physical properties. It helps us create 3D anatomical models for the better planning of surgical procedures when needed, since it can reveal any complex anatomical feature. Images of abdominal aortic aneurysms received by computed tomographic angiography were converted into 3D images using a Google SketchUp free software and saved in stereolithography format. Using a 3D printer (Makerbot), a model made of polylactic acid material (thermoplastic filament) was printed. A 3D model of an abdominal aorta aneurysm was created in 138 min, while the model was a precise copy of the aorta visualized in the computed tomographic images. The total cost (including the initial cost of the printer) reached 1303.00 euros. 3D imaging and modelling using different materials can be very useful in cases when anatomical difficulties are recognized through the computed tomographic images and a tactile approach is demanded preoperatively. In this way, major complications during abdominal aorta aneurysm management can be predicted and prevented. Furthermore, the model can be used as a mould; the development of new, more biocompatible, less antigenic and individualized can become a challenge in the future.

  18. Neurological Complications Following Endoluminal Repair of Thoracic Aortic Disease

    SciTech Connect

    Morales, J. P.; Taylor, P. R.; Bell, R. E.; Chan, Y. C.; Sabharwal, T.; Carrell, T. W. G.; Reidy, J. F.

    2007-09-15

    Open surgery for thoracic aortic disease is associated with significant morbidity and the reported rates for paraplegia and stroke are 3%-19% and 6%-11%, respectively. Spinal cord ischemia and stroke have also been reported following endoluminal repair. This study reviews the incidence of paraplegia and stroke in a series of 186 patients treated with thoracic stent grafts. From July 1997 to September 2006, 186 patients (125 men) underwent endoluminal repair of thoracic aortic pathology. Mean age was 71 years (range, 17-90 years). One hundred twenty-eight patients were treated electively and 58 patients had urgent procedures. Anesthesia was epidural in 131, general in 50, and local in 5 patients. Seven patients developed paraplegia (3.8%; two urgent and five elective). All occurred in-hospital apart from one associated with severe hypotension after a myocardial infarction at 3 weeks. Four of these recovered with cerebrospinal fluid (CSF) drainage. One patient with paraplegia died and two had permanent neurological deficit. The rate of permanent paraplegia and death was 1.6%. There were seven strokes (3.8%; four urgent and three elective). Three patients made a complete recovery, one had permanent expressive dysphasia, and three died. The rate of permanent stroke and death was 2.1%. Endoluminal treatment of thoracic aortic disease is an attractive alternative to open surgery; however, there is still a risk of paraplegia and stroke. Permanent neurological deficits and death occurred in 3.7% of the patients in this series. We conclude that prompt recognition of paraplegia and immediate insertion of a CSF drain can be an effective way of recovering spinal cord function and improving the prognosis.

  19. NOX4-dependent Hydrogen peroxide promotes shear stress-induced SHP2 sulfenylation and eNOS activation.

    PubMed

    Sánchez-Gómez, Francisco J; Calvo, Enrique; Bretón-Romero, Rosa; Fierro-Fernández, Marta; Anilkumar, Narayana; Shah, Ajay M; Schröder, Katrin; Brandes, Ralf P; Vázquez, Jesús; Lamas, Santiago

    2015-12-01

    Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12 dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2-hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor HyPer. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4-null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation.

  20. Targeting eNOS and beyond: Emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

    PubMed Central

    Sawada, Naoki; Liao, James K.

    2010-01-01

    Summary Currently available modalities for the treatment of acute ischemic stroke are aimed to preserve or augment cerebral blood flow (CBF). Experimental evidence suggests that statins, which show 25–30% reduction of stroke incidence in clinical trials, confer stroke protection by upregulation of eNOS and increasing CBF. The upregulation of eNOS by statins is mediated by inhibition of small GTP-binding protein RhoA. Our recent study uncovered a unique role for a Rho-family member Rac1 in stroke protection. Rac1 in endothelium does not affect CBF. Instead, inhibition of endothelial Rac1 leads to broad upregulation of genes relevant to neurovascular protection. Intriguingly, inhibition of endothelial Rac1 enhances neuronal cell survival through endothelium-derived neurotrophic factors including artemin. This review discusses the emerging therapeutic opportunities to target the neurovascular signaling beyond the blood-brain barrier, with special emphasis on the novel role of endothelial Rac1 in stroke protection. PMID:19673606

  1. Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice

    PubMed Central

    Veron, Delma; Aggarwal, Pardeep K.; Velazquez, Heino; Kashgarian, Michael; Moeckel, Gilbert

    2014-01-01

    VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF164 gain of function in eNOS−/− mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF164 gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS−/− mice with podocyte-specific VEGF164 gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF164 gain of function decreased glomerular S-nitrosylation of laminin in eNOS−/− mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilson–like nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin. PMID:24578128

  2. Association of Common Variants in eNOS Gene with Primary Open Angle Glaucoma: A Meta-Analysis

    PubMed Central

    Xiang, Yang; Dong, Yi; Li, Xuan; Tang, Xin

    2016-01-01

    Purpose. To clarify the association of endothelial nitric oxide synthase (eNOS) polymorphisms and primary open angle glaucoma (POAG). Methods. After a systematic literature search in the MEDLINE, EMBASE, and ISI Web of Science databases, all relevant studies evaluating the association between the polymorphisms (rs2070744 and rs1799983) of eNOS gene and POAG were screened and included. The pooled odds ratios (ORs) and the 95% confidence interval (CI) of each single-nucleotide polymorphism (SNP) in five genetic models were estimated using fixed-effect model if I2 < 50% in the test for heterogeneity; otherwise the random-effects model was used. Results. Thirty-one records were obtained, with five being suitable for meta-analysis. The overall results showed that both TT genotype in rs2070744 and GG genotype in rs1799983 are associated with decreased risk of POAG susceptibility. Stratified analysis based on ethnicity showed that the association of rs2070744 with POAG remained only in Caucasians. Results of subgroup analysis by sex indicated association between both polymorphisms and POAG in female group, but not in male group. Conclusions. TT genotype and/or T-allele in rs2070744, as well as GG genotype and/or G-allele in rs1799983, was associated with decreased risk for POAG overall and in female group. PMID:27242919

  3. Finite-volume application of high order ENO schemes to multi-dimensional boundary-value problems

    NASA Technical Reports Server (NTRS)

    Casper, Jay; Dorrepaal, J. Mark

    1990-01-01

    The finite volume approach in developing multi-dimensional, high-order accurate essentially non-oscillatory (ENO) schemes is considered. In particular, a two dimensional extension is proposed for the Euler equation of gas dynamics. This requires a spatial reconstruction operator that attains formal high order of accuracy in two dimensions by taking account of cross gradients. Given a set of cell averages in two spatial variables, polynomial interpolation of a two dimensional primitive function is employed in order to extract high-order pointwise values on cell interfaces. These points are appropriately chosen so that correspondingly high-order flux integrals are obtained through each interface by quadrature, at each point having calculated a flux contribution in an upwind fashion. The solution-in-the-small of Riemann's initial value problem (IVP) that is required for this pointwise flux computation is achieved using Roe's approximate Riemann solver. Issues to be considered in this two dimensional extension include the implementation of boundary conditions and application to general curvilinear coordinates. Results of numerical experiments are presented for qualitative and quantitative examination. These results contain the first successful application of ENO schemes to boundary value problems with solid walls.

  4. Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina

    PubMed Central

    Jiang, Youde; Zhang, Qiuhua; Steinle, Jena J.

    2015-01-01

    Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel β-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)ζ and PKCδ phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCζ and PKCδ phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties. PMID:26115368

  5. Research of Customized Aortic Stent Graft Manufacture

    NASA Astrophysics Data System (ADS)

    Zhang, Lei; Chen, Xin; Liu, Muhan

    2017-03-01

    Thoracic descending aorta diseases include aortic dissection and aortic aneurysm, of which the natural mortality rate is extremely high. At present, endovascular aneurysm repair (EVAR) has been widely used as an effective means for the treatment of descending aortic disease. Most of the existing coating stents are standard design, which are unable to meet the size or structure of different patients. As a result, failure of treatment would be caused by dimensional discrepancy between stent and vessels, which could lead to internal leakage or rupture of blood vessels. Therefore, based on rapid prototyping sacrificial core – coating forming (RPSC-CF), a customized aortic stent graft manufactured technique has been proposed in this study. The aortic stent graft consists of film and metallic stent, so polyether polyurethane (PU) and nickel-titanium (NiTi) shape memory alloy with good biocompatibility were chosen. To minimum film thickness without degrading performance, effect of different dip coating conditions on the thickness of film were studied. To make the NiTi alloy exhibit super-elasticity at body temperature (37°C), influence of different heat treatment conditions on austenite transformation temperature (Af) and mechanical properties were studied. The results show that the customized stent grafts could meet the demand of personalized therapy, and have good performance in blasting pressure and radial support force, laying the foundation for further animal experiment and clinical experiment.

  6. Phonocardiographic diagnosis of aortic ball variance.

    PubMed

    Hylen, J C; Kloster, F E; Herr, R H; Hull, P Q; Ames, A W; Starr, A; Griswold, H E

    1968-07-01

    Fatty infiltration causing changes in the silastic poppet of the Model 1000 series Starr-Edwards aortic valve prostheses (ball variance) has been detected with increasing frequency and can result in sudden death. Phonocardiograms were recorded on 12 patients with ball variance confirmed by operation and of 31 controls. Ten of the 12 patients with ball variance were distinguished from the controls by an aortic opening sound (AO) less than half as intense as the aortic closure sound (AC) at the second right intercostal space (AO/AC ratio less than 0.5). Both AO and AC were decreased in two patients with ball variance, with the loss of the characteristic high frequency and amplitude of these sounds. The only patient having a diminished AO/AC ratio (0.42) without ball variance at reoperation had a clot extending over the aortic valve struts. The phonocardiographic findings have been the most reliable objective evidence of ball variance in patients with Starr-Edwards aortic prosthesis of the Model 1000 series.

  7. Advances in Transcatheter Aortic Valve Replacement

    PubMed Central

    Kleiman, Neal S.; Reardon, Michael J.

    2016-01-01

    Transcatheter aortic valve replacement (TAVR) is becoming widely used for the treatment of symptomatic severe aortic stenosis in patients with high surgical risk. Data from The PARTNER Trial (Placement of AoRtic TraNscathetER Valves) and the Medtronic CoreValve® U.S. Pivotal Investigational Device Exemption trial indicate that survival for extreme-risk patients is superior to best medical therapy and equivalent or superior to surgical aortic valve replacement (SAVR), although long-term durability remains unknown. Paravalvular leak remains higher in TAVR than SAVR, as does permanent pacemaker implantation in self-expanding valves. New-generation valves are addressing these issues, especially for paravalvular leak. There is strong evidence that TAVR is appropriate for both extreme-risk and high-risk patients with symptomatic severe aortic stenosis, and the continued development of new valves are making implantation more reliable. This review discusses the studies supporting the use of TAVR and explores current advances in the field. PMID:27127560

  8. Tracheal replacement with an aortic autograft.

    PubMed

    Azorin, Jacques F; Bertin, Francois; Martinod, Emmanuel; Laskar, Marc

    2006-02-01

    Tracheal replacement after extensive resection remains a challenge for the thoracic surgeon. We propose an innovative solution: the use of an aortic autograft. After an experimental work on animals with aortic autografts and allografts [Martinod E, Seguin A, Pfeuty K, Fornes P, Kambouchner M, Azorin JF, Carpentier AF. Long-term evaluation of the replacement of the trachea with an autologous aortic graft. Ann Thorac Surg 2003;75(5):1572-8; Martinod E, Seguin A, Holder-Espinasse M, Kambouchner M, Duterque-Coquillaud M, Azorin JF, Carpentier AF. Tracheal regeneration following tracheal replacement with an allogenic aorta. Ann Thorac Surg 2005;79(3):942-8], we present the first human case of long tracheal replacement with an aortic autograft. In this case we replaced 7 cm of a tumoral trachea using an aortic infra-renal autograft supported by a silicone stent. The early postoperative course was uneventful. The stent was removed at three months. The patient died at six months from an acute pulmonary infection without any sign of anastomosis leakage or graft rupture. A new field of clinical study has to be investigated.

  9. Primary Stenting in Infrarenal Aortic Occlusive Disease

    SciTech Connect

    Nyman, Ulf; Uher, Petr; Lindh, Mats; Lindblad, Bengt; Ivancev, Krasnodar

    2000-03-15

    Purpose: To evaluate the results of primary stenting in aortic occlusive disease.Methods: Thirty patients underwent primary stenting of focal concentric (n = 2) and complex aortic stenoses (n = 19), and aortic or aorto-iliac occlusions (n = 9). Sixteen patients underwent endovascular outflow procedures, three of whom also had distal open surgical reconstructions. Median follow-up was 16 months (range 1-60 months).Results: Guidewire crossing of two aorto-biiliac occlusions failed, resulting in a 93% (28/30) technical success. Major complications included one access hematoma, one myocardial infarction, one death (recurrent thromboembolism) in a patient with widespread malignancy, and one fatal hemorrhage during thrombolysis of distal emboli from a recanalized occluded iliac artery. One patient did not improve his symptoms, resulting in a 1-month clinical success of 83% (25/30). Following restenting the 26 stented survivors changed their clinical limb status to +3 (n = 17) and +2 (n = 9). During follow-up one symptomatic aortic restenosis occurred and was successfully restented.Conclusions: Primary stenting of complex aortic stenoses and short occlusions is an attractive alternative to conventional surgery. Larger studies with longer follow-up and stratification of lesion morphology are warranted to define its role relative to balloon angioplasty. Stenting of aorto-biiliac occlusions is feasible but its role relative to bypass grafting remains to be defined.

  10. Transcatheter aortic valve implantation: status and challenges.

    PubMed

    Fishbein, Gregory A; Schoen, Frederick J; Fishbein, Michael C

    2014-01-01

    Calcific aortic valve disease of the elderly is the most prevalent hemodynamically-significant valvular disease, and the most common lesion requiring valve replacement in industrialized countries. Transcatheter aortic valve implantation is a less invasive alternative to classical aortic valve replacement that can provide a therapeutic option for high-risk or inoperable patients with aortic stenosis. These devices must be biocompatible, have excellent hemodynamic performance, be easy to insert, be securely anchored without sutures, and be durable, without increased risk of thrombosis or infection. To date, complications are related to the site of entry for insertion, the site of implantation (aorta, coronary ostia, base of left ventricle), and to the structure and design of the inserted device. However, as with any novel technology unanticipated complications will develop. Goals for future development will be to make the devices more effective, more durable, safer, and easier to implant, so as to further improve outcome for patients with severe aortic stenosis. The pathologist participating in research and development, and examination of excised devices will have a critical role in improving outcome for these patients.

  11. Acute aortic syndromes: pathophysiology and management.

    PubMed

    Alli, Oluseun; Jacobs, Larry; Amanullah, Aman M

    2008-01-01

    The acute aortic syndromes carry significant morbidity and mortality, especially when detected late. Symptoms may mimic myocardial ischemia, and physical findings may be absent or, if present, can be suggestive of a diverse range of other conditions. Maintaining a high clinical index of suspicion is crucial in establishing the diagnosis. All patients with suspected aortic disease and evidence of acute ischemia on electrocardiogram should undergo diagnostic imaging studies before thrombolytics are administered. The demonstration of an intimal flap separating 2 lumina is the basis for diagnosis. Tear detection and localization are very important because any therapeutic intervention aims to occlude the entry tear. The goals of medical therapy are to reduce the force of left ventricular contractions, decrease the steepness of the rise of the aortic pulse wave, and reduce the systemic arterial pressure to as low a level as possible without compromising perfusion of vital organs. Surgical therapy still remains the gold standard of care for type A aortic dissection, whereas in type B dissection, percutaneous aortic stenting and fenestration techniques have been developed and are sometimes used in conjunction with medical therapy in certain situations.

  12. 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

  13. Bicuspid aortic valve and severe aortic stenosis in a newborn exposed to carbamazapine during pregnancy

    PubMed Central

    Karataş, Zehra; Karataş, Ahmet; Özlü, Tülay; Goksugur, Sevil B.; Varan, Birgül

    2014-01-01

    The use of antiepileptic drugs increases the risk of major congenital malformations during pregnancy. Here, we report an infant who had a history of in-utero carbamazepine exposure and who was born with a cardiac malformation. The infant was born at 39 weeks of gestation vaginally to an epileptic mother who had been treated with carbamazepine throughout her pregnancy. He was referred due to cardiac murmur in the second week of his life. The mother had not received folic acid supplementation. Transthoracic echocardiography revealed bicuspid aortic valve, mild aortic stenosis, patent ductus arteriosus, patent foramen ovale and the renal ultrasound revealed mild left hydronephrosis. Follow-up echocardiography performed 14 weeks later showed increased severity of aortic stenosis and percutaneous balloon aortic valvuloplasty was performed. To our knowledge, there is only one case report in the literature mentioning the association of a bicuspid aortic valve and aortic stenosis with oxcarbazepine exposure, which is a structural derivative of carbamazepine. However, there are no reports for association with carbamazepine itself. Bicuspid aorta and aortic stenosis may be among the cardiac malformations that result from the teratogenic effect of carbamazepine. PMID:25584038

  14. Local repair of distal thoracal aortic dissections (Locus minoris resistencia).

    PubMed

    Belov, Iu V; Komarov, R N; Stepanenko, A B; Gens, A P; Charchian, E R

    2007-01-01

    The paper presents the method of local repair of distal aortic dissections. Local aortic grafting for surgical correction of type B dissecting aortic aneurysms helped to decrease hospital mortality up to 15.4%, the rate of paraparesis and multiorgan failure - up to 11.5%.

  15. Aortic Calcification: An Early Sign of Heart Valve Problems?

    MedlinePlus

    ... Rekha Mankad, M.D. References AskMayoExpert. Valvular disease – aortic stenosis. Rochester, Minn.: Mayo Foundation for Medical Education and ... Original article: http://www.mayoclinic.org/diseases-conditions/aortic-stenosis/expert-answers/aortic-valve-calcification/FAQ-20058525 . Mayo ...

  16. Suppression of endothelial nitric oxide synthase expression and endothelial cell proliferation by an intronic 27-ntmiRNA and it's a novel link to AP-1.

    PubMed

    Li, Yumei; Yan, Limei; Zhang, Wenyu; Hu, Nan; Chen, Wei; Wang, Hui; Kang, Min; Ou, Hesheng

    2015-01-01

    This study aims to investigate the role of activator protein 1 (AP-1) in the effects of 27nt-miRNA on expression of endothelial nitric oxide synthase (eNOS) gene and proliferation of endothelial cells. Cell proliferation was analyzed by cell number counting, colony formation assay and MTT assay. Cell migration and invasion was detected by transwell assay and invasion assay. Expression of eNOS and AP-1 was measured by real-time RT-PCR (mRNA level) and Western blotting (protein level). Luciferase reporter assay was performed to detect the binding of 27nt-miRNA to AP-1. Overexpression of 27nt-miRNA significantly inhibited endothelial cells proliferation, invasion and migration in vitro. And, eNOS and AP-1 expression at mRNA and protein levels were down-regulated by overexpression of 27nt-miRNA. Interestingly, overexpression of AP-1 protein partially restored eNOS expression and endothelial cell proliferation. Furthermore, the luciferase reporter assay demonstrated that AP-1 was a direct target of 27nt-miRNA. These data demonstrate that overexpression of 27nt-miRNA inhibits endothelial cell proliferation, invasion, migration, eNOS expression and AP-1 expression. Moreover, AP-1, a direct target of 27nt-miRNA, reverses the inhibitory effects of 27nt-miRNA. Thus, the effects of 27nt-miRNA might be acted through targeting AP-1.

  17. Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms and sporadic aneurysms

    PubMed Central

    He, Rumin; Guo, Dong-Chuan; Sun, Wei; Papke, Christina L.; Duraisamy, Senthil; Estrera, Anthony L.; Safi, Hazim J.; Ahn, Chul; Buja, L. Maximilian; Arnett, Frank C.; Zhang, Jingwu; Geng, Yong-Jian; Milewicz, Dianna M.

    2008-01-01

    Objectives This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm (TAAs) in patients with Marfan syndrome (MFS), familial TAA (FTAA), and non-familial TAA cases. Background TAAs are associated with a pathologic lesion termed medial degeneration, which was described as a noninflammtory lesion. TAAs are a complication of MFS and also can be inherited in an autosomal dominant manner of FTAA. Methods Full aortic segments were collected from patients undergoing elective repair with MFS (n=5), FTAA (n=6) and TAAs (n=9), along with control aortas (n=5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time PCR analysis was performed to quantify the expression level of T cell receptor β chain variable region gene. Results Immunohistochemisty of TAA aortas demonstrated that the media and adventitia from MFS, FTAA and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient’s age at the time of prophylactic surgical repair of the aorta. Surprisingly, T cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had MFS, FTAA or sporadic disease. Conclusion These results indicate that infiltration of inflammatory cells contributes to the pathogenesis of TAAs. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of the TAA patients may contribute to the initial immune response. Ultramini-Abstract This study sought to investigate the infiltration of T-lymphocytes and macrophage in the aortas of patients with MFS, FTAA and sporadic TAAs. The results indicate that infiltration of inflammatory cells contributes to the pathogenesis of TAAs and superantigen-driven stimulation of T-lymphocytes may contribute to

  18. Heritable retinoblastoma and accelerated aortic valve disease

    PubMed Central

    Abeyratne, L R; Kingston, J E; Onadim, Z; Dubrey, S W

    2013-01-01

    Heritable retinoblastoma is associated with a germline mutation in the tumour suppressor gene RBI. The Rb protein (pRb) arises from the RB1 gene, which was the first demonstrated cancer susceptibility gene in humans. 1 Second primary malignancies are recognised complications of retinoblastoma. Furthermore, pRb is implicated in valve remodelling in calcific aortic valve disease. 2 3 We report a family with hereditary retinoblastoma and associated secondary primary malignancies. There are two interesting aspects to this family. The first is the concept of ‘cancer susceptibility genes’; the RBI gene being the first reported in humans. A further feature of note is that two family members also have bicuspid aortic valves. We discuss a potential association between the gene defect responsible for retinoblastoma (with its associated propensity for further malignancies) and accelerated deterioration of the bicuspid aortic valve in the proband carrying this gene defect. PMID:23595191

  19. Cathepsin G deficiency reduces peri-aortic calcium chloride injury-induced abdominal aortic aneurysms in mice

    PubMed Central

    Wang, Jing; Sukhova, Galina K.; Liu, Jian; Ozaki, Keith; Lesner, Adam; Libby, Peter; Kovanen, Petri T.; Shi, Guo-Ping

    2014-01-01

    Objective Cathepsin G (CatG) is a serine protease that mediates angiotensin-I (Ang-I) to angiotensin-II (Ang-II) conversion and is highly expressed in human abdominal aortic aneurysms (AAAs). However, it remains untested whether this protease participates in the pathogenesis of AAA. Methods and Results Immunofluorescent double staining demonstrated the expression of CatG in smooth-muscle cells (SMCs), macrophages, and endothelial cells (ECs) in human AAA lesions (n=12), but not in AAA-free aortas (n=10). While inflammatory cytokines induced CatG expression, high glucose increased CatG activity in producing Ang-II and angiotensin-converting enzyme (ACE) in SMCs, which could be fully blocked by a CatG-selective inhibitor or its siRNA. To test whether CatG contributes to AAA development, we generated CatG and low-density lipoprotein receptor (LDLr) double deficient (Ldlr−/−Ctsg−/−) mice and their littermate controls (Ldlr−/−Ctsg+/+). Absence of CatG did not affect Ang-II infusion-induced AAAs. In contrast, in Ang-II-independent AAAs induced by peri-aortic CaCl2 injury (n=12 per group), CatG deficiency significantly reduced aortic diameter increase (58.33%±6.83% vs. 31.67%±5.75%, P=0.007), aortic lesion area (0.35±0.04 mm2 vs. 0.21±0.02 mm2, P=0.005), and aortic wall elastin fragmentation grade (2.75±0.18 vs. 1.58±0.17, P=0.002) along with reduced lesion collagen content grade (2.80±0.17 vs. 2.12±0.17, P=0.009) without affecting indices of lesion inflammation, angiogenesis, cell proliferation, or apoptosis. In vitro elastin degradation assays demonstrated that CaCl2-induced AAA lesions from Ldlr−/−Ctsg−/− mice contained much lower elastinolytic activity than in those from littermate control mice. Gelatin gel zymogram assay suggested that absence of CatG in CaCl2-induced AAA lesions also reduced the activity of elastinolytic matrix metalloproteinase (MMP)-2 and MMP-9. Conclusion CatG may contribute to CaCl2-induced experimental AAAs directly

  20. Ventricular Septal Defect from Aortic Regurgitation Jet Lesion in Aortic Valve Infective Endocarditis.

    PubMed

    Darabant, Sergiu; Oberton, Shelby B; Roldan, Luis P; Roldan, Carlos A

    2016-03-01

    Aortic valve infective endocarditis (IE) can be complicated with severe aortic regurgitation (AR) jet-related lesions such as vegetations, pseudoaneurysms, aneurysms or perforations on the anterior mitral leaflet. Herein is reported the case of a 69-year-old male with culture-negative aortic valve endocarditis complicated with aortic valve perforations resulting in severe and eccentric AR and an AR jet-related ventricular septal defect (VSD). Neither transthoracic echocardiography (TTE) nor two-dimensional transesophageal echocardiography (2D-TEE) were unable to clearly discriminate an aorto-right ventricular fistula from a VSD. By contrast, three-dimensional TEE (3D-TEE) demonstrated multiple aortic valve vegetations, aortic valve perforations, severe AR, and an AR jet-related VSD. The 3D-TEE findings were confirmed at surgery, the aortic valve was replaced with a bioprosthetic valve, and the VSD was repaired with a pericardial patch. To the authors' knowledge, this is the first case of a VSD resulting from an AR jet lesion to be detected and characterized using 3D-TEE. The accurate preoperative diagnosis and characterization of the VSD with 3D-TEE contributed to successful surgery and the patient's short- and long-term survival. Video 1A: This four-chamber transthoracic echocardiography (TTE) view with color Doppler shows a color-Doppler jet traversing the basal interventricular septum (IVS) into the right ventricle, predominantly during systole. However, the origin of the jet resulting from an aortic-right ventricular fistula cannot be determined. A mild to moderate degree of tricuspid regurgitation is also noted. Video 1B: Close-up view of the basal IVS demonstrates a color Doppler jet traversing the IVS, predominantly during systole and apparently originating in the left ventricular outflow tract side, as illustrated by a color Doppler acceleration zone. However, and as in Fig. 1A, the origin of the jet resulting from an aortic-right ventricular fistula cannot

  1. Aortic injuries in newer vehicles.

    PubMed

    Ryb, Gabriel E; Dischinger, Patricia C; Kleinberger, Michael; McGwin, Gerald; Griffin, Russell L

    2013-10-01

    The occurrence of AI was studied in relation to vehicle model year (MY) among front seat vehicular occupants, age≥16 in vehicles MY≥1994, entered in the National Automotive Sampling System Crashworthiness Data System between 1997 and 2010 to determine whether newer vehicles, due to their crashworthiness improvements, are linked to a lower risk of aortic injuries (AI). MY was categorized as 1994-1997, 1998-2004, or 2005-2010 reflecting the introduction of newer occupant protection technology. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals for the association between AI and MY independent of possible confounders. Analysis was repeated, stratified by frontal and near lateral impacts. AI occurred in 19,187 (0.06%) of the 31,221,007 (weighted) cases, and contributed to 11% of all deaths. AIs were associated with advanced age, male gender, high BMI, near-side impact, rollover, ejection, collision against a fixed object, high ΔV, vehicle mismatch, unrestrained status, and forward track position. Among frontal crashes, MY 98-04 and MY 05-10 showed increased adjusted odds of AI when compared to MY 94-97 [OR 1.84 (1.02-3.32) and 1.99 (0.93-4.26), respectively]. In contrast, among near-side impact crashes, MY 98-04 and MY 05-10 showed decreased adjusted odds of AI [OR 0.50 (0.25-0.99) and 0.27 (0.06-1.31), respectively]. While occupants of newer vehicles experience lower odds of AI in near side impact crashes, a higher AI risk is present in frontal crashes.

  2. Expression analysis of NOS family and HSP genes during thermal stress in goat ( Capra hircus)

    NASA Astrophysics Data System (ADS)

    Yadav, Vijay Pratap; Dangi, Satyaveer Singh; Chouhan, Vikrant Singh; Gupta, Mahesh; Dangi, Saroj K.; Singh, Gyanendra; Maurya, Vijay Prakash; Kumar, Puneet; Sarkar, Mihir

    2016-03-01

    Approximately 50 genes other than heat shock protein (HSP) expression changes during thermal stress. These genes like nitric oxide synthase (NOS) need proper attention and investigation to find out their possible role in the adaptation to thermal stress in animals. So, the present study was undertaken to demonstrate the expressions of inducible form type II NOS (iNOS), endothelial type III NOS (eNOS), constitutively expressed enzyme NOS (cNOS), HSP70, and HSP90 in peripheral blood mononuclear cells (PBMCs) during different seasons in Barbari goats. Real-time polymerase chain reaction, western blot, and immunocytochemistry were applied to investigate messenger RNA (mRNA) expression, protein expression, and immunolocalization of examined factors. The mRNA and protein expressions of iNOS, eNOS, cNOS, HSP70, and HSP90 were significantly higher ( P < 0.05) during peak summer, and iNOS and eNOS expressions were also observed to be significantly higher ( P < 0.05) during peak winter season as compared with moderate season. The iNOS, eNOS, cNOS, HSP70, and HSP90 were mainly localized in plasma membrane and cytoplasm of PBMCs. To conclude, data generated in the present study indicate the possible involvement of the NOS family genes in amelioration of thermal stress so as to maintain cellular integrity and homeostasis in goats.

  3. Expression analysis of NOS family and HSP genes during thermal stress in goat (Capra hircus).

    PubMed

    Yadav, Vijay Pratap; Dangi, Satyaveer Singh; Chouhan, Vikrant Singh; Gupta, Mahesh; Dangi, Saroj K; Singh, Gyanendra; Maurya, Vijay Prakash; Kumar, Puneet; Sarkar, Mihir

    2016-03-01

    Approximately 50 genes other than heat shock protein (HSP) expression changes during thermal stress. These genes like nitric oxide synthase (NOS) need proper attention and investigation to find out their possible role in the adaptation to thermal stress in animals. So, the present study was undertaken to demonstrate the expressions of inducible form type II NOS (iNOS), endothelial type III NOS (eNOS), constitutively expressed enzyme NOS (cNOS), HSP70, and HSP90 in peripheral blood mononuclear cells (PBMCs) during different seasons in Barbari goats. Real-time polymerase chain reaction, western blot, and immunocytochemistry were applied to investigate messenger RNA (mRNA) expression, protein expression, and immunolocalization of examined factors. The mRNA and protein expressions of iNOS, eNOS, cNOS, HSP70, and HSP90 were significantly higher (P < 0.05) during peak summer, and iNOS and eNOS expressions were also observed to be significantly higher (P < 0.05) during peak winter season as compared with moderate season. The iNOS, eNOS, cNOS, HSP70, and HSP90 were mainly localized in plasma membrane and cytoplasm of PBMCs. To conclude, data generated in the present study indicate the possible involvement of the NOS family genes in amelioration of thermal stress so as to maintain cellular integrity and homeostasis in goats.

  4. A bovine aortic arch in humans

    PubMed Central

    Arnáiz-García, María Elena; González-Santos, Jose María; López-Rodriguez, Javier; Dalmau-Sorli, María José; Bueno-Codoñer, María; Arévalo-Abascal, Adolfo; Fdez García-Hierro, Jose Ma; Arnáiz-García, Ana María; Arnáiz, Javier

    2014-01-01

    We describe a curious congenital variation of human aortic arch (AA) branching pattern termed the “bovine aortic arch”. Rather than arising directly from the AA as a separate branch as occurs in the most common AA branching pattern, the left common carotid artery moves to the right and merges from the brachiocephalic trunk. It is the normal AA branching pattern presented in a number of animals (canines, felines or Macaque monkeys) but it has nothing to do with anatomy of AA in ruminant animals, including cattle and buffalo. That is why it is one of the most widely misnomers used in medical literature whose origin is nowadays unknown. PMID:24973853

  5. A bovine aortic arch in humans.

    PubMed

    Arnáiz-García, María Elena; González-Santos, Jose María; López-Rodriguez, Javier; Dalmau-Sorli, María José; Bueno-Codoñer, María; Arévalo-Abascal, Adolfo; Fdez García-Hierro, Jose Ma; Arnáiz-García, Ana María; Arnáiz, Javier

    2014-01-01

    We describe a curious congenital variation of human aortic arch (AA) branching pattern termed the "bovine aortic arch". Rather than arising directly from the AA as a separate branch as occurs in the most common AA branching pattern, the left common carotid artery moves to the right and merges from the brachiocephalic trunk. It is the normal AA branching pattern presented in a number of animals (canines, felines or Macaque monkeys) but it has nothing to do with anatomy of AA in ruminant animals, including cattle and buffalo. That is why it is one of the most widely misnomers used in medical literature whose origin is nowadays unknown.

  6. Supravalvular aortic stenosis after arterial switch operation.

    PubMed

    Maeda, Takuya; Koide, Masaaki; Kunii, Yoshifumi; Watanabe, Kazumasa; Kanzaki, Tomohito; Ohashi, Yuko

    2016-07-01

    Supravalvular aortic stenosis as a late complication of transposition of the great arteries is very rare, and only a few cases have been reported. We describe the case of a 14-year-old girl who developed supravalvular aortic stenosis as a late complication of the arterial switch operation for transposition of the great arteries. The narrowed ascending aorta was replaced with a graft. The right pulmonary artery was transected to approach the ascending aorta which adhered severely to the main pulmonary trunk, and we obtained a good operative field.

  7. Idiopathic thoracic aortic aneurysm at pediatric age.

    PubMed

    Marín-Manzano, E; González-de-Olano, D; Haurie-Girelli, J; Herráiz-Sarachaga, J I; Bermúdez-Cañete, R; Tamariz-Martel, A; Cuesta-Gimeno, C; Pérez-de-León, J

    2009-03-01

    A 6-year-old-boy presented with epigastric pain and vomiting over 1 year. Chest X-ray and esophagogastric transit showed a mediastinal mass. A chest computerized tomography angiogram demonstrated a descending thoracic aortic aneurysm. Analytical determinations carried out were all negative. The aneurysm was surgically repaired using a Dacron patch. The anatomopathological study described atherosclerotic lesions with calcifications, compatible with an atherosclerotic aneurysm wall. Aneurysms are uncommon in the pediatric population. Usually, no pathogenesis can be determined, and thus, such cases are grouped as idiopathic. Direct repair with or without patch is a therapeutic alternative in pediatric aneurysms and can allow the growth of the aortic circumference.

  8. [Genetic aspects of the pathogenesis of aortic abdominal aneurysms].

    PubMed

    Waliszewski, Krzysztof; Słomski, Ryszard; Oszkinis, Grzegorz; Majewski, Wacław

    2005-01-01

    In industrialized countries the number of abdominal aortic aneurysms (AAA) is continuously rising. In recent years the mortality rate tripled and it is the number 13 cause of death in United States. Despite many identified risk factors and understanding of their pathomechanisms, the pathogenesis of AAA remains unclear. Thanks to the epidemiological researches and improvement of molecular techniques it was noted that AAA may have a genetic bases. The diversity between the possible genomic defects that could lead to the development of aneurytic changes was also suggested. This has a direct relationship with the complexity of the aortic wall structure and therefore with the number of potential injury locations. Current genetic research confirms the changes in expression and the many polymorphic variants of genes coding structural and enzymatic proteins. Thus, AAA seems to be a disease with multifactor pathogenesis and numerous possible genome anomaly variants. Hence, it seems that the complete understanding of the genetic bases of AAA continuous to be distant. However, efforts in this matter remain valuable, giving hope for an improved diagnosis, prophylaxis and treatment of this disease. This article is a review of the available knowledge regarding the genetic origin of AAA.

  9. Endovascular treatment for traumatic thoracic aortic pseudoaneurysm: a case report

    PubMed Central

    2013-01-01

    Cases of an endovascular treatment for traumatic aortic injury are extremely rare. A prompt diagnosis of traumatic thoracic aortic pseudoaneurysm through a 3-dimensional computed tomographic angiography of aorta and emergency repair are mandatory to rescue the life-threatening condition. An endovascular treatment is a trend for traumatic aortic injury because of lower invasivity, morbidity and mortality. We reported a rare case of traumatic aortic injury with thoracic aortic pseudoaneurysm definitively diagnosed by the reconstructional computed tomographic angiography of aorta and successfully treated with endovascular stent-graft. PMID:23452982

  10. Portico Sheathless Transcatheter Aortic Valve Implantation via Distal Axillary Artery.

    PubMed

    Bruschi, Giuseppe; Colombo, Paola; Botta, Luca; Nava, Stefano; Merlanti, Bruno; Belli, Oriana; Musca, Francesco; Soriano, Francesco; Russo, Claudio F; Oliva, Fabrizio

    2017-02-01

    Transcatheter aortic valve implantation has been designed to treat older patients affected by severe aortic stenosis who are considered high-risk surgical candidates because of multiple comorbidities. The least invasive approach for transcatheter aortic valves implantation should be considered the transfemoral retrograde route, because it is minimally invasive and is feasible with local anesthesia and mild sedation. Despite significant technical improvements in recent years, the transfemoral approach is contraindicated in cases of severe peripheral artery disease. We describe the first case of a Portico transcatheter aortic valve implantation system (St. Jude Medical, Minneapolis, MN) made through the distal axillary artery in a 90-year-old patient affected by severe aortic stenosis.

  11. First reported case of fetal aortic valvuloplasty in Asia

    PubMed Central

    Yoon, Sun-Young; Lee, Mi-Young; Cho, Min Kyong; Jung, Euiseok; Kim, Ki-Soo; Kim, Young-Hwue

    2017-01-01

    Prenatal intervention of severe fetal aortic valve stenosis by ultrasound-guided percutaneous balloon valvuloplasty has been performed to prevent the progression to hypoplastic left heart syndrome, and achieve biventricular circulation in neonates. Here we report a case of fetal aortic valvuloplasty prenatally diagnosed with aortic stenosis at 24 weeks of gestation and showed worsening features on a follow-up echocardiography. Prenatal aortic valvuloplasty was performed at 29 weeks of gestation, and was a technical success. However, fetal bradycardia sustained, and an emergency cesarean delivery was performed. To the best of our knowledge, this is the first reported case of fetal aortic valvuloplasty which was performed in Asia. PMID:28217680

  12. Proposed modification for valve-sparing aortic root replacement.

    PubMed

    Mahesh, Balakrishnan; Deville, Claude; Nashef, Samer

    2014-05-01

    Valve-sparing aortic root replacement (ARR) is the procedure of choice in young patients with aortic root aneurysm and preserved aortic valve leaflets; however, coronary ostial anastomoses remain an issue. Troublesome bleeding sometimes occurs during surgery, and in the long term, there is a risk of aneurysmal formation in the residual aortic wall of the ostial "button." We describe a technique of valve-sparing ARR wherein each coronary button along with its flange of aortic tissue is implanted within the prosthetic graft used for ARR, thereby eliminating the risk of both immediate surgical bleeding and late coronary button aneurysms.

  13. Endovascular Management of Chronic Type B Dissecting Aortic Aneurysm Utilizing Aortic and Renal Stents

    SciTech Connect

    Taylor, J. D. Dunckley, M.; Thompson, M.; Morgan, R. A.

    2008-07-15

    Over the last 10 years endovascular stent-graft placement has been increasingly used to treat complicated acute Type B thoracic aortic dissections. While studies have demonstrated the use of additional aortic stent-grafts to treat continued false lumen perfusion and case reports have detailed the use of renal artery stents to treat renal ischemia related to aortic dissection, to our knowledge the adjuvant use of renal artery stents to reduce false lumen perfusion has not been reported. We present the case of a 72-year-old male who had previously undergone endovascular repair of a complicated Type B thoracic aortic dissection and presented with an expanding false lumen in the peridiaphragmatic aorta despite coverage of the entire thoracic aorta. This was treated by closure of a right renal fenestration using a renal stent.

  14. Aortic Valvular Replacement: Clinical Experience With 13 Cases

    PubMed Central

    Grondin, Pierre; Lepage, Gilles; Castonguay, Yves

    1964-01-01

    Acquired aortic disease is now currently corrected by total prosthetic replacement of the aortic valve. Aortic valve replacement was performed in 13 cases at the Montreal Heart Institute in 1963. In the first four cases, Bahnson aortic leaflets were used; in the remaining nine, the Starr-Edwards semirigid aortic valve prosthesis. The surgical technique employed is described. There were two operative deaths and two late deaths. The results have been excellent in all of the survivors but one. They have returned to full-time activities and four of them to strenuous physical work. It is the contention of the authors that aortic valve replacement is a surgical procedure with acceptable risks, offering hope for a near-normal life to patients crippled by severe aortic valvular lesions. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7 PMID:14179061

  15. Aortic insufficiency. A result of intermittent migration of aortic valve prosthesis poppet.

    PubMed

    Kunstadt, D; Adeyemo, A; Clauss, R H

    1976-06-28

    A bizarre mechanism of aortic valve incompetence was observed when the occluder of a Braunwald-Cutter aortic valve prosthesis decreased in diameter, volume, and weight, and from time to time fell into the left ventricle. The patient's symptoms were palpitation, coughing, chocking sensations, and fright. An operation disclosed a small, smooth ball with disrupted cloth on all the struts. The residual torn mesh was removed, and the ball was replaced.

  16. [Evaluation of aortic valve replacement involving small severely calcified aortic annulus in elderly patients].

    PubMed

    Iwahashi, M; Nishimura, Y; Hiramatsu, K; Komori, S; Shibata, M; Yuzaki, M; Okamura, Y

    2006-04-01

    We performed aortic valve replacement in 24 patients aged over 70 with small calcified valves. The surgical management of such patients remains controversial as the extensive calcification compromises implantation. Hence, we used an ultrasonic debridement instrument to remove calcium and selected a small prosthesis with the largest possible orifice without enlargement of the aortic annulus. Echocardiography showed significant reductions in left ventricular mass index compared with preoperative values. Early and mid-term prognosis has been relatively good.

  17. Computed tomography evaluation for transcatheter aortic valve implantation (TAVI): imaging of the aortic root and iliac arteries.

    PubMed

    Schoenhagen, Paul; Kapadia, Samir R; Halliburton, Sandra S; Svensson, Lars G; Tuzcu, E Murat

    2011-01-01

    For patients with severe aortic stenosis, open-heart surgical valve replacement remains the current clinical standard with documented, excellent long-term outcome. Over the past few years, transcatheter aortic valve implantation (TAVI) has developed into a treatment alternative for high-risk patients with severe aortic stenosis. Because transcatheter valvular procedures are characterized by lack of exposure of the operative field, image guidance is critical. This Pictorial Essay describes the role of 3-dimensional imaging with multidetector row computed tomography for detailed reconstructions of the aortic valve, aortic root, and iliac arteries in the context of TAVI.

  18. The long non-coding HOTAIR is modulated by cyclic stretch and WNT/β-CATENIN in human aortic valve cells and is a novel repressor of calcification genes.

    PubMed

    Carrion, Katrina; Dyo, Jeffrey; Patel, Vishal; Sasik, Roman; Mohamed, Salah A; Hardiman, Gary; Nigam, Vishal

    2014-01-01

    Aortic valve calcification is a significant and serious clinical problem for which there are no effective medical treatments. Individuals born with bicuspid aortic valves, 1-2% of the population, are at the highest risk of developing aortic valve calcification. Aortic valve calcification involves increased expression of calcification and inflammatory genes. Bicuspid aortic valve leaflets experience increased biomechanical strain as compared to normal tricuspid aortic valves. The molecular pathogenesis involved in the calcification of BAVs are not well understood, especially the molecular response to mechanical stretch. HOTAIR is a long non-coding RNA (lncRNA) that has been implicated with cancer but has not been studied in cardiac disease. We have found that HOTAIR levels are decreased in BAVs and in human aortic interstitial cells (AVICs) exposed to cyclic stretch. Reducing HOTAIR levels via siRNA in AVICs results in increased expression of calcification genes. Our data suggest that β-catenin is a stretch responsive signaling pathway that represses HOTAIR. This is the first report demonstrating that HOTAIR is mechanoresponsive and repressed by WNT β-catenin signaling. These findings provide novel evidence that HOTAIR is involved in aortic valve calcification.

  19. The Long Non-Coding HOTAIR Is Modulated by Cyclic Stretch and WNT/β-CATENIN in Human Aortic Valve Cells and Is a Novel Repressor of Calcification Genes

    PubMed Central

    Carrion, Katrina; Dyo, Jeffrey; Patel, Vishal; Sasik, Roman; Mohamed, Salah A.; Hardiman, Gary; Nigam, Vishal

    2014-01-01

    Aortic valve calcification is a significant and serious clinical problem for which there are no effective medical treatments. Individuals born with bicuspid aortic valves, 1–2% of the population, are at the highest risk of developing aortic valve calcification. Aortic valve calcification involves increased expression of calcification and inflammatory genes. Bicuspid aortic valve leaflets experience increased biomechanical strain as compared to normal tricuspid aortic valves. The molecular pathogenesis involved in the calcification of BAVs are not well understood, especially the molecular response to mechanical stretch. HOTAIR is a long non-coding RNA (lncRNA) that has been implicated with cancer but has not been studied in cardiac disease. We have found that HOTAIR levels are decreased in BAVs and in human aortic interstitial cells (AVICs) exposed to cyclic stretch. Reducing HOTAIR levels via siRNA in AVICs results in increased expression of calcification genes. Our data suggest that β-CATENIN is a stretch responsive signaling pathway that represses HOTAIR. This is the first report demonstrating that HOTAIR is mechanoresponsive and repressed by WNT β-CATENIN signaling. These findings provide novel evidence that HOTAIR is involved in aortic valve calcification. PMID:24788418

  20. Aortic root aneurysm in an adult patient with aortic coarctation: a single-stage approach.

    PubMed

    Ananiadou, Olga G; Koutsogiannidis, Charilaos; Ampatzidou, Fotini; Drossos, George E

    2012-09-01

    Coarctation of the aorta is a common congenital defect that may be undiagnosed until adulthood. Moreover, coarctation is associated with congenital and acquired cardiac pathology that may require surgical intervention. The management of an adult patient with aortic coarctation and an associated cardiac defect poses a great technical challenge since there are no standard guidelines for the therapy of such a complex pathology. Several extra-anatomic bypass grafting techniques have been described, including methods in which distal anastomosis is performed on the descending thoracic aorta, allowing simultaneous intracardiac repair. We report here a 37-year old man who was diagnosed with an aortic root aneurysm and aortic coarctation. The patient was treated electively with a single-stage approach through a median sternotomy that consisted of valve-sparing replacement of the aortic root and ascending-to-descending extra-anatomic aortic bypass, using a 18-mm Dacron graft. Firstly, the aortic root was replaced with the Yacoub remodelling procedure, and then the distal anastomosis was performed to the descending aorta, behind the heart, with the posterior pericardial approach. The extra-anatomic bypass graft was brought laterally from the right atrium and implanted in the ascending graft. Postoperative recovery was uneventful and a control computed tomographic angiogram 1 month after complete repair showed good results.

  1. Aortic valve replacement with sutureless and rapid deployment aortic valve prostheses

    PubMed Central

    Berretta, Paolo; Di Eusanio, Marco

    2016-01-01

    Aortic valve stenosis is the most common valve disease in the western world. Over the past few years the number of aortic valve replacement (AVR) interventions has increased with outcomes that have been improved despite increasing age of patients and increasing burden of comorbidities. However, despite such excellent results and its well-established position, conventional AVR has undergone great development over the previous two decades. Such progress, by way of less invasive incisions and use of new technologies, including transcatheter aortic valve implantation and sutureless valve prostheses, is intended to reduce the traumatic impact of the surgical procedure, thus fulfilling lower risk patients' expectations on the one hand, and extending the operability toward increasingly high-risk patients on the other. Sutureless and rapid deployment aortic valves are biological, pericardial prostheses that anchor within the aortic annulus with no more than three sutures. The sutureless prostheses, by avoiding the passage and the tying of the sutures, significantly reduce operative times and may improve outcomes. However, there is still a paucity of robust, evidence-based data on the role and performance of sutureless AVR. Therefore, strongest long-term data, randomized studies and registry data are required to adequately assess the durability and long-term outcomes of sutureless aortic valve replacement. PMID:27582765

  2. Ultrasonic delineation of aortic microstructure: The relative contribution of elastin and collagen to aortic elasticity

    NASA Astrophysics Data System (ADS)

    Marsh, Jon N.; Takiuchi, Shin; Lin, Shiow Jiuan; Lanza, Gregory M.; Wickline, Samuel A.

    2004-05-01

    Aortic elasticity is an important factor in hemodynamic health, and compromised aortic compliance affects not only arterial dynamics but also myocardial function. A variety of pathologic processes (e.g., diabetes, Marfan's syndrome, hypertension) can affect aortic elasticity by altering the microstructure and composition of the elastin and collagen fiber networks within the tunica media. Ultrasound tissue characterization techniques can be used to obtain direct measurements of the stiffness coefficients of aorta by measurement of the speed of sound in specific directions. In this study we sought to define the contributions of elastin and collagen to the mechanical properties of aortic media by measuring the magnitude and directional dependence of the speed of sound before and after selective isolation of either the collagen or elastin fiber matrix. Formalin-fixed porcine aortas were sectioned for insonification in the circumferential, longitudinal, or radial direction and examined using high-frequency (50 MHz) ultrasound microscopy. Isolation of the collagen or elastin fiber matrices was accomplished through treatment with NaOH or formic acid, respectively. The results suggest that elastin is the primary contributor to aortic medial stiffness in the unloaded state, and that there is relatively little anisotropy in the speed of sound or stiffness in the aortic wall.

  3. Aortic valve leaflet replacement with bovine pericardium to preserve native dynamic capabilities of the aortic annulus.

    PubMed

    Kim, Kyung Hwa; Choi, Jong Bum; Kim, Min Ho; Kim, Won Ho; Lee, Mi Kyung; Lee, Sam Youn

    2014-02-01

    Valve replacement is typically the most appropriate option for treating aortic valve stenotic insufficiency. However, neither mechanical nor bioprosthetic replacement components preserve the circumferential expansion and contraction of a native aortic annulus during the cardiac cycle, because the prosthetic ring is affixed to the annulus. A 64-year-old man presented with a bicuspid and stenotic aortic valve, and the native annulus was too small to accommodate a porcine replacement valve. We fashioned new aortic leaflets from bovine pericardium with use of a template, and we affixed the sinotubular junction with use of inner and outer stabilization rings. Postoperative echocardiograms revealed coaptation of the 3 new leaflets with no regurgitation. At the patient's 5.5-year follow-up examination, echocardiograms showed flexible leaflet movement with a coaptation height of 7 mm, and expansion and contraction of the aortic annulus similar to that of a normal native annulus. The transvalvular pressure gradient was insignificant. If long-term durability of the new leaflets is confirmed, this method of leaflet replacement and fixation of the sinotubular junction might serve as an acceptable alternative to valve replacement in the treatment of aortic valve stenosis. We describe the patient's case and present our methods and observations.

  4. Aortic Valve Leaflet Replacement with Bovine Pericardium to Preserve Native Dynamic Capabilities of the Aortic Annulus

    PubMed Central

    Kim, Kyung Hwa; Kim, Min Ho; Kim, Won Ho; Lee, Mi Kyung; Lee, Sam Youn

    2014-01-01

    Valve replacement is typically the most appropriate option for treating aortic valve stenotic insufficiency. However, neither mechanical nor bioprosthetic replacement components preserve the circumferential expansion and contraction of a native aortic annulus during the cardiac cycle, because the prosthetic ring is affixed to the annulus. A 64-year-old man presented with a bicuspid and stenotic aortic valve, and the native annulus was too small to accommodate a porcine replacement valve. We fashioned new aortic leaflets from bovine pericardium with use of a template, and we affixed the sinotubular junction with use of inner and outer stabilization rings. Postoperative echocardiograms revealed coaptation of the 3 new leaflets with no regurgitation. At the patient's 5.5-year follow-up examination, echocardiograms showed flexible leaflet movement with a coaptation height of 7 mm, and expansion and contraction of the aortic annulus similar to that of a normal native annulus. The transvalvular pressure gradient was insignificant. If long-term durability of the new leaflets is confirmed, this method of leaflet replacement and fixation of the sinotubular junction might serve as an acceptable alternative to valve replacement in the treatment of aortic valve stenosis. We describe the patient's case and present our methods and observations. PMID:24512414

  5. Aortic root aneurysm in an adult patient with aortic coarctation: a single-stage approach

    PubMed Central

    Ananiadou, Olga G.; Koutsogiannidis, Charilaos; Ampatzidou, Fotini; Drossos, George E.

    2012-01-01

    Coarctation of the aorta is a common congenital defect that may be undiagnosed until adulthood. Moreover, coarctation is associated with congenital and acquired cardiac pathology that may require surgical intervention. The management of an adult patient with aortic coarctation and an associated cardiac defect poses a great technical challenge since there are no standard guidelines for the therapy of such a complex pathology. Several extra-anatomic bypass grafting techniques have been described, including methods in which distal anastomosis is performed on the descending thoracic aorta, allowing simultaneous intracardiac repair. We report here a 37-year old man who was diagnosed with an aortic root aneurysm and aortic coarctation. The patient was treated electively with a single-stage approach through a median sternotomy that consisted of valve-sparing replacement of the aortic root and ascending-to-descending extra-anatomic aortic bypass, using a 18-mm Dacron graft. Firstly, the aortic root was replaced with the Yacoub remodelling procedure, and then the distal anastomosis was performed to the descending aorta, behind the heart, with the posterior pericardial approach. The extra-anatomic bypass graft was brought laterally from the right atrium and implanted in the ascending graft. Postoperative recovery was uneventful and a control computed tomographic angiogram 1 month after complete repair showed good results. PMID:22647969

  6. Current Indications for Surgical Repair in Patients with Bicuspid Aortic Valve and Ascending Aortic Ectasia

    PubMed Central

    Etz, Christian D.; Misfeld, Martin; Borger, Michael A.; Luehr, Maximilian; Strotdrees, Elfriede; Mohr, Friedrich-Wilhelm

    2012-01-01

    Preventive surgical repair of the moderately dilated ascending aorta/aortic root in patients with bicuspid aortic valve (BAV) is controversial. Most international reference centers are currently proposing a proactive approach for BAV patients with a maximum ascending aortic/root diameter of 45 mm since the risk of dissection/rupture raises significantly with an aneurysm diameter >50 mm. Current guidelines of the European Society of Cardiology (ESC) and the joint guidelines of the American College of Cardiology (ACC)/American Heart Association (AHA) recommend elective repair in symptomatic patients with dysfunctional BAV (aortic diameter ≥45 mm). In asymptomatic patients with a well-functioning BAV, elective repair is recommended for diameters ≥50 mm, or if the aneurysm is rapidly progressing (rate of 5 mm/year), or in case of a strong family history of dissection/rupture/sudden death, or with planned pregnancy. As diameter is likely not the most reliable predictor of rupture and dissection and the majority of BAV patients may never experience an aortic catastrophe at small diameters, an overly aggressive approach almost certainly will put some patients with BAV unnecessarily at risk of operative and early mortality. This paper discusses the indications for preventive, elective repair of the aortic root, and ascending aorta in patients with a BAV and a moderately dilated—or ectatic—ascending aorta. PMID:23050195

  7. Painless aortic dissection presenting as paraplegia.

    PubMed

    Colak, Necmettin; Nazli, Yunus; Alpay, Mehmet Fatih; Akkaya, Ismail Olgun; Cakir, Omer

    2012-01-01

    Acute dissection of the aorta can be life-threatening. As a presenting manifestation of aortic dissection, neurologic complications such as paraplegia are rare. Herein, we report the case of a 51-year-old man who presented with sudden-onset paraplegia and ischemia of the legs, with no chest or back pain. His medical history included coronary artery bypass grafting. Physical examination revealed pulseless lower extremities, and computed tomography showed aortic dissection from the ascending aorta to the common iliac arteries bilaterally. A lumbar catheter was inserted for cerebrospinal fluid drainage, and axillary arterial cannulation was established. With the use of cardiopulmonary bypass, the aortic dissection was corrected, and the previous coronary artery grafts were reattached. The surgery restored spinal and lower-extremity perfusion, and the patient walked unaided from the hospital upon his discharge 5 days later. Although acute aortic dissection presenting as paraplegia is rare, it should be considered in patients who have pulseless femoral arteries bilaterally and sudden-onset paraplegia, despite no pain in the chest or back. Prompt diagnosis and intervention can prevent morbidity and death.

  8. Complication of Behcet's disease: spontaneous aortic pseudoaneurysm.

    PubMed

    Ugurlucan, Murat; Sayin, Omer Ali; Surmen, Benguhan; Kafali, Eylul; Basaran, Murat; Alpagut, Ufuk; Dayioglu, Enver; Onursal, Ertan

    2006-01-01

    Behcet's disease is an autoimmune multisystemic disorder based on vasculitis. In this disease, the most important predictor of morbidity and mortality is the vascular complications. Appropriate surgical interventions are critical and must be planned strategically. Here, we will describe a very rare complication of the disease; spontaneous aortic pseudoaneurysm in a 33-year-old patient.

  9. [Albert Einstein and his abdominal aortic aneurysm].

    PubMed

    Cervantes Castro, Jorge

    2011-01-01

    The interesting case of Albert Einstein's abdominal aortic aneurysm is presented. He was operated on at age 69 and, finding that the large aneurysm could not be removed, the surgeon elected to wrap it with cellophane to prevent its growth. However, seven years later the aneurysm ruptured and caused the death of the famous scientist.

  10. Middle aortic syndrome in a teenager.

    PubMed

    Eyileten, Zeynep; Taşar, Mehmet; Yazıcıoğlu, Levent; Kaya, Bülent; Fitöz, Suat; Uysalel, Adnan

    2014-01-01

    Middle aortic syndrome (MAS) is a rare pathology that involves diffuse/segmental narrowing of the distal thoracic or abdominal aorta. The most common clinical manifestation is severe hypertension, which requires multiple antihypertensive medications and/or surgical repair. We report the surgical repair of MAS in a 14-year-old male.

  11. [Ascending-descending Aortic Bypass and Aortic Valve Replacement for Aortic Coarctation with Bicuspid Aortic Valve and an Aberrant Right Subclavian Artery;Report of a Case].

    PubMed

    Asano, Ryota; Nakano, Kiyoharu; Kodera, Kojiro; Sato, Atsuhiko; Kataoka, Go; Tatsuishi, Wataru; Kubota, Sayaka; Namiki, Shigetaka; Suzuki, Seiya

    2015-08-01

    A 53-year-old woman was developed congestive heart failure. She was diagnosed as having aortic coarctation, incompetent bicuspid aortic valve and an aberrant right subclavian artery by using echocardiography and enhanced computed tomography. Ankle brachial pressure index(ABI)in the right was 0.71 and 0.69 in the left. Blood pressure of the right arm was 60 mmHg lower than that of the left arm. To avoid perioperative adverse cardiac events due to a 2-staged operation, we performed ascending-descending aortic bypass and aortic valve replacement simultaneously through a median sternotomy. The heart was retracted cranially, and a vascular prosthesis was anastomosed to the descending aorta just above the diaphragm in an end-to-side manner. Then the graft was placed curvilinearly around the right atrium and was anastomosed to the ascending aorta. After the operation, the right and left ABI increased to 0.90 and 0.98 respectively. There was no pressure difference between the arms. The postoperative course was uneventful.

  12. Aortic mismatch in heart transplantation: readaptation.

    PubMed

    Miralles, A

    1997-10-01

    Great vessel mismatch between donor and recipient is very usual in heart transplantation. Different procedures have been used to manage this situation. A tailoring aortoplasty is described, as a technical alternative, in cases of considerable size incongruence between donor and recipient aortic diameters.

  13. Aortic aneurysm mimicking a right atrial mass.

    PubMed

    Mohamed, Ahmed; Elsayed, Mahmoud; Kalra, Rajat; Bulur, Serkan; Nanda, Navin C

    2016-10-01

    We present a case of a 54-year-old female who was initially thought to have a cystic mass in the right atrium on two-dimensional transthoracic echocardiography. Careful transducer angulation and off-axis imaging showed this mass-like effect was produced by an aortic root aneurysm impinging on the right atrium.

  14. Winged scapula after aortic valve replacement.

    PubMed

    Schmitz, Christoph; Sodian, Ralf; Witt, Thomas N; Juchem, Gerd; Lang, Nora; Bruegger, Christian; Kowalski, Christian; Reichart, Bruno

    2009-04-01

    Iatrogenic nerve lesions affecting the long thoracic nerve are very rare after a median sternotomy. Here we report on a patient who developed clinical signs of a so-called "winged scapula" after an uneventful aortic valve replacement for infective endocarditis.

  15. Fatal Saccharomyces Cerevisiae Aortic Graft Infection

    NASA Technical Reports Server (NTRS)

    Meyer, Michael (Technical Monitor); Smith, Davey; Metzgar, David; Wills, Christopher; Fierer, Joshua

    2002-01-01

    Saccharomyces cerevisiae is a yeast commonly used in baking and a frequent colonizer of human mucosal surfaces. It is considered relatively nonpathogenic in immunocompetent adults. We present a case of S. cerevisiae fungemia and aortic graft infection in an immunocompetent adult. This is the first reported case of S. cerevisiue fungemia where the identity of the pathogen was confirmed by rRNA sequencing.

  16. A Multilevel Prediction of Physiological Response to Challenge: Interactions among Child Maltreatment, Neighborhood Crime, eNOS and GABRA6

    PubMed Central

    Lynch, Michael; Manly, Jody Todd; Cicchetti, Dante

    2015-01-01

    Physiological response to stress has been linked to variety of healthy and pathological conditions. The current study conducted a multilevel examination of interactions among environmental toxins – i.e., neighborhood crime and child maltreatment – and specific genetic polymorphisms of eNOS and GABRA6. A total of 186 children were recruited at age 4. At this time, the presence or absence of child maltreatment was determined, as was the amount of crime that occurred in their neighborhood during the previous year. At age 9, the children were brought to the lab where their physiological response to a cognitive challenge – i.e., change in the amplitude of RSA – was assessed and DNA samples were collected for subsequent genotyping. Results confirmed that complex G x G, E x E, and G x E interactions were associated with different patterns of RSA reactivity. The implications for future research and evidence-