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Sample records for increased aortic enos

  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. 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}.

  3. 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

  4. Lipedema is associated with increased aortic stiffness.

    PubMed

    Szolnoky, G; Nemes, A; Gavallér, H; Forster, T; Kemény, L

    2012-06-01

    Lipedema is a disproportional obesity due to unknown pathomechanism. Its major hallmark is frequent hematoma formation related to increased capillary fragility and reduced venoarterial reflex. Beyond microangiopathy, both venous and lymphatic dysfunction have also been documented. However, arterial circulation in lipedema has not been examined, and therefore we explored aortic elastic properties by echocardiography. Fourteen women with and 14 without lipedema were included in the study. Each subject consented to blood pressure measurement, physical examination, and transthoracic echocardiography. Aortic stiffness index (beta), distensibility, and strain were evaluated from aortic diameter and blood pressure data. Mean systolic (30.0 +/- 3.2 vs. 25.5 +/- 3.6, P < 0.05) and diastolic (27.8 +/- 3.3 vs. 22.3 +/- 3.1) aortic diameters (in mm) and aortic stiffness index (9.05 +/- 7.45 vs. 3.76 +/- 1.22, P < 0.05) were significantly higher, while aortic strain (0.082 +/- 0.04 vs. 0.143 +/- 0.038, P < 0.05) and distensibility (2.24 +/- 1.07 vs. 4.38 +/- 1.61, P < 0.05) were significantly lower in lipedematous patients compared to controls. Thus, lipedema is characterized with increased aortic stiffness.

  5. Caffeine increases aortic stiffness in hypertensive patients.

    PubMed

    Vlachopoulos, Charalambos; Hirata, Kozo; Stefanadis, Christodoulos; Toutouzas, Pavlos; O'Rourke, Michael F

    2003-01-01

    Caffeine is the most widely used pharmacologic substance. Aortic stiffness is an important factor for cardiovascular system performance and a prognosticator of cardiovascular risk. We investigated the effect of caffeine on aortic stiffness in treated hypertensive patients. We studied the effect of caffeine (250 mg) in 12 treated hypertensive patients according to a randomized, placebo-controlled, double-blind, cross-over design during a 3-h period. Aortic stiffness was evaluated by carotid-femoral pulse wave velocity. Systolic blood pressure (BP) and pulse pressure increased significantly throughout the study (by 12.3 and 7.4 mm Hg, P =.005 and P <.01, respectively), whereas diastolic BP did not change. Pulse wave velocity increased (by 0.57 m/sec, P <.05) denoting an increase in aortic stiffness. This effect of caffeine lasted throughout the study (3 h), peaking at 60 min and decreasing progressively thereafter. These results demonstrate, for the first time, that caffeine exerts an acute unfavorable effect on aortic stiffness in treated hypertensive patients. This finding has important implications for the impact of caffeine consumption on cardiovascular risk in hypertension.

  6. Increased vascular eNOS and cystathionine-γ-lyase protein after 6 weeks oral administration of 3, 5, 7, 3', 4'-pentamethoxyflavone to middle-aged male rats.

    PubMed

    Yorsin, Somruedee; Kanokwiroon, Kanyanatt; Radenahmad, Nisaudah; Jansakul, Chaweewan

    2016-11-01

    Effects of treatment of middle-aged male rats with 3, 5, 7, 3', 4'-pentamethoxyflavone (PMF) on vascular and perivascular adipose tissue (PVAT) functions and blood chemistry were investigated. Rats received PMF (22 mg/kg), orally or vehicle, twice a day for 6 weeks. The PMF-treated rats had lower serum glucose, higher HDL-C levels, but no change in other parameters. Thoracic aortic and mesenteric rings of PMF treated rats produced lower maximal contraction to phenylephrine that was normalized by N(G)-nitro-L-arginine (L-NA) or endothelial removal. The aortic- and mesenteric rings of the PMF treated rats showed improved relaxation to acetylcholine, but not to glyceryl trinitrate, and had higher eNOS protein. DL-propargylglycine (PAG) caused greater increase in the baseline tension of the PMF-treated aortic ring and higher contraction to low concentrations of phenylephrine. PVAT lowered the contractile response of the L-NA pretreated aortic rings to phenylephrine for both groups, but PAG had no effect. The cystathionine-γ-lyase (CSE) protein of the thoracic rings, but not of the PVAT, shows increased expression after PMF treatment. Overall, PMF treatment of middle aged rats appeared to increase production of NO and H2S from the blood vessels by upregulating the expression of eNOS and CSE. PMF also decreased fasting serum glucose and increased HDL-C levels, with no toxicity to liver and kidney functions. Thus, PMF is a novel compound for possible use as a health product to prevent and/or to reduce the development of diabetes type II and/or cardiovascular disease.

  7. 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

  8. Mutation at the tomato excessive number of floral organs (ENO) locus impairs floral meristem development, thus promoting an increased number of floral organs and fruit size.

    PubMed

    Fernández-Lozano, Antonia; Yuste-Lisbona, Fernando J; Pérez-Martín, Fernando; Pineda, Benito; Moreno, Vicente; Lozano, Rafael; Angosto, Trinidad

    2015-03-01

    A novel tomato (Solanum lycopersicum L.) mutant affected in reproductive development, excessive number of floral organs (eno), is described in this study. The eno plants yielded flowers with a higher number of floral organs in the three innermost floral whorls and larger fruits than those found in wild-type plants. Scanning-electron microscopy study indicated that the rise in floral organ number and fruit size correlates with an increased size of floral meristem at early developmental stages. It has been reported that mutation at the FASCIATED (FAS) gene causes the development of flowers with supernumerary organs; however, complementation test and genetic mapping analyses proved that ENO is not an allele of the FAS locus. Furthermore, expression of WUSCHEL (SlWUS) and INHIBITOR OF MERISTEM ACTIVITY (IMA), the two main regulators of floral meristem activity in tomato, is altered in eno but not in fas flowers indicating that ENO could exert its function in the floral meristem independently of FAS. Interestingly, the eno mutation delayed the expression of IMA leading to a prolonged expression of SlWUS, which would explain the greater size of floral meristem. Taken together, results showed that ENO plays a significant role in the genetic pathway regulating tomato floral meristem development. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome.

    PubMed

    Franken, Romy; El Morabit, Abdelali; de Waard, Vivian; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Marquering, Henk; Planken, Nils R N; Zwinderman, Aeilko H; Mulder, Barbara J M; Groenink, Maarten

    2015-09-01

    Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications. 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, and body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilatation rate during 3 years of follow-up were investigated. ATI intra- and interobserver agreements were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92 ± 0.2 vs. 1.82 ± 0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87 ± 0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3 ± 8.8 months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98 ± 0.2 vs. 1.86 ± 0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95. Increased ATI is associated with a more severe aortic phenotype in MFS patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Indexing aortic valve area by body surface area increases the prevalence of severe aortic stenosis.

    PubMed

    Jander, Nikolaus; Gohlke-Bärwolf, Christa; Bahlmann, Edda; Gerdts, Eva; Boman, Kurt; Chambers, John B; Egstrup, Kenneth; Nienaber, Christoph A; Pedersen, Terje R; Ray, Simon; Rossebø, Anne B; Willenheimer, Ronnie; Kienzle, Rolf-Peter; Wachtell, Kristian; Neumann, Franz-Josef; Minners, Jan

    2014-01-01

    To account for differences in body size in patients with aortic stenosis, aortic valve area (AVA) is divided by body surface area (BSA) to calculate indexed AVA (AVAindex). Cut-off values for severe stenosis are <1.0 cm2 for AVA and <0.6 cm2/m2 for AVAindex. To investigate the influence of indexation on the prevalence of severe aortic stenosis and on the predictive accuracy regarding clinical outcome. Echocardiographic and anthropometric data from a retrospective cohort of 2843 patients with aortic stenosis (jet velocity >2.5 m/s) and from 1525 patients prospectively followed in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial were analysed. The prevalence of severe stenosis increased with the AVAindex criterion compared to AVA from 71% to 80% in the retrospective cohort, and from 29% to 44% in SEAS (both p<0.001). Overall, the predictive accuracy for aortic valve events was virtually identical for AVA and AVAindex in the SEAS population (mean follow-up of 46 months; area under the receiver operating characteristic curve: 0.67 (95% CI 0.64 to 0.70) vs. 0.68 (CI 0.65 to 0.71) (NS). However, 213 patients additionally categorised as severe by AVAindex experienced significantly less valve related events than those fulfilling only the AVA criterion (p<0.001). Indexing AVA by BSA (AVAindex) significantly increases the prevalence of patients with criteria for severe stenosis by including patients with a milder degree of the disease without improving the predictive accuracy for aortic valve related events.

  11. Fenofibrate Improves Vascular Endothelial Function by Reducing Oxidative Stress While Increasing eNOS in Healthy Normolipidemic Older Adults

    PubMed Central

    Walker, Ashley E; Kaplon, Rachelle E; Lucking, Sara Marian S; Russell-Nowlan, Molly J; Eckel, Robert H; Seals, Douglas R

    2013-01-01

    Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation(EDD), and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve EDD in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation (FMD), a measure of EDD, was assessed in 22healthy adults aged 50-77 years before and after 7days of fenofibrate (145 mg/d; n=12/7M) or placebo (n=10/5M). Brachial FMD was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1±0.7 vs. 2d: 6.0±0.7 and 7d: 6.4±0.6 %Δ; both P<0.005). The improvements in FMD after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and LDL-cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Infusion (i.v.) of the antioxidant vitamin C improved brachial FMD at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma oxidized LDL, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase (eNOS) protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54±0.03 vs. 2d: 0.52±0.04 and 7d: 0.76±0.11 intensity/HUVEC control; P<0.05 7d). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged/older adults by reducing oxidative stress and induces increases in eNOS. PMID:23108655

  12. 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

  13. 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.

  14. NADPH Oxidase 4 Promotes Endothelial Angiogenesis Through eNOS Activation

    PubMed Central

    Craige, Siobhan M.; Kai, Chen; Pei, Yongmei; Chunying, Li; Xiaoyun, Huang; Christine, Chen; Shibata, Rei; Sato, Kaori; Walsh, Kenneth; Keaney, John F.

    2013-01-01

    Background Reactive Oxygen Species (ROS) serve signaling functions in the vasculature, and hypoxia has been associated with increased ROS production. NADPH oxidase 4 (Nox4) is an ROS-producing enzyme that is highly expressed in the endothelium, yet its specific role is unknown. We sought to determine the role of Nox4 in the endothelial response to hypoxia. Methods and Results Hypoxia induced Nox4 expression both in vitro and in vivo and overexpression of Nox4 was sufficient to promote endothelial proliferation, migration, and tube formation. To determine the in vivo relevance of our observations, we generated transgenic mice with endothelial-specific Nox4 overexpression using the VE-cadherin promoter (VECad-Nox4 mice). In vivo, the VECad-Nox4 mice had accelerated recovery from hind limb ischemia and enhanced aortic capillary sprouting. Because endothelial nitric oxide synthase (eNOS) is involved in endothelial angiogenic responses and eNOS is activated by ROS, we probed the effect of Nox4 on eNOS. In cultured ECs overexpressing Nox4 we observed a significant increase in eNOS protein expression and activity. To causally address the link between eNOS and Nox4 we crossed our transgenic Nox4 mice with eNOS-/- mice. Aorta from these mice did not demonstrate enhanced aortic sprouting and VECad-Nox4 mice on the eNOS-/- background did not demonstrate enhanced recovery from hind limb ischemia. Conclusions Collectively, we demonstrate that augmented endothelial Nox4 expression promotes angiogenesis and recovery from hypoxia in an eNOS-dependent manner. PMID:21788590

  15. Increased aortic pulse wave velocity in obese children.

    PubMed

    Celik, Ataç; Ozçetin, Mustafa; Yerli, Yasemin; Damar, Ibrahim Halil; Kadı, Hasan; Koç, Fatih; Ceyhan, Köksal

    2011-10-01

    Obesity may start in childhood and obese children are more likely to grow up to be obese adults. Atherosclerosis is one of the most important complications of obesity. Pulse wave velocity (PWV), a noninvasive measure of arterial stiffness, is accepted to be an indicator of subclinical atherosclerosis. The aim of the study was to determine PWV in obese children. The study included 30 obese (12 boys, 18 girls; mean age 13 ± 2 years) and 30 lean children (13 boys, 17 girls; mean age 12.5 ± 1.7 years). Weight and height were measured and obesity was defined as body mass index (BMI) of greater than the 95th percentile for age. All the subjects underwent echocardiographic evaluation and blood samples were obtained. Pulse-wave velocity was calculated using the following equation: PWV (m/sec) = height-based aortic length (cm)/(100xtransit time [sec]). The latter was measured as the difference in the time of onset of two flows at the diaphragm and the aortic valve. Obese subjects had significantly higher blood pressure levels compared to the control group (p<0.001). The two groups were similar with respect to fasting glucose, hemoglobin, serum creatinine, and lipid levels. Among echocardiographic parameters, left ventricular end-diastolic dimension, interventricular septum thickness, posterior wall thickness, left ventricular mass index, left atrium dimension, and aortic root dimension were significantly increased in obese subjects compared to controls (p<0.01). Obese children had significantly higher PWV values than the controls (4.0 ± 0.8 vs. 3.3 ± 0.7 m/sec, p<0.001). A positive significant correlation was found between PWV and BMI (r=0.391, p=0.002). Our findings show that aortic PWV is increased in obese children, suggesting that obesity may cause subclinical atherosclerosis even at early ages.

  16. Increasing incidence of aortic aneurysms in England and Wales.

    PubMed Central

    Fowkes, F. G.; Macintyre, C. C.; Ruckley, C. V.

    1989-01-01

    The numbers of patients being admitted to hospital with aortic aneurysms have increased recently. A study was carried out to try to find out whether this was a true increase in incidence or whether it could be attributable to more accurate diagnosis and better surgical techniques. From analyses of routine statistics it was found that from 1950 to 1984 age standardised mortality rose 20-fold in men to 47.1 per 100,000 population and 11-fold in women to 22.2 per 100,000 and that this was mainly due to more deaths from abdominal aneurysms. Hospital admissions of men with abdominal aneurysms were found to have increased steadily from 1968 to 1983, but the increase for women admitted did not begin until 1978. An increase in both emergency and elective admissions and only a marginal fall in deaths in hospital (from 45% to 39%) suggest that admissions for abdominal aneurysms increased across a wide range of severity of disease. It is concluded for the following reasons that the true incidence of aortic aneurysms, particularly abdominal aneurysms, has been increasing in England and Wales: the trends are not wholly compatible with advances in diagnosis and surgery, there are inconsistencies by age and sex, and increases have occurred in the number of complicated as well as uncomplicated cases. PMID:2492850

  17. Cytochalasin inhibition of slow tension increase in rat aortic rings.

    PubMed

    Wright, G; Hurn, E

    1994-10-01

    We separated the K(+)-induced contraction of rat aortic rings into its initial (fast) and secondary (slow) components. It was found that temperature sensitivity, K+ depolarization, and Ca2+ dependency could each be utilized to differentiate between these two components of the contractile response. Increasing the passive tension preload of the tissue increased the fast response but had no significant effect on the secondary slow rise in tension. Cytochalasins, which inhibit actin polymerization, reversibly inhibited tension development by rat aortic rings with the effect selectively confined to the slow component of the K(+)-induced contraction. In a similar fashion, cytochalasin was shown to attenuate the slow tension increase caused by phorbol 12,13-dibutyrate. Finally, it was found that low concentrations of the protein kinase C (PKC) inhibitor staurosporine (8 x 10(-9) M) selectively attenuated the slow component of the K(+)-induced contraction. The results suggest that distinctly different mechanisms regulate the initial fast and secondary slow contractile responses induced by elevation of extracellular K+. Both mechanisms are voltage sensitive and use extracellular Ca2+. The fast but not the slow component was altered by changing the passive tension preload in a fashion consistent with a sliding filament mechanism of force development. The specific nature of the slow component is not certain but may involve low-level PKC activity and require the integrity and capability for remodeling of a specific portion of the actin-containing cytoskeleton.

  18. Chinese medicine Tongxinluo modulates vascular endothelial function by inducing eNOS expression via the PI-3K/Akt/HIF-dependent signaling pathway.

    PubMed

    Liang, Jun Qing; Wu, Kun; Jia, Zhen Hua; Liu, Chang; Ding, Jin; Huang, Shan Na; Yin, Pei Pei; Wu, Xiang Chun; Wei, Cong; Wu, Yi Ling; Wang, Hong Yang

    2011-01-27

    To investigate the molecular mechanisms whereby the Chinese medicinal compound Tongxinluo improves vascular endothelial function through studying the induction of endothelial nitric oxide synthase (eNOS) and its upstream signaling pathway. Hyperhomocysteinemia was induced in Wistar rats by a methionine-rich diet followed by Tongxinluo treatment. The aorta ring was isolated for measuring vascular dilation of aorta and eNOS expression. Human umbilical vein endothelial cells (HUVECs) were transfected with AP-1, NF-κB, HRE or eNOS reporter plasmid followed by Tongxinluo exposure. Expression of the reporter genes was measured by luciferase assay. The level of eNOS was studied by western blot and the nitric oxide content was measured using the nitrate reductase method. HUVECs were also transiently transfected with the dominant negative mutant of HIF-1, PI-3K or Akt to explore the role of HIF and PI-3K/Akt pathway in eNOS induction by Tongxinluo. Tongxinluo could significantly up-regulate the expression of eNOS in the aortic tissue and improve the endothelium-dependent vasodilation of the aorta ring. Additionally, Tongxinluo at various doses could significantly enhance the expression of HRE and eNOS reporter gene as well as up-regulate the protein level of eNOS. Meanwhile, Tongxinluo caused a dose-dependent increase in the NO content in the supernatant of HUVECs. Suppression of HIF-1 activation by DN-HIF or inhibition of PI-3K/Akt pathway by ΔP85 or DN-Akt both attenuated HRE reporter gene activation and eNOS induction by Tongxinluo. Tongxinluo, a compound Chinese traditional medicine, up-regulates the expression of eNOS via the PI-3K/Akt/HIF-dependent signaling pathway, thus improving the endothelium-dependent vasodilation. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Hydralazine decreases sodium nitroprusside-induced rat aortic ring relaxation and increased cGMP production by rat aortic myocytes.

    PubMed

    Vidrio, Horacio; González-Romo, Pilar; Alvarez, Ezequiel; Alcaide, Carlos; Orallo, Francisco

    2005-10-28

    Association of hydralazine with nitrova-sodilators has long been known to be beneficial in the vasodilator treatment of heart failure. We previously found that hydralazine appeared to reduce the increase in cGMP induced by sodium nitroprusside in cultured rat aortic myocytes. In order to further explore this seemingly paradoxical interaction, we extended our initial observations in rat aortic myocytes and also determined the influence of hydralazine on sodium nitroprusside-induced relaxation of rat aortic rings. Hydralazine produced a concentration-dependent inhibition of sodium nitroprusside stimulation of cGMP production and caused a rightward shift of concentration-relaxation curves in aortic rings. A possible mechanism of the hydralazine-nitroprusside interaction could be the interference with bioactivation of the nitro-vasodilator to release nitric oxide. Recent evidence indicates that vascular NADH oxidase, an enzyme known to be inhibited by hydralazine, could be involved in this process. Accordingly, hydralazine was found to inhibit NADH oxidase activity in rat aortic myocytes at concentrations similar to those reducing sodium nitroprusside responses. It was concluded that antagonism of sodium nitroprusside action by hydralazine could be a consequence of interference with bioactivation of the former, apparently through inhibition of vascular NADH oxidase.

  20. D-lactate increases pulmonary apoptosis by restricting phosphorylation of bad and eNOS in a rat model of hemorrhagic shock.

    PubMed

    Jaskille, Amín; Alam, Hasan B; Rhee, Peter; Hanes, William; Kirkpatrick, John R; Koustova, Elena

    2004-08-01

    Resuscitation with racemic lactated Ringer's solution (containing equal amounts of D and L isomers of lactate) has been shown to induce pulmonary apoptosis. Substitution of DL-isomer lactate with ketone bodies (beta-hydroxybutyrate, BHB), sodium pyruvate, or L-isomer of lactate decrease this injury without changing the energy status of the tissues or the expression of apoptotic genes. These modified solutions however alter the function of apoptotic proteins through an unknown mechanism. We postulated that DL-LR induces apoptosis by restricting the phosphorylation of key apoptotic proteins. Male Sprague Dawley rats (n = 30, 5/group) were subjected to a three stage, volume-controlled hemorrhage and randomized to the following groups. 1) No hemorrhage (Sham); 2) Hemorrhage and no resuscitation (NR); 3) Resuscitation with 3x shed blood volume of racemic LR (DL-LR); 4) Resuscitation with 3x shed blood volume of LR containing only the L-isomer of lactate (L-LR); 5) Resuscitation with 3s shed blood volume of pyruvate Ringer's (PR); 6) Resuscitation with 3s shed blood volume of ketone Ringer's (KR). The modified Ringer's solutions were identical to racemic LR except for equimolar substitution of DL-lactate for L-lactate, pyruvate and BHB respectively. Lung tissue was obtained 2 hours later and subjected to Western Blotting. The levels of Akt, Bad, and eNOS (total and phosphorylated) proteins were measured. Finally, the expression of gene coding for protein 14-3-3 was measured using RT-PCR. Resuscitation with DL-LR caused a significant (p < 0.05) increase in the total Bad and a decrease in phosphorylated Bad protein expression in the lung. It also caused an increase in the phosphorylated Akt levels and a decrease in gene coding for protein 14-3-3. These changes were consistent with signaling imbalances that favor apoptosis. Modified LR solutions, on the other hand, did not cause these alterations. Phosphorylation pattern of eNOS supported the involvement of PI3K/Akt pathway

  1. Target renal damage: the microvascular associations of increased aortic stiffness in patients with COPD

    PubMed Central

    2013-01-01

    Background Although renal impairment has been described in COPD, there is opportunity to evaluate further to determine nature and consider optimal management. Increased aortic stiffness, as seen in COPD, leads to reduced buffering of pulsatile flow. We hypothesised that urinary albumin creatinine ratio (UACR) would reflect glomerular damage related to aortic stiffness. Methods Patients with COPD and controls underwent spirometry, blood pressure, arterial stiffness - aortic pulse wave velocity (PWV) and provided a spot urine sample for UACR, with other renal biomarkers measured. Results The UACR was increased in patients (n = 52): 0.80 mg/mmol compared to controls (n = 34): 0.46 mg/mmol, p < 0.05. Aortic PWV was related to log10 UACR in all subjects (r = 0.426, p < 0.001) and COPD patients alone. Aortic PWV was a significant variable for UACR with oxygen saturations, after accounting for potential confounders. Eight subjects (7 patients) reached a defined clinical microalbuminuria threshold, with aortic PWV greater in these patients compared to those patients without, although albuminuria is a continuum. Proximal tubular damage biomarkers, unlike the glomerular marker, were not different between patients and controls. Conclusions There is glomerular damage in patients with COPD evidenced by increased UACR, related to increased aortic stiffness. Besides the macrovascular prognostic implications of increased aortic stiffness, the microvascular state in COPD management should be considered. PMID:23497267

  2. No increased mortality with early aortic aneurysm disease.

    PubMed

    Mell, Matthew; White, Julie J; Hill, Bradley B; Hastie, Trevor; Dalman, Ronald L

    2012-11-01

    In addition to increased risks for aneurysm-related death, previous studies have determined that all-cause mortality in abdominal aortic aneurysm (AAA) patients is excessive and equivalent to that associated with coronary heart disease. These studies largely preceded the current era of coronary heart disease risk factor management, however, and no recent study has examined contemporary mortality associated with early AAA disease (aneurysm diameter between 3 and 5 cm). As part of an ongoing natural history study of AAA, we report the mortality risk associated with presence of early disease. Participants were recruited from three distinct health care systems in Northern California between 2006 and 2011. Aneurysm diameter, demographic information, comorbidities, medication history, and plasma for biomarker analysis were collected at study entry. Survival status was determined at follow-up. Data were analyzed with t-tests or χ(2) tests where appropriate. Freedom from death was calculated via Cox proportional hazards modeling; the relevance of individual predictors on mortality was determined by log-rank test. The study enrolled 634 AAA patients; age 76.4 ± 8.0 years, aortic diameter 3.86 ± 0.7 cm. Participants were mostly male (88.8%), not current smokers (81.6%), and taking statins (76.7%). Mean follow-up was 2.1 ± 1.0 years. Estimated 1- and 3-year survival was 98.2% and 90.9%, respectively. Factors independently associated with mortality included larger aneurysm size (hazard ratio, 2.12; 95% confidence interval, 1.26-3.57 for diameter >4.0 cm) and diabetes (hazard ratio, 2.24; 95% confidence interval, 1.12-4.47). After adjusting for patient-level factors, health care system independently predicted mortality. Contemporary all-cause mortality for patients with early AAA disease is lower than that previously reported. Further research is warranted to determine important factors that contribute to improved survival in early AAA disease. Copyright © 2012 Society for

  3. No Increased Mortality With Early Aortic Aneurysm Disease

    PubMed Central

    Mell, Matthew; White, Julie J.; Hill, Bradley B.; Hastie, Trevor; Dalman, Ronald L.

    2012-01-01

    Objective In addition to increased risks for aneurysm-related death, previous studies have determined that all-cause mortality in abdominal aortic aneurysm (AAA) patients is excessive and equivalent to that associated with coronary heart disease (CHD). These studies largely preceded the current era of CHD risk factor management, however, and no recent study has examined contemporary mortality associated with early AAA disease (aneurysm diameter between 3 and 5 cm). As part of an ongoing natural history study of AAA, we report the mortality risk associated with presence of early disease. Methods Participants were recruited from three distinct health care systems in Northern California between 2006 and 2011. Aneurysm diameter, demographic information, co-morbidities, medication history, and plasma for biomarker analysis were collected at study entry. Survival status was determined at follow-up. Data were analyzed with t- or chi-square tests where appropriate. Freedom from death was calculated via Cox proportional hazards modeling; the relevance of individual predictors on mortality was determined by log-rank test. Results The study enrolled 645 AAA patients; age 76.4 +/− 8.0 years, aortic diameter 3.86+/− 0.7 cm. Participants were mostly male (88.8%) not current smokers (81.6%) and taking statins (76.7%). Mean follow-up was 2.1 +/− 1.0 years. Estimated 1- and 3-year survival was 98.2% and 90.9%, respectively. Factors independently associated with mortality included larger aneurysm size (HR 2.12, 95% CI 1.26 – 3.57 for diameter >4.0 cm) and diabetes (HR 2.24, 95% CI 1.12 – 4.47). After adjusting for patient-level factors, health care system independently predicted mortality. Conclusion Contemporary all-cause mortality for patients with early AAA disease is lower than that previously reported. Further research is warranted to determine important factors that contribute to imporved survival in early AAA disease. PMID:22832264

  4. Adrenocorticotropic Hormone and PI3K/Akt Inhibition Reduce eNOS Phosphorylation and Increase Cortisol Biosynthesis in Long-Term Hypoxic Ovine Fetal Adrenal Cortical Cells.

    PubMed

    Newby, Elizabeth A; Kaushal, Kanchan M; Myers, Dean A; Ducsay, Charles A

    2015-08-01

    This study was designed to determine the role of the MEK/ERK1/2 and PI3K/Akt pathways in cortisol production and endothelial nitric oxide synthase (eNOS) phosphorylation (peNOS) in the ovine fetal adrenal in response to long-term hypoxia (LTH). Pregnant ewes were maintained at high altitude (3820 m) for the last 100 days of gestation (dGa). At 138 to 142 dGa, fetal adrenal cortical cells (FACs) were collected from LTH and age-matched normoxic fetuses. Cortisol production and peNOS were measured in response to pretreatment with the MEK/ERK1/2 pathway inhibitor UO126 (UO) and adrenocorticotropic hormone (ACTH) stimulation. UO126 reduced ACTH-stimulated cortisol in both normoxic and LTH FACs. UO126 alone or in combination with ACTH reduced peNOS in the normoxic group, while ACTH alone or ACTH + UO inhibited peNOS in LTH FACs. Additionally, cortisol was measured in response to pretreatment with UO and treatment with 22R-hydroxycholesterol (22R-OHC) or water-soluble cholesterol (WSC) with and without ACTH stimulation. UO126 had no effect on 22R-OHC-treated cells, but reduced cortisol in cells treated with WSC and/or ACTH. Cortisol and peNOS were also measured in response to pretreatment with PI3K/Akt pathway inhibitor Wortmannin (WT) and ACTH stimulation. Wortmannin further increased cortisol under ACTH-stimulated conditions and, like ACTH, reduced peNOS in LTH but not normoxic FACs. Together, these data suggest that in LTH FACs MEK/ERK1/2 does not regulate peNOS but that UO acts downstream from eNOS, possibly at cholesterol transport, to affect cortisol production in LTH FACs, while the PI3K/Akt pathway, along with ACTH, regulates peNOS and plays a role in the fetal adaptation to LTH in FACs.

  5. 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

  6. Bicuspid aortic valve increases risk of permanent pacemaker implant following aortic root replacement.

    PubMed

    Guglielmetti, Laura; Nazif, Tamim; Sorabella, Robert; Akkoc, Deniz; Kantor, Alex; Gomez, Andres; Wang, Catherine; Takayama, Hiroo; Dizon, Jose; Borger, Michael; George, Isaac

    2016-09-01

    We aimed to assess the incidence and possible differences in postoperative conduction delay after aortic root replacement (ARR) in bicuspid aortic valve (BAV) patients compared with a tricuspid aortic valve (TAV). A total of 380 patients undergoing ARR at our institution between 2005 and 2013 were included in the analysis. Patients were stratified by aortic valve anatomy: BAV, n = 191 vs TAV, n = 189. Electrocardiographic and echocardiographic data were retrospectively analysed at different time points (pre-, postoperatively and at follow-up). Primary outcome of interest was permanent pacemaker (PPM) implantation within 30 days, the composite of new PPM or new left fascicular or bundle branch block (PPM or LBBB) was the secondary outcome of interest. Age range was 24-89.5 years and incidence of preoperative moderate to severe aortic stenosis was 9.7%. BAV patients had higher incidence of PPM implantation within 30 days (5.8 vs 1.6% in TAV, P = 0.053); moreover, the composite of PPM or LBBB was also more frequent in BAV (8.4 vs 2.1%, P = 0.010). BAV was independently associated with PPM insertion (OR 4.08, P = 0.047) and also an independent predictor of PPM or LBBB in multiple regression (OR 4.96, P = 0.006). Significantly higher incidence of PPM implantation or LBBB may exist after ARR in bicuspid patients and BAV was confirmed to be an independent predictor for postoperative conduction disturbances by multivariable regression. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  7. Increased blood levels of transforming growth factor β in patients with aortic dilatation.

    PubMed

    Rueda-Martínez, Carmen; Lamas, Oscar; Carrasco-Chinchilla, Fernando; Robledo-Carmona, Juan; Porras, Carlos; Sánchez-Espín, Gemma; Navarro, Manuel Jiménez; Fernández, Borja

    2017-10-01

    Recent studies have shown that patients with syndromic thoracic aortic aneurysm, particularly patients with bicuspid aortic valve, have increased blood levels of transforming growth factor β1 (TGF-β1), indicating this molecule as a prognostic biomarker. However, it is not known whether TGF-β1 is also elevated in the blood of patients with tricuspid aortic valve and aortic dilatation. We analysed the plasma levels of TGF-β1 in 52 patients with tricuspid or bicuspid aortic valve and with normal or dilated ascending aorta who underwent cardiac surgery in our hospital. TGF-β1 blood level was significantly increased two-fold in patients with tricuspid aortic valve and dilated aorta compared to patients with tricuspid aortic valve and normal aorta. Our results suggest that TGF-β1 blood levels may serve as a prognostic biomarker for patients with syndromic and non-syndromic thoracic aortic aneurysm. Further studies with larger cohorts of patients should be performed to confirm these results.

  8. 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

  9. Loss of STAT1 is Associated with Increased Aortic Rupture in an Experimental Model of Aortic Dissection and Aneurysm Formation

    PubMed Central

    Eagleton, Matthew J.; Xu, Jun; Liao, Mingfang; Parine, Brittney; Chisolm, Guy M.; Graham, Linda M.

    2009-01-01

    Background Transcription factor signal transducer and activator of transcription (STAT) 1 has been linked to a variety of pathologic states involved with matrix remodeling, but its role in aortic pathology has not been previously described. The current study hypothesizes that STAT1 regulates aneurysmal degeneration and its role will be evaluated in human aortic aneurysms and in a mouse model of aortic dissection. Methods Apolipoprotein E knockout mice (ApoE−/−) or ApoE/STAT1 double knockout mice (ApoE/STAT1−/−) were infused with 1000 ng/kg/min of angiotensin II (Ang II). Systolic blood pressure (SBP) was measured in the rodent tail. At sacrifice, aortic diameters and extent of aneurysm formation were measured by digital microscopy. STAT1 and phosphorylated-STAT1 protein levels were assessed in ApoE−/− mice at 0, 7, 14, and 28 days (n=8/time point) by ELISA. Histology was performed using H&E and Movat stains. Statistical analyses included chi-square test, T-test, and ANOVA. Results STAT1 mRNA and total protein were greater in human AAA compared to non-aneurysmal controls. In addition, aneurysms occurred in 8%, 50%, and 80% of apoE−/− mice at 7, 14, and 28 days respectively. Total STAT1 levels were not altered during the course of Ang II infusion, but phosphorylated STAT1 levels peaked at 7 days with a 1.4-fold increase over baseline (P<0.05). Aneurysms occurred in 0%, 100%, and 100% of apoE/STAT1−/− mice at 3, 5, and 28 days. In mice infused with Ang II for more than 3 days, aortic rupture occurred more frequently in apoE/STAT−/− mice (53% v. 19%, P<0.05) and at earlier time points (4.0±0.5 v. 9.2±0.77 days, P<0.05) compared with apoE−/− mice. SBP did not differ between the groups during Ang II infusion. By 28 days, aneurysms were larger in apoE/STAT1−/− mice compared to apoE−/− mice (2.7±0.4 v. 1.9±0.1 mm, P<0.05), and were more extensive arising at the level of the left subclavian artery and extending to the infrarenal aorta

  10. 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.

  11. Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms.

    PubMed

    Albini, Paul T; Segura, Ana Maria; Liu, Guanghui; Minard, Charles G; Coselli, Joseph S; Milewicz, Dianna M; Shen, Ying H; LeMaire, Scott A

    2014-02-01

    The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA. Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 ± 12.0 years) and 15 controls (mean age, 56.6 ± 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types ≥ 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque. SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Effect of increased intra-aortic balloon pressure on catheter volume: relationship to changing altitudes.

    PubMed

    Mertlich, G B; Quaal, S J; Borgmeier, P R; DeVries, K L

    1992-02-01

    To evaluate the effect of intra-aortic balloon membrane response under increasing intracatheter pressure by indexing these data to associated barometric pressures that occur with changes in altitude. A static compliance test was performed to assess the effect of internal pressure on intra-aortic balloon compliance (simulating helium gas within the intra-aortic balloon affected by barometric pressure). Testing consisted of incrementally increasing pressure within eight percutaneous intra-aortic balloons from four leading manufacturers. The University of Utah Department of Mechanical Engineering Laboratory. No patients were involved. This study was a bench test lab study. No patient interventions were utilized. Results for all trials showed a curvilinear relationship between intracatheter pressure and balloon volume. Clinically significant balloon expansion data were obtained, with manufacturer variation observed at moderate-to-high pressures. Based on the results of this study, recommendations for operation of intra-aortic balloon pumps during altitude ascent and descent are proposed, from which individual institutional protocols may be developed.

  13. 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

  14. 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.

  15. Diabetes mellitus increases the risk of ruptured abdominal aortic aneurysms.

    PubMed

    Wierzba, Waldemar; Sliwczynski, Andrzej; Pinkas, Jaroslaw; Jawien, Arkadiusz; Karnafel, Waldemar

    2017-09-01

    The publication is a polemical response to reports that present data that diabetes reduces the risk of rupture of abdominal aortic aneurysm (AAA). The study analyzed all cases of developing AAA in patients with and without diabetes in 2012 in Poland. Data for the analysis were obtained with a unique and complete resources of the National Health Fund (NFZ) and population data from the Central Statistical Office (GUS). In Poland during 2012 2,227,453 patients with diabetes were treated, 975,364 males and 1,252,089 females. The incidence of AAA without rupture in patients without diabetes calculated per 100,000 of the non-diabetes general population was 25.0 +/- 9.0 in males and 5.6 +/- 2.3 in females. The incidence of ruptured AAA in the general population without diabetes was 3.6 +/- 0.9 in males, and 0.6 +/- 0.3 in females calculated per 100,000 of inhabitants without diabetes. The incidence of AAA without rupture in patients with diabetes was 184.897 +/- 70.653 in males and 35.364 +/- 24.925 in females calculated per 100,000 of patients diagnosed with diabetes. The incidence of ruptured AAA in patients with diabetes was 21.090 +/- 6.050 in males and 5.170 +/- 3.053 in females calculated per 100,000 of patients diagnosed with diabetes. The incidence rate for ruptured AAA in 2012 in Poland is statistically higher both in females and males in the population with diabetes. The incidence rate for AAA without rupture in 2012 in Poland is statistically higher in patients diagnosed with diabetes.

  16. 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.

  17. Effects of increasing flow rate on aortic stenotic indices: evidence from percutaneous transvenous balloon dilatation of the mitral valve in patients with combined aortic and mitral stenosis.

    PubMed Central

    Lee, T. M.; Su, S. F.; Chen, M. F.; Liau, C. S.; Lee, Y. T.

    1996-01-01

    OBJECTIVES: To investigate the effects of transvalvar flow rate on aortic valve resistance and valve area after percutaneous transvenous balloon dilatation of the mitral valve in a homogeneous group of patients with rheumatic heart disease. DESIGN: Retrospective analysis of 12 patients with combined aortic and mitral stenosis who had undergone balloon dilatation of the mitral valve over a period of 9 years. SETTING: Tertiary referral centre. PATIENTS: Twelve (8 women, 4 men; mean (SD) age 37 (9) of 227 consecutive patients with critical mitral stenosis undergoing transvenous balloon dilation of the mitral valve in the centre also had aortic stenosis, defined as a transaortic pressure gradient of more than 25 mm Hg measured at a catheterisation study before valvuloplasty. INTERVENTIONS: Echocardiographic variables (mitral valve area measured by the pressure half-time method and planimetry, and the aortic valve area derived from the continuity equation) and haemodynamic measurements (cardiac output, left ventricular mean systolic pressure, aortic mean pressure, transaortic valve pressure gradient, mitral valve and aortic valve areas derived from the Gorlin formula, and aortic valve resistance) were assessed before and after transvenous balloon dilatation of the mitral valve. Follow up catheterisation to measure haemodynamic variables was performed one week after mitral valvuloplasty. RESULTS: Mean transaortic flow rate increased 33% after mitral valvuloplasty (from 198 (68) to 254 (41) ml/s, P = 0.002). Aortic valve areas derived from the Gorlin formula were significantly increased from 0.57 (0.12) to 0.73 (0.14) cm2 (P = 0.006) after mitral valvuloplasty. However, aortic valve area and valve resistance derived from the continuity equation were independent of the increase in flow rate after mitral valvuloplasty (from 1.29 (0.35) to 1.30 (0.29) cm2 and from 317 (65) to 259 (75) dyn.s.cm-5, both P = NS). CONCLUSION: The Gorlin-derived aortic valve area tends to be flow

  18. Programmed Speed Reduction Enables Aortic Valve Opening and Increased Pulsatility in the LVAD-Assisted Heart.

    PubMed

    Tolpen, Sam; Janmaat, Jochem; Reider, Claudine; Kallel, Faouzi; Farrar, David; May-Newman, Karen

    2015-01-01

    Aortic valve opening (AVO) during left ventricular assist device (LVAD) support aids in preventing valve fusion, incompetence, and thrombosis. The programmed low speed algorithm (PLSA) allows AVO intermittently by reducing continuous motor speed during a dwell time. AVO and hemodynamics in the LVAD-assisted heart were measured using a HeartMate II (Thoratec Corporation, Pleasanton, CA) LVAD with a PLSA controller in a mock circulatory loop. Left ventricle and aortic pressures, LVAD, and total aortic flow were measured during pre-LVAD, non-PLSA and PLSA combinations of cardiac function, and LVAD speed. The low cardiac setting corresponded to a pre-LVAD cardiac output of 2.8 L/min, stroke volume of 40 ml, and ejection fraction of 22%; the medium setting produced values of 3.5 L/min, 50 ml, and 28%, respectively. Results show that the PLSA controller set at 10 krpm, dropping to 7 krpm for dwell time of 6 s, adequately produced AVO for all tested cardiac functions with only minimal changes in cardiac output. However, AVO frequency was independent of opening area and systolic duration, which both decreased with increasing LVAD support. Furthermore, aortic pulsatility index quadrupled in the aortic root and doubled in the distal aorta during PLSA conditions, providing evidence that AVO and blood mixing are enabled by PLSA control at the appropriate speed.

  19. Increased reversal and oscillatory shear stress cause smooth muscle contraction-dependent changes in sheep aortic dynamics: role in aortic balloon pump circulatory support.

    PubMed

    Bia, D; Zócalo, Y; Armentano, R; Camus, J; Forteza, E de; Cabrera-Fischer, E

    2008-04-01

    The intra-aortic balloon pumping (IABP) changes pressure and increases the aorta shear stress reversal (SS(R)) and oscillatory (SS(O)) components. Hence, IABP-dependent changes in aortic biomechanics would be expected, because of vascular smooth muscle (VSM) tone (i.e. flow-induced endothelium-dependent response, related to SS(R) and SS(O) variations) and/or pressure changes. To characterize: (i) the IABP effects on the aortic and global (systemic circulation) biomechanics, analysing their dependence on pressure and VSM basic tone changes and (ii) the relation between the SS(R) and SS(O) and the aortic biomechanical changes associated with the VSM tone variations. Aortic flow, pressure and diameter were measured in eight sheep during basal, augmented and assisted beats (1 : 1 and 1 : 2 IABP modalities). Calculations: (i) aortic effective and isobaric elasticity, viscosity, circumferential stress, pulse wave velocity, shear stress and buffer and conduit functions, (ii) peripheral resistance, global compliance, reflection coefficient and wave propagation times and (iii) the relation between SS(R) and SS(O) and biomechanical changes associated with variations in the aortic VSM tone. Augmented and assisted beats showed: global VSM relaxation pattern (reduced peripheral resistance and reflection coefficient; increased propagation times) and local VSM contraction pattern (increased viscosity; reduced diameter, elasticity and circumferential stress), associated with SS(R) and SS(O), levels and changes. The vascular changes reduced the ventricle afterload determinants, increased the vascular buffer performance and kept the conduit capability. In addition to pressure-dependent changes, IABP determined biomechanical changes related to variations in the VSM tone. The increased SS(R) and SS(O) were associated with the aortic VSM contraction pattern and biomechanical changes.

  20. A nonintrinsic regional basis for increased infrarenal aortic MMP-9 expression and activity.

    PubMed

    Ailawadi, Gorav; Knipp, Brian S; Lu, Guanyi; Roelofs, Karen J; Ford, John W; Hannawa, Kevin K; Bishop, Keith; Thanaporn, Porama; Henke, Peter K; Stanley, James C; Upchurch, Gilbert R

    2003-05-01

    This investigation was undertaken to determine whether intrinsic or regional factors at different anatomic sites of the aorta affect expression and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Aortas from Sprague-Dawley rats (n = 22) were divided into arch, descending thoracic, and infrarenal abdominal segments. Specimens were stimulated with interleukin-1beta (IL-1beta) (2 ng/mL) for 72 hours. In separate experiments, syngeneic aortic segments were transplanted from the thoracic or abdominal aortas of donor rats into the infrarenal aortic position of recipient rats (n = 12 each). At 4 weeks, aortas from rats who had received transplants were harvested, sectioned into arch, thoracic, and transplanted thoracic or transplanted abdominal segments, and stimulated with IL-1beta. Reverse transcriptase polymerase chain reaction, zymography, and reverse zymography were performed to assess MMP-9, MMP-2, and TIMP-1 in all aortic segments. Differences were assessed with analysis of variance (ANOVA) and post-hoc Tukey test. In control rats, abdominal segments had significantly higher MMP-9 expression compared with arch and thoracic segments (P <.002). Total MMP-9 activity was also higher in abdominal segments (P <.02). In rats who received transplants, transplanted thoracic (P <.004) and transplanted abdominal (P <.05) segments demonstrated upregulation of MMP-9 expression, compared with control arch and thoracic segments. Zymography documented increased total MMP-9 activity in transplanted thoracic (P <.03) and transplanted abdominal (P <.04) segments versus arch and thoracic segments. No significant difference in MMP-9 expression was found between control abdominal, transplanted thoracic, or transplanted abdominal segments. No significant differences in MMP-2 or TIMP-1 expression or activity were demonstrated in either control or transplanted segments. These data demonstrate that variations in aortic MMP-9 expression and

  1. Iatrogenic Major Venous Injury Is Associated with Increased Morbidity of Aortic Reconstruction.

    PubMed

    Hans, Sachinder S; Vang, Steven; Sachwani-Daswani, Gul

    2017-09-05

    Major venous injury during open aortic reconstruction though uncommon often result in sudden and massive blood loss resulting in increased morbidity and mortality. This study details the etiology, management, and outcome of such injuries. A retrospective review of 945 patients (1981-2017) undergoing aortic reconstruction from 2 midsized (350 bed each) teaching hospitals was conducted. Seven hundred twenty-three patients (76.5%) underwent open abdominal aortic aneurysm (AAA) repair/iliac aneurysm repair, 222 patients (23.5%) underwent aortofemoral grafting (AFG). Patients sustaining major venous injury (sudden loss of more than 500 mL of blood) during major aortic reconstruction were studied. The number of units of packed red blood cells transfused, location of injured vessel, type of repair, postoperative morbidity, and mortality were collected in our vascular registry on a continuous basis. All patients identified with iliac vein/inferior vena cava/femoral vein injury had follow-up noninvasive venous examination of the lower extremities. Eighteen major venous injuries (1.9%) occurred during aortic reconstruction in 17 patients (1 patient had 2 major venous injuries): IVC (n = 4), iliac vein (n = 10), left renal vein (n = 4, this includes a posterior retroaortic renal vein injury n = 1). Of the 18 major venous injuries, 7 occurred during open AAA repair for ruptured AAA and another 9 occurred during repair of intact AAA (P = 0.001), 2 venous injuries occurred after AFG, and 1 after primary AFG (P = 0.05). Using multivariate regression analysis, periarterial inflammation had significant association with major venous injury (P < 0.001). The presence of associated iliac aneurysm with abdominal aortic aneurysm also increased the incidence of major venous injury during AAA surgery (P = 0.05). Two patients (11.8%) died, one from uncontrolled bleeding due to tear of right common iliac vein during ruptured AAA repair and second patient from disseminated

  2. Evidence suggests rigid aortic grafts increase systolic blood pressure: results of a preliminary study.

    PubMed

    O'Brien, T; Morris, L; McGloughlin, T

    2008-01-01

    Abdominal aortic aneurysm (AAA) is a serious complication of the aorta and is treated using vascular bypass grafts. Two main classes of graft are available to treat AAA; grafts implanted by open surgery and stent-grafts implanted using minimally invasive endovascular techniques. Both classes of graft consist of an aortic section which bifurcates into two iliac sections. It has been hypothesized that implantation of aortic grafts and stent-grafts serve to significantly increase abdominal aortic pressures. In this study, an open-loop computer-controlled pumping system was built to produce physiologically realistic pressure and flow-rates. Models of a compliant abdominal aortic aneurysm, a compliant walled graft and a tapered graft were manufactured using an injection moulding technique and fused deposition modelling was used to create a rigid walled graft. A specific transient flow-rate waveform was then applied at the inlet of each model and the resulting pressure waveforms 30 mm upstream from the bifurcation was recorded. Peak pressure measurements were recorded over the course of the pulse for each model. The compliant aneurysm model was found to have a systolic pressure of 107 mmHg while the complaint graft model was 153 mmHg. The rigid graft model had a peak systolic pressure of 199 mmHg. In the tapered graft, the peak pressure dropped to 142 mmHg. The data suggests that implanting a graft model in place of an aneurysm model in an in vitro flow circuit can increase the pressures recorded upstream from the iliac bifurcation and that tapered grafts may alleviate this problem.

  3. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population.

    PubMed

    Mayer, O; Seidlerová, J; Wohlfahrt, P; Filipovský, J; Vaněk, J; Cífková, R; Windrichová, J; Topolčan, O; Knapen, M H J; Drummen, N E A; Vermeer, C

    2016-07-01

    Matrix Gla protein (MGP), a natural inhibitor of calcification, strongly correlates with the extent of coronary calcification. Vitamin K is the essential cofactor for the activation of MGP. The nonphosphorylated-uncarboxylated isoform of MGP (dp-ucMGP) reflects the status of this vitamin. We investigated whether there is an association between dp-ucMGP and stiffness of elastic and muscular-type large arteries in a random sample from the general population. In a cross-sectional design, we analyzed 1087 subjects from the Czech post-MONICA study. Aortic and femoro-popliteal pulse wave velocities (PWVs) were measured using a Sphygmocor device. Dp-ucMGP concentrations were assessed in freshly frozen samples by enzyme-linked immunosorbent assay methods using the InaKtif MGP iSYS pre-commercial kit developed by IDS and VitaK. Aortic PWV significantly (P<0.0001) increased across the dp-ucMGP quartiles. After adjustment for all potential confounders, aortic PWV independently correlated with dp-ucMGP (with beta coefficient (s.d.) 11.61 (5.38) and P-value=0.031). In a categorized manner, subjects in the top quartile of dp-ucMGP (⩾ 671 pmol l(-1)) had a higher risk of elevated aortic PWV, with corresponding adjusted odds ratio (95% confidence interval) 1.73 (1.17-2.5). In contrast, no relation between dp-ucMGP and femoro-popliteal PWV was found. In conclusion, increased dp-ucMGP, which is a circulating biomarker of vitamin K status and vascular calcification, is independently associated with aortic stiffness, but not with stiffness of distal muscular-type arteries.

  4. Vascular Smooth Muscle Cell Stiffness as a Mechanism for Increased Aortic Stiffness with Aging

    PubMed Central

    Qiu, Hongyu; Zhu, Yi; Sun, Zhe; Trzeciakowski, Jerome P.; Gansner, Meredith; Depre, Christophe; Resuello, Ranillo R.G.; Natividad, Filipinas F.; Hunter, William C.; Genin, Guy M.; Elson, Elliot L.; Vatner, Dorothy E.; Meininger, Gerald A.; Vatner, Stephen F.

    2010-01-01

    Rationale Increased aortic stiffness, an important feature of many vascular diseases, e.g., aging, hypertension, atherosclerosis and aortic aneurysms, is assumed due to changes in extracellular matrix (ECM). Objective We tested the hypothesis that the mechanisms also involve intrinsic stiffening of vascular smooth muscle cells (VSMCs). Methods and Results Stiffness was measured in vitro both by atomic force microscopy (AFM) and in a reconstituted tissue model, using VSMCs from aorta of young versus old male monkeys (Macaca fascicularis, n=7/group), where aortic stiffness increases by 200 % in vivo. The apparent elastic modulus was increased (P<0.05) in old VSMCs (41.7±0.5 kPa) versus young (12.8±0.3 kPa), but not after disassembly of the actin cytoskeleton with cytochalasin D. Stiffness of the VSMCs in the reconstituted tissue model was also higher (P<0.05) in old (23.3±3.0 kPa) than in young (13.7±2.4 kPa). Conclusions These data support the novel concept, not appreciated previously, that increased vascular stiffness with aging is due not only to changes in ECM, but also to intrinsic changes in VSMCs. PMID:20634486

  5. Proximal aortic stiffness is increased in systemic lupus erythematosus activity in children and adolescents.

    PubMed

    El Gamal, Yehia Mohamad; Elmasry, Ola Abd Elaziz; El Hadidi, Iman Saleh; Soliman, Ola Kamel

    2013-01-01

    Patients with systemic lupus erythematosus (SLE) are prone to premature atherosclerosis and are at risk for the development of cardiovascular disease. Increased arterial stiffness is emerging as a marker of subclinical atherosclerosis. Purpose. To measure proximal aortic stiffness in children and adolescents with SLE. Methods. We studied 16 patients with SLE in activity (mean age 15 ± 2.42 years; 16 females), 14 patients with SLE not in activity (mean age 15.7 ± 1.89 years; 4 males, 10 females), and 16 age- and sex-comparable healthy children and adolescents (15.5 ± 1.71 years; 4 males, 12 females). Disease activity was determined by the SLE disease activity index (SLEDAI). All subjects underwent echocardiography for assessment of proximal aortic pulse wave velocity (PWV) [Ao distance/Ao wave transit time in the aortic arch]. Venous blood samples were collected for ESR. Results. Patients in activity had significantly higher PWV values than controls (P < 0.05), while no significant difference was found between patients not in activity and controls. Conclusions. SLE patients with disease activity demonstrate increased PWV and arterial stiffness of the proximal aorta, while patients without disease activity do not. This suggests that inflammation secondary to SLE activity, and not subclinical atherosclerosis, is the major underlying cause for increased arterial stiffness in this age group.

  6. Transgenic overexpression of human lecithin: cholesterol acyltransferase (LCAT) in mice does not increase aortic cholesterol deposition.

    PubMed

    Furbee, James W; Parks, John S

    2002-11-01

    Results from several atherosclerosis studies using morphometric procedures have proven controversial with regard to whether over-expression of human LCAT in transgenic (Tg) mice is atherogenic. The purpose of the present study was to determine the effect of 10-fold over-expression of human LCAT on aortic free and esterified cholesterol (EC) deposition as well as plasma lipoprotein cholesteryl ester (CE) fatty acid composition in mice fed an atherogenic diet containing cholic acid. C57Bl/6 (control) and human LCAT-Tg mice were fed chow or an atherogenic diet (15% of calories from palm oil, 1.0% cholesterol and 0.5% cholic acid) for 24 weeks before measurement of aortic cholesterol content. Compared with the chow diet, control and LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in plasma total, free and EC, a 7-fold increase in plasma apoB lipoprotein cholesterol, and a 40-50-fold increase in hepatic cholesterol content. The aortic EC content was increased in control (0.7 vs. 1.2 mg/g protein) and LCAT-Tg (0.3 vs. 1.5 mg/g protein) mice fed the atherogenic diet compared with those consuming the chow diet; however, there was no difference in aortic free (14.4+/-6.8 vs. 18.5+/-7.7 mg/g protein) or esterified (1.2+/-1.0 vs. 1.5+/-1.2 mg/g protein) cholesterol content between atherogenic diet-fed control and LCAT-Tg mice, respectively. LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in the ratio of saturated+monounsaturated to polyunsaturated CE species in plasma apoB lipoproteins compared with control mice (9.4+/-2.4 vs. 4.9+/-0.7). We conclude that over-expression of human LCAT in Tg mice fed an atherogenic diet containing cholic acid does not result in increased aortic cholesterol deposition compared with control mice, even though the CE fatty acid saturation index of plasma apoB lipoproteins was doubled.

  7. Increased aortic stiffness and related factors in patients with peripheral arterial disease.

    PubMed

    Catalano, Mariella; Scandale, Giovanni; Carzaniga, Gianni; Cinquini, Michela; Minola, Marzio; Dimitrov, Gabriel; Carotta, Maria

    2013-10-01

    A number of conditions have been associated with functional changes of large arteries. The aim of this study was to evaluate the factors associated with aortic stiffness in patients with peripheral arterial disease (PAD). The authors studied 86 patients with PAD (ankle-brachial pressure index [ABPI] ≤0.9) and 86 controls. Aortic stiffness was determined by pulse wave velocity (aPWV) using applanation tonometry. In PAD patients, aPWV was higher compared with controls (11 ± 3 vs 9.8 ± 1.8; P=.002). In multiple regression analysis, aPWV was independently associated with pulse pressure (β=0.05, P=.01) in the PAD patients and with age in the control group (β=0.08, P=.0005). The results of this study confirm an aPWV increase in patients with PAD and emphasize the association between blood pressure and aPWV. Further studies are necessary to assess whether higher aortic stiffening adds prognostic value to ABPI, which is the most powerful prognostic indicator in PAD. ©2013 Wiley Periodicals, Inc.

  8. Arterial pulse wave dynamics after percutaneous aortic valve replacement: fall in coronary diastolic suction with increasing heart rate as a basis for angina symptoms in aortic stenosis.

    PubMed

    Davies, Justin E; Sen, Sayan; Broyd, Chris; Hadjiloizou, Nearchos; Baksi, John; Francis, Darrel P; Foale, Rodney A; Parker, Kim H; Hughes, Alun D; Chukwuemeka, Andrew; Casula, Roberto; Malik, Iqbal S; Mikhail, Ghada W; Mayet, Jamil

    2011-10-04

    Aortic stenosis causes angina despite unobstructed arteries. Measurement of conventional coronary hemodynamic parameters in patients undergoing valvular surgery has failed to explain these symptoms. With the advent of percutaneous aortic valve replacement (PAVR) and developments in coronary pulse wave analysis, it is now possible to instantaneously abolish the valvular stenosis and to measure the resulting changes in waves that direct coronary flow. Intracoronary pressure and flow velocity were measured immediately before and after PAVR in 11 patients with unobstructed coronary arteries. Using coronary pulse wave analysis, we calculated the intracoronary diastolic suction wave (the principal accelerator of coronary blood flow). To test physiological reserve to increased myocardial demand, we measured at resting heart rate and during pacing at 90 and 120 bpm. Before PAVR, the basal myocardial suction wave intensity was 1.9±0.3×10(-5) W · m(-2) · s(-2), and this increased in magnitude with increasing severity of aortic stenosis (r=0.59, P=0.05). This wave decreased markedly with increasing heart rate (β coefficient=-0.16×10(-4) W · m(-2) · s(-2); P<0.001). After PAVR, despite a fall in basal suction wave (1.9±0.3 versus 1.1±0.1×10(-5) W · m(-2) · s(-2); P=0.02), there was an immediate improvement in coronary physiological reserve with increasing heart rate (β coefficient=0.9×10(-3) W · m(-2) · s(-2); P=0.014). In aortic stenosis, the coronary physiological reserve is impaired. Instead of increasing when heart rate rises, the coronary diastolic suction wave decreases. Immediately after PAVR, physiological reserve returns to a normal positive pattern. This may explain how aortic stenosis can induce anginal symptoms and their prompt relief after PAVR. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01118442.

  9. The infrarenal aortic diameter in relation to age: only part of the population in older age groups shows an increase.

    PubMed

    Wilmink, A B; Pleumeekers, H J; Hoes, A W; Hubbard, C S; Grobbee, D E; Quick, C R

    1998-11-01

    To resolve whether the infrarenal aortic diameter (IAD) continues to increase throughout life; to ascertain the relationship between IAD and age, sex, body size, and smoking status, and to determine whether these factors influence the IAD over the entire range of aortic diameters or only in a proportion. Combined cross-sectional data from two population-based screening programmes for abdominal aortic aneurysms (AAA) in Huntingdon (U.K.) and Rotterdam (The Netherlands). The antero-posterior diameter of the infrarenal aorta was measured. The influences of age, gender, body size and smoking status were examined. Data were analysed from 3066 women and 8270 men. In men, mean IAD rose from 20.7 mm to 23.5 mm in the older age groups. However, IADs remained constant below the 75th perentile in men and the 85th percentile in women. Similarly only the top 15-25% of the aortic diameters were larger in smokers compared with non-smokers. The aortic diameter increased with age in only a minority of the population. Furthermore, known risk factors for AAA contributed to aortic dilatation in only the upper tail of the frequency distribution. Thus only 25% of men and 15% of women may be prone to aortic dilatation.

  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. 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

  12. Acute increase in reversal blood flow during counterpulsation is associated with vasoconstriction and changes in the aortic mechanics.

    PubMed

    Bia, Daniel; Zócalo, Yanina; Armentano, Ricardo; de Forteza, Eduardo; Cabrera-Fischer, Edmundo

    2007-01-01

    While the effects of increases in forward blood flow on the arterial diameter and elasticity are known, the effects of reversal flow on the arterial properties remain to be characterized. The intra-aortic balloon pumping (IABP), the device most frequently used in circulatory support, acts generating changes in aortic flow (i.e. increasing reversal flow). Recently, in vitro studies showed that flow reversion reduces the endothelial release of relaxing factors. Hence, vascular smooth muscle (VSM) dependent changes in the aortic properties would be expected during IABP. The aim was to analyze the changes in flow during IABP and to characterize the potential effects of reversal blood flow on the aortic biomechanics. Pressure, flow and diameter were measured in sheep, before and during IABP circulatory support. Potential effects of IABP-dependent high reversal flow conditions on viscous and elastic aortic modulus were analyzed, using isobaric analysis. Flow and pressure waveforms were analyzed in the time domain, and the contribution of oscillatory forward and backward waves to the IABP-dependent changes in flow patterns were evaluated. We found that IABP changed mainly diastolic blood flow, with an increase in the reversal flow, secondary to an increase in the oscillatory backward wave amplitude. The acute increase in reversal flow during IABP was associated with vasoconstriction and changes in the aortic mechanics, possibly due to VSM activation.

  13. Increased plant sterol deposition in vascular tissue characterizes patients with severe aortic stenosis and concomitant coronary artery disease.

    PubMed

    Luister, Alexandra; Schött, Hans Frieder; Husche, Constanze; Schäfers, Hans-Joachim; Böhm, Michael; Plat, Jogchum; Gräber, Stefan; Lütjohann, Dieter; Laufs, Ulrich; Weingärtner, Oliver

    2015-07-01

    The aim of the study was to evaluate the relationship between phytosterols, oxyphytosterols, and other markers of cholesterol metabolism and concomitant coronary artery disease (CAD) in patients with severe aortic stenosis who were scheduled for elective aortic valve replacement. Markers of cholesterol metabolism (plant sterols and cholestanol as markers of cholesterol absorption and lathosterol as an indicator of cholesterol synthesis) and oxyphytosterols were determined in plasma and aortic valve tissue from 104 consecutive patients with severe aortic stenosis (n=68 statin treatment; n=36 no statin treatment) using gas chromatography-flame ionization and mass spectrometry. The extent of CAD was determined by coronary angiography prior to aortic valve replacement. Patients treated with statins were characterized by lower plasma cholesterol, cholestanol, and lathosterol concentrations. However, statin treatment did not affect the sterol concentrations in cardiovascular tissue. The ratio of campesterol-to-cholesterol was increased by 0.46±0.34μg/mg (26.0%) in plasma of patients with CAD. The absolute values for the cholesterol absorption markers sitosterol and campesterol were increased by 18.18±11.59ng/mg (38.8%) and 11.40±8.69ng/mg (30.4%) in the tissues from patients with documented CAD compared to those without concomitant CAD. Campesterol oxides were increased by 0.06±0.02ng/mg (17.1%) in the aortic valve cusps and oxidized sitosterol-to-cholesterol ratios were up-regulated by 0.35±0.2ng/mg (22.7%) in the plasma of patients with CAD. Of note, neither cholestanol nor the ratio of cholestanol-to-cholesterol was associated with CAD. Patients with concomitant CAD are characterized by increased deposition of plant sterols, but not cholestanol in aortic valve tissue. Moreover, patients with concomitant CAD were characterized by increased oxyphytosterol concentrations in plasma and aortic valve cusps.

  14. The initial tangent of the aortic pressure increase is an estimate of left ventricular contractility in pigs.

    PubMed

    Kisch-Wedel, Hille; Kemming, Gregor; Meisner, Franz; Flondor, Michael; Bruhn, Sebastian; Koehler, Carolina; Zwissler, Bernhard

    2008-10-01

    The aim was, to identify an estimate of left ventricular contractility derived from the aortic pressure wave without load changing manoeuvres. For this purpose, left ventricular contractility was assessed with several aortic pressure wave form derived parameters and was compared to standard parameters of left ventricular contractility (conductance technique) in an experimental study. Measurements were taken during baseline, after beta-stimulation and after injection of a beta-antagonist. The initial and the secondary tangent, the area under the aortic pressure, and the stroke volume were correlated with the endsystolic elastance, a mainly load independent measure of left ventricular contractility: The initial tangent of the aortic pressure increase correlated significantly with the endsystolic elastance (r = 0.54, P < 0.05). The initial tangent of the aortic pressure increase was significantly increased from baseline at beta-stimulation (from 20.2 +/- 4.7 to 36.4 +/- 6.8 mmHg s(-1), P < 0.05) and decreased after injection of a beta-antagonist (from 20.2 +/- 4.7 to 12.3 +/- 2.0, P < 0.05). Thus, we conclude that the initial tangent of the aortic pressure increase is a valid estimate of left ventricular contractility in piglets.

  15. 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

  16. 25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus.

    PubMed

    Reynolds, John A; Haque, Sahena; Berry, Jacqueline L; Pemberton, Philip; Teh, Lee-Suan; Ho, Pauline; Gorodkin, Rachel; Bruce, Ian N

    2012-03-01

    To determine the relationship between serum vitamin D and markers of subclinical cardiovascular disease (CVD) in patients with SLE. We recruited SLE patients (≥ 4 ACR 1997 criteria) from outpatient clinics between January 2007 and January 2009. Vitamin D deficiency was defined as serum 25(OH)D <20 ng/ml measured by ELISA. Disease activity was measured using the SLEDAI-2K score. Aortic pulse wave velocity (aPWV) was measured using PulseTrace 3600 (Micromedical) and carotid plaque (CP) and intima-media thickness (IMT) assessed using B-mode Doppler US. Seventy-five women with SLE were recruited with a median (interquartile range) disease duration of 16 (8-27) years. Patients with vitamin D deficiency had higher BMI (P = 0.014) and insulin resistance (P = 0.023) than those with 25(OH)D >20 ng/ml. Subjects with SLEDAI-2K ≥ 4 had lower 25(OH)D than those with SLEDAI-2K <4 (median 12.9 vs 20.3 ng/ml, P = 0.031). Aortic stiffness was significantly associated with serum 25(OH)D [log(aPWV) β (95% CI) -0.0217 (-0.038, -0.005), P = 0.010] independently of BMI, CVD risk factors and serum insulin. Adjustment for disease activity reduced the strength of the association. There was no association between 25(OH)D and CP or IMT. Vitamin D deficiency is associated with increased aortic stiffness in SLE, independent of CVD risk factors and insulin. Increased inflammatory disease activity may be the mechanism by which vitamin D deficiency mediates vascular stiffness in this patient group.

  17. Presence of simple renal cysts is associated with increased risk of aortic dissection: a common manifestation of connective tissue degeneration?

    PubMed

    Kim, Eun Kyoung; Choi, E Ryoung; Song, Bong Gun; Jang, Shin Yi; Ko, Sung Min; Choi, Seung-Hyuk; Sung, Jidong; Sung, Kiick; Choe, Yeon Hyeon; Oh, Jae K; Kim, Duk-Kyung

    2011-01-01

    Aortic dissection is a multifactorial disease whose primary pathology is connective tissue degeneration of the aorta's medial layer. It was hypothesised that the presence of renal cysts, another possible manifestation of connective tissue weakness, would be associated with increased risk of aortic dissection. The incidence of simple renal cysts on CT angiography in 518 patients with aortic dissection (AD group) and 1366 healthy subjects (control group) who underwent CT for routine health screening was compared. To reduce the effects of selection bias and confounding variables, data were adjusted by propensity score matching. The prevalence of simple renal cysts was 37.8% in the AD group and 22.0% in the control group, a statistically significant difference (p<0.0001). The prevalence of renal cysts was even greater in patients with the following characteristics: intramural haematoma, type B dissection, normal blood pressure or advanced age. In the 311 matched cohorts after propensity score matching, the prevalence of simple renal cysts was still significantly higher in the AD group than in the control group (33.8% vs 25.7%, p = 0.023). Multivariate analysis confirmed that the presence of renal cysts (OR 1.49, p = 0.0245) could be a marker of having a common underlying mechanism with aortic dissection. Patients with aortic dissection have an increased burden of renal cysts compared with healthy controls. This finding suggests that the connective tissue weakness that predisposes patients to renal cysts may be associated with aortic dissection.

  18. Aortic Atheroma Increases the Risk of Long-Term Mortality in 20,000 Patients.

    PubMed

    Butler, Carolyn Goldberg; Ho Luxford, Jamahal Maeng; Huang, Chuan-Chin; Ejiofor, Julius I; Rawn, James D; Wilusz, Kerry; Fox, John A; Shernan, Stanton K; Muehlschlegel, Jochen Daniel

    2017-10-01

    The association between long-term survival and aortic atheroma in cardiac surgical patients has not been comprehensively investigated. In this study we determine the relation between grade of atheroma and the risk of long-term mortality in a retrospective cohort of more than 20,000 patients undergoing cardiac operation during a 20-year period. We included 22,304 consecutive intraoperative transesophageal and epiaortic ultrasound examinations performed at Brigham and Women's Hospital between 1995 and 2014, with long-term follow-up. The extent of atheromatous disease recorded in each examination was used for analysis. Mortality data were obtained from our institution's data registry. Mortality analyses were done using Cox proportional hazard regression models with follow-up as a time scale. We repeated the analysis in a subgroup of 14,728 patients with more detailed demographic characteristics, including postoperative stroke, queried from the institutional Society of Thoracic Surgeons database. A total of 7,722 mortality events and 872 stroke events occurred. Patients with atheromatous disease demonstrated a significant increase in mortality across all grades of severity, both for the ascending and descending aorta. This relation remained unchanged after adjusting for additional covariates. Adjustments for postoperative stroke resulted in only minimal attenuation in the risk of postoperative mortality related to aortic atheroma. Aortic atheromatous disease of any grade in the ascending and descending aorta is a significant long-term risk of long-term, all-cause mortality in cardiac operation patients. This association remains independent of other conventional risk factors and is not related to postoperative cerebrovascular accidents. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  19. The effect of an increase in aortic pressure upon the inotropic state of eat and dog left ventricles

    PubMed Central

    Elzinga, G.; Noble, M. I. M.; Stubbs, J.

    1977-01-01

    1. The effect of increased aortic pressure on the inotropic state of the left ventricle was studied in isolated cat hearts, perfused with bovine red cells in Tyrode solution, ejecting into a hydraulic model with the same input impedance as that of the cat aorta. 2. Inotropic state was assessed at a controlled left ventricular end-diastolic pressure by interpolating single isovolumic beats by means of an occluder in the aortic cannula. 3. When such isovolumic beats during periods of raised aortic pressure were compared with those during control periods, the difference in peak isovolumic pressure ranged from -0·3 to +0·5 kPa indicating differences in inotropic state which were small and inconsistent in direction. 4. The maximum rate of rise of left ventricular pressure (dP/dtmax.) of ejecting beats was little affected by a rise of aortic pressure and the direction of changes was inconsistent. 5. The effect of increased aortic pressure was studied in intact dogs after cardiac denervation; left ventricular end-diastolic pressure was uncontrolled and therefore rose to a higher steady level. 6. No consistent change of dP/dtmax. was found during the period of increased aortic pressure. 7. All flow and pressure variables remained steady during the period of increased aortic pressure after the higher level of left ventricular end-diastolic pressure had been established. 8. These results demonstrate that neither the positive inotropic effect nor the negative inotropic effect of increased load dominates in these preparations. This may be the result of a balance between the two effects, or they may be of unimportant magnitude under physiological conditions. ImagesFig. 2Fig. 3 PMID:604450

  20. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events.

    PubMed

    Baudhuin, Linnea M; Kotzer, Katrina E; Lagerstedt, Susan A

    2015-03-01

    Marfan syndrome is a systemic disorder that typically involves FBN1 mutations and cardiovascular manifestations. We investigated FBN1 genotype-phenotype correlations with aortic events (aortic dissection and prophylactic aortic surgery) in patients with Marfan syndrome. Genotype and phenotype information from probands (n = 179) with an FBN1 pathogenic or likely pathogenic variant were assessed. A higher frequency of truncating or splicing FBN1 variants was observed in Ghent criteria-positive patients with an aortic event (n = 34) as compared with all other probands (n = 145) without a reported aortic event (79 vs. 39%; P < 0.0001), as well as Ghent criteria-positive probands (n = 54) without an aortic event (79 vs. 48%; P = 0.0039). Most probands with an early aortic event had a truncating or splicing variant (100% (n = 12) and 95% (n = 21) of patients younger than 30 and 40 years old, respectively). Aortic events occurred at a younger median age in patients with truncating/splicing variants (29 years) as compared with those with missense variants (51 years). A trend toward a higher frequency of truncating/splicing variants in patients with aortic dissection (n = 21) versus prophylactic surgery (n = 13) (85.7 vs. 69.3%; not significant) was observed. These aortic event- and age-associated findings may have important implications for the management of Marfan syndrome patients with FBN1 truncating and splicing variants.Genet Med 17 3, 177-187.

  1. Changes in wall shear stresses in abdominal aortic aneurysms with increasing wall stiffness

    NASA Astrophysics Data System (ADS)

    Salsac, Anne-Virginie; Fernandez, Miguel

    2006-11-01

    During the growth of abdominal aortic aneurysms, local changes occur in the composition and structure of the diseased wall, resulting in its stiffening. A numerical simulation of the fluid structure interactions is performed in idealized models of aneurysms using a finite element method. A full coupling of the equations governing the pulsatile blood flow and the deformation of the compliant wall is undertaken. The effect of the progressive stiffening of the wall is analyzed at various stages in the growth of the aneurysm. Increasing the wall stiffness alters the distribution of wall shear stresses and leads to an increase in their magnitude. The wall compliance is shown to have a more pronounced effect on non-axisymmetric aneurysms, which sustain large displacements. The overall movement of the aneurysm models increases the three-dimensionality of the flow.

  2. Glycosaminoglycan Overproduction in the Aorta Increases Aortic Calcification in Murine Chronic Kidney Disease

    PubMed Central

    Purnomo, Eko; Emoto, Noriaki; Nugrahaningsih, Dwi Aris Agung; Nakayama, Kazuhiko; Yagi, Keiko; Heiden, Susi; Nadanaka, Satomi; Kitagawa, Hiroshi; Hirata, Ken‐ichi

    2013-01-01

    Background Vascular calcification accompanying chronic kidney disease increases the mortality and morbidity associated with cardiovascular disorders, but no effective therapy is available. We hypothesized that glycosaminoglycans may contribute to osteoblastic differentiation of vascular smooth muscle cells during vascular calcification. Methods and Results We used exostosin‐like glycosyltranferase 2–deficient (EXTL2 knockout) mice expressing high levels of glycosaminoglycans in several organs including the aorta. We performed 5/6 subtotal nephrectomy and fed the mice a high‐phosphate diet to induce chronic kidney disease. Overexpression of glycosaminoglycans in the aorta enhanced aortic calcification in chronic kidney disease in EXTL2 knockout mice. Ex vivo and in vitro, matrix mineralization in aortic rings and vascular smooth muscle cells of EXTL2 knockout mice was augmented. Furthermore, removal of glycosaminoglycans in EXTL2 knockout and wild‐type mice‐derived vascular smooth muscle cells effectively suppressed calcium deposition in a high‐phosphate environment. Conclusions These results illustrate an important role for glycosaminoglycans in the development of vascular calcification. Manipulation of glycosaminoglycan expression may have beneficial effects on the progression of vascular calcification in chronic kidney disease patients. PMID:23985378

  3. The role of endothelial nitric oxide synthase (eNOS) in the pathogenesis of sinonasal polyps.

    PubMed

    Muluk, N Bayar; Arikan, O K; Atasoy, P; Kiliç, R; Yalçinozan, E Tuna

    2014-01-01

    The pathogenesis of sinonasal polyps has not been known completely. We investigated the role of endothelial Nitric Oxide Synthase (eNOS) in the pathogenesis of sinonasal polyps. Study group (Groups 1-3) consisted of nasal polyp samples of patients with sinonasal polyps; and control group consisted of inferior turbinate samples of patients without nasal polyp. In Group 1: 14 specimens from ethmoid sinus; in Group 2: 10 specimens from nasal cavity; in Group 3: 10 specimens from maxillary sinus; and in Group 4 (Control): 9 specimens from inferior turbinate were included. By immunohistochemical staining technique, eNOS Positivity Index in mucosal layers; and in the inflammatory cells were assessed. eNOS Positivity Index was higher at apical layer of epithelium; and perivascular and glandular parts of subepithelial layer. As a rate of mononuclear cells increased, eNOS positivity increased at basal part of epithelium. In eNOS Positivity Index of mononuclear cells increased ones, eNOS values also increased at glands of subepithelial layer. In nasal cavity, eNOS positivity index of all cells was significantly higher than that of the control group. Increased eNOS all cells positivity index values were seen with decreased glandular and endothelial eNOS values. In all cells group, fibroblasts were seen beside the mononuclear cells. It was observed that eNOS was not expressed in PMNC (mainly neutrophils), growing more in acute inflammatory process; and was expressed in MNCs and all cells group with fibroblasts which were the cells of chronic inflammatory process. Especially MNCs and fibroblasts may play a role in the polyp formation process. In males and in patients with longer polyp duration, eNOS values decreased. We concluded that eNOS Positivity Index was higher at apical layer of epithelium; and perivascular and glandular parts of subepithelial layer. eNOS plays role in vascular dilatation, increases in vascular permeability; increases in nasal secretion due to glandular

  4. Increased angiogenic response in aortic explants of collagen XVIII/endostatin-null mice.

    PubMed

    Li, Qing; Olsen, Bjorn R

    2004-08-01

    Endostatin, a proteolytic fragment of basement membrane-associated collagen XVIII, has been shown to be a potent angiogenesis inhibitor both in vivo and in vitro when given at high concentrations. The precise molecular mechanisms by which it functions and whether or not it plays a role in physiological regulation of angiogenesis are not clear. In mice with targeted null alleles of Col18a1, there appears to be no major abnormality in vascular patterns or capillary density in most organs. Furthermore, the growth of experimental tumors is not increased. However, a detailed analysis of induced angiogenesis in these mice has not been performed. Therefore, we compared the angiogenic responses induced by in vitro culture of aortic explants from collagen XVIII/endostatin-null mice (ko) to wild-type (wt) littermates. We found a twofold increase in microvessel outgrowth in explants from ko mice, relative to wt explants. This increased angiogenesis was reduced to the wt level by the addition of low levels (0.1 microg/ml) of recombinant mouse or human endostatin during the culture period. To address cellular/molecular mechanisms underlying this difference in angiogenic response between ko and wt mice, we isolated endothelial cells from both strains and compared their biological behavior. Proliferation assays showed no difference between the two types of endothelial cells. In contrast, adhesion assays showed a striking difference in their ability to adhere to fibronectin suggesting that collagen XVIII/endostatin may regulate interactions between endothelial cells and underlying basement membrane-associated components, including fibronectin, such that in the absence of collagen XVIII/endostatin, endothelial cells are more adhesive to fibronectin. In the aortic explant assay, characterized by dynamic processes of microvessel elongation and regression, this may result in stabilization of newly formed vessels, reduced regression, and a net increase in microvessel outgrowth in

  5. Aortic angiography

    MedlinePlus

    ... problem with the aorta or its branches, including: Aortic aneurysm Aortic dissection Congenital (present from birth) problems AV ... Mean Abnormal results may be due to: Abdominal aortic aneurysm Aortic dissection Aortic regurgitation Aortic stenosis Congenital (present ...

  6. Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.

    PubMed

    Tan, Xing-Lin; Xue, Yue-Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait U; McDonald, Michael P; Dopico, Alejandro M; Liao, Francesca-Fang

    2015-06-24

    Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/-) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice. These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.

  7. Health Status After Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Increased Surgical Risk: Results From the CoreValve US Pivotal Trial.

    PubMed

    Arnold, Suzanne V; Reynolds, Matthew R; Wang, Kaijun; Magnuson, Elizabeth A; Baron, Suzanne J; Chinnakondepalli, Khaja M; Reardon, Michael J; Tadros, Peter N; Zorn, George L; Maini, Brij; Mumtaz, Mubashir A; Brown, John M; Kipperman, Robert M; Adams, David H; Popma, Jeffrey J; Cohen, David J

    2015-08-17

    This study sought to compare the health status outcomes for patients treated with either self-expanding transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). In patients at increased surgical risk, TAVR with a self-expanding bioprosthesis is associated with improved 1-year survival compared with AVR. However, elderly patients may be just as concerned with quality-of-life improvement as with prolonged survival as a goal of treatment. Between 2011 and 2012, 795 patients with severe aortic stenosis at increased surgical risk were randomized to TAVR or AVR in the CoreValve US Pivotal Trial. Health status was assessed at baseline, 1 month, 6 months, and 1 year using the Kansas City Cardiomyopathy Questionnaire, Medical Outcomes Study Short-Form 12 Questionnaire, and EuroQOL 5-dimension questionnaire; growth curve models were used to examine changes over time. Over the 1-year follow-up period, disease-specific and generic health status improved substantially for both treatment groups. At 1 month, there was a significant interaction between the benefit of TAVR over AVR and access site. Among surviving patients eligible for iliofemoral (IF) access, there was a clinically relevant early benefit with TAVR across all disease-specific and generic health status measures. Among the non-IF cohort, however, most health status measures were similar for TAVR and AVR, although there was a trend toward early benefit with TAVR on the Short-Form 12 Questionnaire's physical health scale. There were no consistent differences in health status between TAVR and AVR at the later time points. Health status improved substantially in surviving patients with increased surgical risk who were treated with either self-expanding TAVR or AVR. TAVR via the IF route was associated with better early health status compared with AVR, but there was no early health status benefit with non-IF TAVR compared with AVR. (Safety and Efficacy Study of the Medtronic Core

  8. Increased aortic intimal proliferation due to MasR deletion in vitro

    PubMed Central

    Alsaadon, Hiba; Kruzliak, Peter; Smardencas, Arthur; Hayes, Alan; Bader, Michael; Angus, Peter; Herath, Chandana; Zulli, Anthony

    2015-01-01

    A growing body of evidence suggests that the vascular actions of Ang-(1-7) appear to involve increased production of nitric oxide (NO), an important vasodilator, through the activation of MasR, thus indicating the involvement of the MasR in preventing endothelial dysfunction. However, it is unknown whether the MasR could be involved in the progression of the next step in atherosclerosis, neo-intimal formation. To determine whether the deletion of the MasR is involved in the development of intimal thickening in an in vitro model. Mice [three background controls (C57Bl/6) and 3 MasR (−/−)] were killed and the aortas excised and cleaned of connective tissue and cut into 3 mm rings. Rings were placed in an organ culture medium for 5 weeks, embedded in paraffin, cut at 5 μm and stained with haematoxylin and eosin and Masson’s trichrome. In addition, aortic reactivity was measured in organ baths. After 5 weeks of culture, the intima:media ratio increased in the aortas from MasR (−/−) mice compared to the control group by 4.5-fold (P < 0.01). However, no significant difference in nuclei area count (cell proliferation) between the MasR (−/−) mice and control group was observed (0.87 ± 0.29% vs. 0.94 ± 0.18%, respectively, P = ns). Functional studies showed only a minor vasoconstrictive and full vasodilative response. This study shows that the deletion of the MasR causes marked increase in the aortic intima:media ratio, which is not due to generalized cellular proliferation. These results provide a functional role for the MasR in atherogenesis. PMID:25676544

  9. Increased aortic intimal proliferation due to MasR deletion in vitro.

    PubMed

    Alsaadon, Hiba; Kruzliak, Peter; Smardencas, Arthur; Hayes, Alan; Bader, Michael; Angus, Peter; Herath, Chandana; Zulli, Anthony

    2015-06-01

    A growing body of evidence suggests that the vascular actions of Ang-(1-7) appear to involve increased production of nitric oxide (NO), an important vasodilator, through the activation of MasR, thus indicating the involvement of the MasR in preventing endothelial dysfunction. However, it is unknown whether the MasR could be involved in the progression of the next step in atherosclerosis, neo-intimal formation. To determine whether the deletion of the MasR is involved in the development of intimal thickening in an in vitro model. Mice [three background controls (C57Bl/6) and 3 MasR (-/-)] were killed and the aortas excised and cleaned of connective tissue and cut into 3 mm rings. Rings were placed in an organ culture medium for 5 weeks, embedded in paraffin, cut at 5 μm and stained with haematoxylin and eosin and Masson's trichrome. In addition, aortic reactivity was measured in organ baths. After 5 weeks of culture, the intima:media ratio increased in the aortas from MasR (-/-) mice compared to the control group by 4.5-fold (P < 0.01). However, no significant difference in nuclei area count (cell proliferation) between the MasR (-/-) mice and control group was observed (0.87 ± 0.29% vs. 0.94 ± 0.18%, respectively, P = ns). Functional studies showed only a minor vasoconstrictive and full vasodilative response. This study shows that the deletion of the MasR causes marked increase in the aortic intima:media ratio, which is not due to generalized cellular proliferation. These results provide a functional role for the MasR in atherogenesis.

  10. Transient postoperative atrial fibrillation after abdominal aortic aneurysm repair increases mortality risk

    PubMed Central

    Kothari, Anai N.; Halandras, Pegge M.; Drescher, Max; Blackwell, Robert H.; Graunke, Dawn M.; Kliethermes, Stephanie; Kuo, Paul C.; Cho, Jae S.

    2016-01-01

    Objective The purpose of this study was to determine whether new-onset transient postoperative atrial fibrillation (TPAF) affects mortality rates after abdominal aortic aneurysm (AAA) repair and to identify predictors for the development of TPAF. Methods Patients who underwent open aortic repair or endovascular aortic repair for a principal diagnosis AAA were retrospectively identified using the Healthcare Cost and Utilization Project-State Inpatient Database (Florida) for 2007 to 2011 and monitored longitudinally for 1 year. Inpatient and 1-year mortality rates were compared between those with and without TPAF. TPAF was defined as new-onset atrial fibrillation that developed in the postoperative period and subsequently resolved in patients without a history of atrial fibrillation. Cox proportional hazards models, adjusted for age, gender, comorbidities, rupture status, and repair method, were used to assess 1-year survival. Predictive models were built with preoperative patient factors using Chi-squared Automatic Interaction Detector decision trees and externally validated on patients from California. Results A 3.7% incidence of TPAF was identified among 15,148 patients who underwent AAA repair. The overall mortality rate was 4.3%. The inpatient mortality rate was 12.3% in patients with TPAF vs 4.0% in those without TPAF. In the ruptured setting, the difference in mortality was similar between groups (33.7% vs 39.9%, P = .3). After controlling for age, gender, comorbid disease severity, urgency (ruptured vs nonruptured), and repair method, TPAF was associated with increased 1-year postoperative mortality (hazard ratio, 1.48; P < .001) and postdischarge mortality (hazard ratio, 1.56; P = .028). Chi-squared Automatic Interaction Detector-based models (C statistic = 0.70) were integrated into a Web-based application to predict an individual's probability of developing TPAF at the point of care. Conclusions The development of TPAF is associated with an increased risk

  11. 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

  12. 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.

  13. Adult degenerative scoliosis associated with increased aortic diameter and plaque burden and composition.

    PubMed

    Ayça, Burak; Rakıcı, Taşkın; Atıcı, Yunus; Avsar, Murat; Yuksel, Yasin; Akın, Fatih; Okuyan, Ertugrul; Hakan Dinckal, M

    2016-06-01

    In this study, we aimed to investigate the relationship between adult degenerative scoliosis (ADS) and the aortic plaques and diameters. We included 219 patients with ADS and 100 control patients without ADS. Diameters of ascending, arch, descending and abdominal aorta and number, localization and types of the aortic plaques, and the Cobb angles of all patients were measured from computed tomography (CT) images. We divided the patients with ADS into three groups according to the Cobb angle, and divided them into four groups according to level of spine deformity. The patients with ADS had a larger aorta and more aortic plaques (both, p < 0.001). The patients with ADS had more fibro-fatty and mix plaques (both, p < 0.001). The patients with severe ADS had larger diameters of the ascending and arch of the aorta (p = 0.026 and p = 0.027, respectively). The patients with the main thoracic curve had a larger ascending aorta and the patients with a thoracolumbar curve had more aortic plaques (p = 0.035 and p = 0.029, respectively). In multivariate regression analysis, the ADS was an independent risk factor for both aortic dilatation (>3.6 cm) and aortic plaque build-up (both, p < 0.001). The ADS may be a risk factor for aortic dilatation and aortic atherosclerosis. © The Author(s) 2015.

  14. 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

  15. Increased production of cytokines and growth factors by aortic allografts: A possible explanation for myointimal hyperplasia formation.

    PubMed

    Sterpetti, A V; Cucina, A; Randone, B; Guglielmi, M B; Fragale, A; Cavallaro, A

    1999-01-01

    Accelerated myointimal hyperplasia is a major complication of arterial allografts. The aim of our study was to analyze the role of growth factors in the genesis of myointimal hyperplasia in arterial allografts. Two groups of experiments were performed: Isografts and Allografts. The Isograft group consisted of 18 inbred Lewis rats in which a 1-cm long segment of aorta was inserted as abdominal aortic interposition graft. The aortic segments were obtained from syngeneic Lewis rats. The Allograft group consisted of 18 inbred Lewis rats, in which a 1-cm long segment of aorta was interposed at the level of the abdominal aorta. The aortic segments were obtained from allogeneic Brown-Norway rats. No immunosuppression was used. The animals were sacrificed 4 weeks after surgery and the aortic grafts were analyzed by light, electron microscopy (n = 3 for each group) and immunohistochemistry (n = 3 for each group). In addition, aortic segments (n = 12 for each group) were put in an organ culture to assess production of growth factors. All allografts showed evidence of severe myointimal hyperplasia, which was minimal in isografts. PDGF, bFGF and TGF-beta(1) production, generally considered to be the cause of myointimal hyperplasia, was not increased in allografts, whereas IL-1, TNF-alpha and GM-CSF production was increased in allografts and probably lymphocytes were the source of these cytokines (p < 0.001). We conclude that myointimal hyperplasia in aortic allografts is associated with an increase of IL-1, TNF-alpha and GM-CSF produced by lymphocytes.

  16. Flaxseed oil increases aortic reactivity to phenylephrine through reactive oxygen species and the cyclooxygenase-2 pathway in rats

    PubMed Central

    2014-01-01

    Background Flaxseed oil has the highest concentration of omega-3 α-linolenic acid, which has been associated with cardiovascular benefit. However, the mechanism underlying the vascular effects induced through flaxseed oil is not well known. Thus, in the present study, we investigated the effects of flaxseed oil on vascular function in isolated rat aortic rings. Methods Wistar rats were treated daily with flaxseed oil or a control (mineral oil) intramuscular (i.m.) for fifteen days. Isolated aortic segments were used to evaluate cyclooxygenase-2 (COX-2) protein expression, superoxide anion levels and vascular reactivity experiments. Results Flaxseed oil treatment increased the vasoconstrictor response of aortic rings to phenylephrine. Endothelium removal increased the response to phenylephrine in aortic segments isolated from both groups, but the effect was smaller in the treated group. L-NAME incubation similarly increased the phenylephrine response in segments from both groups. The TXA2 synthase inhibitor furegrelate, the selective COX-2 inhibitor NS 398, the TP receptor antagonist SQ 29.548, the reactive oxygen species (ROS) scavenger apocynin, the superoxide anion scavengers tiron and the phospholipase A2 inhibitor dexamethasone partially reversed the flaxseed oil-induced increase in reactivity to phenylephrine. Conclusions These findings suggest that flaxseed oil treatment increased vascular reactivity to phenylephrine through an increase in ROS production and COX-2-derived TXA2 production. The results obtained in the present study provide new insight into the effects of flaxseed oil treatment (i.m.) on vascular function. PMID:24993607

  17. Increased systolic load causes adverse remodeling of fetal aortic and mitral valves

    PubMed Central

    Louey, Samantha; Espinoza, Herbert; Chattergoon, Natasha; You, Fanglei; Thornburg, Kent L.; Giraud, George

    2015-01-01

    While abnormal hemodynamic forces alter fetal myocardial growth, little is known about whether such insults affect fetal cardiac valve development. We hypothesized that chronically elevated systolic load would detrimentally alter fetal valve growth. Chronically instrumented fetal sheep received either a continuous infusion of adult sheep plasma to increase fetal blood pressure, or a lactated Ringer's infusion as a volume control beginning on day 126 ± 4 of gestation. After 8 days, mean arterial pressure was higher in the plasma infusion group (63.0 mmHg vs. 41.8 mmHg, P < 0.05). Mitral annular septal-lateral diameter (11.9 mm vs. 9.1 mm, P < 0.05), anterior leaflet length (7.7 mm vs. 6.4 mm, P < 0.05), and posterior leaflet length (P2; 4.0 mm vs. 3.0 mm, P < 0.05) were greater in the elevated load group. mRNA levels of Notch-1, TGF-β2, Wnt-2b, BMP-1, and versican were suppressed in aortic and mitral valve leaflets; elastin and α1 type I collagen mRNA levels were suppressed in the aortic valves only. We conclude that sustained elevated arterial pressure load on the fetal heart valve leads to anatomic remodeling and, surprisingly, suppression of signaling and extracellular matrix genes that are important to valve development. These novel findings have important implications on the developmental origins of valve disease and may have long-term consequences on valve function and durability. PMID:26354842

  18. 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.

  19. Health Status after Transcatheter or Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis at Increased Surgical Risk. Results from the CoreValve US Pivotal Trial

    PubMed Central

    Arnold, Suzanne V.; Reynolds, Matthew R.; Wang, Kaijun; Magnuson, Elizabeth A.; Baron, Suzanne J.; Chinnakondepalli, Khaja M.; Reardon, Michael J.; Tadros, Peter N.; Zorn, George L.; Maini, Brij; Mumtaz, Mubashir A.; Brown, John M.; Kipperman, Robert M.; Adams, David H.; Popma, Jeffrey J.; Cohen, David J.

    2015-01-01

    Background In patients at increased surgical risk, TAVR with a self-expanding bioprosthesis is associated with improved 1-year survival compared with AVR. However, elderly patients may be just as concerned with quality of life improvement as with prolonged survival as a goal of treatment. Objectives To compare the health status outcomes for patients treated with either self-expanding transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). Methods Between 2011 and 2012, 795 patients with severe aortic stenosis at increased surgical risk were randomized to TAVR or AVR in the CoreValve US Pivotal Trial. Health status was assessed at baseline, 1 month, 6 months, and 1 year using the Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-12, and EQ-5D; growth curve models were used to examine changes over time. Results Over the 1-year follow-up period, disease-specific and generic health status improved substantially for both treatment groups. At 1-month, there was a significant interaction between the benefit of TAVR over AVR and access site. Among surviving patients eligible for iliofemoral (IF) access, there was a clinically relevant early benefit with TAVR across all disease-specific and generic health status measures. Among the non-IF cohort; however, most health status measures were similar for TAVR and AVR, although there was a trend toward early benefit with TAVR on the SF-12 physical health scale. There were no consistent differences in health status between TAVR and AVR at the later time points. Conclusions Health status improved substantially in surviving patients with increased surgical risk who were treated with either self-expanding TAVR or AVR. TAVR via the IF route was associated with better early health status compared with AVR, but there was no early health status benefit with non-IF TAVR compared with AVR. PMID:26292584

  20. 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.

  1. Arsenic, cadmium and neuron specific enolase (ENO2, γ-enolase) expression in breast cancer

    PubMed Central

    2011-01-01

    Background Neuron specific enolase (ENO2, γ-enolase) has been used as a biomarker to help identify neuroendocrine differentiation in breast cancer. The goal of the present study was to determine if ENO2 expression in the breast epithelial cell is influenced by the environmental pollutants, arsenite and cadmium. Acute and chronic exposure of MCF-10A cells to As+3 and Cd+2 sufficient to allow colony formation in soft agar, was used to determine if ENO2 expression was altered by these pollutants. Results It was shown that both As+3 and Cd+2 exposure caused significant increases in ENO2 expression under conditions of both acute and chronic exposure. In contrast, ENO1, the major glycolytic enolase in non-muscle and neuronal cells, was largely unaffected by exposure to either As+3 or Cd+2. Localization studies showed that ENO2 in the MCF-10A cells transformed by As+3 or Cd+2 had both a cytoplasmic and nuclear localization. In contrast, ENO1 was localized to the cytoplasm. ENO2 localized to the cytoplasm was found to co-localized with ENO1. Conclusion The results are the first to show that ENO2 expression in breast epithelial cells is induced by acute and chronic exposure to As+3 or Cd+2. The findings also suggest a possible link between As+3 and Cd+2 exposure and neuroendocrine differentiation in tumors. Overall, the results suggest that ENO2 might be developed as a biomarker indicating acute and/or chronic environmental exposure of the breast epithelial cell to As+3 and Cd+2. PMID:22098917

  2. Assessment of Increase in Aortic and Carotid Intimal Medial Thickness in Type 1 Diabetic Patients

    PubMed Central

    Dayem, Soha M. Abd El; Battah, Ahmed A.; El Bohy, Abo El Magd

    2016-01-01

    AIM: To assess aortic and carotid intima-media thickness (aIMT and cIMT) in diabetic patients. PATIENTS AND METHODS: The study included 75 type 1 diabetic patients and 30 age and sex matched healthy volunteer. A blood sample was taken for analysis of HbA1 and lipid profile and the urine sample was taken for analysis of albumin/creatinine ratio. aIMT and cIMT via ultrasound were also done. RESULTS: cIMT & aIMT were significantly higher in diabetics. aIMT was found to be significantly higher than cIMT in diabetic patients (0.72 ± 0.11 vs. 0.52 ± 0.06, P = 0.0001). Ten of our patients (14%) with normal cIMT revealed significantly increased aIMT. aIMT had a significant positive correlation with age of patients, waist/hip ratio & cIMT. CONCLUSION: Diabetic patients had increased aIMT and cIMT with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children. We recommend frequent follow up of diabetic patients for early detection of diabetic complication. PMID:28028403

  3. Does concomitant aortic bypass and renal artery revascularization using the retroperitoneal approach increase perioperative risk?

    PubMed

    Darling, R C; Shah, D M; Chang, B B; Leather, R P

    1995-08-01

    While elective repair of abdominal aortic aneurysms and aortoiliac occlusive disease is associated with an acceptable (3%) mortality rate, combined aortic and renal revascularization has usually been reported to have a higher perioperative mortality. Over the past 5 years, 785 elective aortic procedures have been performed at the authors' medical center. During the same period, 77 renal artery reconstructions have been performed in 73 patients in conjunction with aortic procedures. All were done using the retroperitoneal approach to the aorta and renal arteries. Indication for concomitant renal artery revascularization included 79% (61 of 77 patients) for either significant stenosis or anatomic involvement, 18% for renovascular hypertension (14 of 73) and 3% (two of 73) for renal impairment. The demographics and risk factors were similar in both groups. Operative mortality rate was 2.9% (23 of 785) in the aortic group and 3% (two of 73) in the combined group. Complications in the combined group were one stroke (1.4%), one re-exploration for bleeding (1.4%), two pulmonary pneumonia (2.7%) and five patients had elevated serum creatinine (> 350 mumol/l) after operation. Of these patients two died, one had an occluded graft and two eventually improved. There was one early graft thrombosis and one late thrombosis. In the authors' experience, concomitant aortic bypass and renal artery revascularization can be performed with an acceptable mortality and morbidity using the retroperitoneal approach.

  4. Preeclampsia Is Associated with Increased Central Aortic Pressure, Elastic Arteries Stiffness and Wave Reflections, and Resting and Recruitable Endothelial Dysfunction

    PubMed Central

    Farro, Ignacio; Zócalo, Yanina; Farro, Federico; Sosa, Claudio; Scasso, Santiago; Alonso, Justo; Bia, Daniel

    2015-01-01

    Introduction. An altered endothelial function (EF) could be associated with preeclampsia (PE). However, more specific and complementary analyses are required to confirm this topic. Flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and hyperemic-related changes in carotid-radial pulse wave velocity (PWVcr) offer complementary information about “recruitability” of EF. Objectives. To evaluate, in healthy and hypertensive pregnant women (with and without PE), central arterial parameters in conjunction with “basal and recruitable” EF. Methods. Nonhypertensive (HP) and hypertensive pregnant women (gestational hypertension, GH; preeclampsia, PE) were included. Aortic blood pressure (BP), wave reflection parameters (AIx@75), aortic pulse wave velocity (PWVcf) and PWVcr, and brachial and common carotid stiffness and intima-media thickness were measured. Brachial FMD and L-FMC and hyperemic-related change in PWVcr were measured. Results. Aortic BP and AIx@75 were elevated in PE. PE showed stiffer elastic but not muscular arteries. After cuff deflation, PWVcr decreased in HP, while GH showed a blunted PWVcr response and PE showed a tendency to increase. Maximal FMD and L-FMC were observed in HP followed by GH; PE did not reach significant arterial constriction. Conclusion. Aortic BP and wave reflections as well as elastic arteries stiffness are increased in PE. PE showed both “resting and recruitable” endothelial dysfunctions. PMID:26351578

  5. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling

    PubMed Central

    Förstermann, Ulrich; Li, Huige

    2011-01-01

    Nitric oxide (NO) produced by the endothelium is an important protective molecule in the vasculature. It is generated by the enzyme endothelial NO synthase (eNOS). Similar to all NOS isoforms, functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy-terminal reductase domain, to the heme in the amino-terminal oxygenase domain. Here, the substrate L-arginine is oxidized to L-citrulline and NO. Cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia or cigarette smoking reduce bioactive NO. These risk factors lead to an enhanced production of reactive oxygen species (ROS) in the vessel wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors. NADPH-oxidase-derived superoxide avidly reacts with eNOS-derived NO to form peroxynitrite (ONOO-). The essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH4) is highly sensitive to oxidation by this ONOO-. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting NOS to a superoxide-producing enzyme. Among conventional drugs, compounds interfering with the renin-angiotensin-aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO. In recent years, we have identified a number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eNOS expression. These include the protein kinase C inhibitor midostaurin, the pentacyclic triterpenoids ursolic acid and betulinic acid, the eNOS enhancing compounds AVE9488 and AVE3085, and the polyphenolic phytoalexin trans-resveratrol. Such compounds enhance NO production from eNOS also under pathophysiological conditions and may thus have therapeutic potential. PMID:21198553

  6. 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

  7. Decreased Collagen and Increased Matrix Metalloproteinase-13 in Experimental Abdominal Aortic Aneurysms in Males Compared with Females

    PubMed Central

    Cho, Brenda S; Roelofs, Karen J; Ford, John W; Stanley, James C; Henke, Peter K; Upchurch, Gilbert R

    2009-01-01

    Background This study examined gender differences in collagen regulation during rodent experimental abdominal aortic aneurysm (AAA) formation. Methods Infrarenal aortas of male and female rats were perfused with elastase or saline (control). Aortic diameters were measured at baseline (day 0), and on post-operative days 7 and 14. TGF-β1, collagen subtypes I and III, and MMP-13 (collagenase) expression and/or protein levels from aortic tissue were determined by RT-PCR and Western Blotting. Aortic tissue was stained for total collagen, neutrophils, and macrophages using immunohistochemistry on days 4 and 7. Results Seven and 14 days following perfusion, aortic diameter increased significantly in elastase-perfused males compared with females (P<0.001 for each). Four and 7 days post-perfusion, significantly more neutrophils and macrophages were present in elastase-perfused males compared with females. Seven days post-perfusion, protein levels of TGF-β1 were lower in males compared with females (P=0.04). Type I collagen levels also decreased on days 7 (P<0.001) and 14 (P=0.002), and type III collagen levels decreased on days 7 (P<0.001) and 14 (P<0.001), in males compared with females. By Masson's Trichrome, less adventitial collagen was present in the elastase-perfused males compared with females. MMP-13 expression (P<0.001) and protein levels (P=0.006) in elastase-perfused males were higher than females on day 14. Conclusions This study documents a decrease in types I and III collagen with a concurrent increase in MMP-13 following elastase perfusion in males compared with females. These data suggest that alterations in extracellular matrix collagen turnover may be responsible for altered AAA formation between genders. PMID:19767051

  8. 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

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

    PubMed

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

    2015-08-18

    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 Ser(1177), 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 Ser(1177) 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. Copyright © 2015, American Association for the Advancement of Science.

  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. 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.

  12. 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.

  13. Internalization of eNOS via caveolae regulates PAF-induced inflammatory hyperpermeability to macromolecules.

    PubMed

    Sánchez, Fabiola A; Kim, David D; Durán, Ricardo G; Meininger, Cynthia J; Durán, Walter N

    2008-10-01

    Endothelial nitric oxide (NO) synthase (eNOS) is thought to regulate microvascular permeability via NO production. We tested the hypotheses that the expression of eNOS and eNOS endocytosis by caveolae are fundamental for appropriate signaling mechanisms in inflammatory endothelial permeability to macromolecules. We used bovine coronary postcapillary venular endothelial cells (CVECs) because these cells are derived from the microvascular segment responsible for the transport of macromolecules in inflammation. We stimulated CVECs with platelet-activating factor (PAF) at 100 nM and measured eNOS phosphorylation, NO production, and CVEC monolayer permeability to FITC-dextran 70 KDa (Dx-70). PAF translocated eNOS from plasma membrane to cytosol, induced changes in the phosphorylation state of the enzyme, and increased NO production from 4.3+/-3.8 to 467+/-22.6 nM. PAF elevated CVEC monolayer permeability to FITC-Dx-70 from 3.4+/-0.3 x 10(-6) to 8.5+/-0.4 x 10(-6) cm/s. The depletion of endogenous eNOS with small interfering RNA abolished PAF-induced hyperpermeability, demonstrating that the expression of eNOS is required for inflammatory hyperpermeability responses. The inhibition of the caveolar internalization by blocking caveolar scission using transfection of dynamin dominant-negative mutant, dyn2K44A, inhibited PAF-induced hyperpermeability to FITC-Dx-70. We interpret these data as evidence that 1) eNOS is required for hyperpermeability to macromolecules and 2) the internalization of eNOS via caveolae is an important mechanism in the regulation of endothelial permeability. We advance the novel concept that eNOS internalization to cytosol is a signaling mechanism for the onset of microvascular hyperpermeability in inflammation.

  14. Reduced cardiac fructose 2,6 bisphosphate increases hypertrophy and decreases glycolysis following aortic constriction.

    PubMed

    Wang, Jianxun; Xu, Jianxiang; Wang, Qianwen; Brainard, Robert E; Watson, Lewis J; Jones, Steven P; Epstein, Paul N

    2013-01-01

    This study was designed to test whether reduced levels of cardiac fructose-2,6-bisphosphate (F-2,6-P(2)) exacerbates cardiac damage in response to pressure overload. F-2,6-P(2) is a positive regulator of the glycolytic enzyme phosphofructokinase. Normal and Mb transgenic mice were subject to transverse aortic constriction (TAC) or sham surgery. Mb transgenic mice have reduced F-2,6-P(2) levels, due to cardiac expression of a transgene for a mutant, kinase deficient form of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) which controls the level of F-2,6-P(2). Thirteen weeks following TAC surgery, glycolysis was elevated in FVB, but not in Mb, hearts. Mb hearts were markedly more sensitive to TAC induced damage. Echocardiography revealed lower fractional shortening in Mb-TAC mice as well as larger left ventricular end diastolic and end systolic diameters. Cardiac hypertrophy and pulmonary congestion were more severe in Mb-TAC mice as indicated by the ratios of heart and lung weight to tibia length. Expression of α-MHC RNA was reduced more in Mb-TAC hearts than in FVB-TAC hearts. TAC produced a much greater increase in fibrosis of Mb hearts and this was accompanied by 5-fold more collagen 1 RNA expression in Mb-TAC versus FVB-TAC hearts. Mb-TAC hearts had the lowest phosphocreatine to ATP ratio and the most oxidative stress as indicated by higher cardiac content of 4-hydroxynonenal protein adducts. These results indicate that the heart's capacity to increase F-2,6-P(2) during pressure overload elevates glycolysis which is beneficial for reducing pressure overload induced cardiac hypertrophy, dysfunction and fibrosis.

  15. Reduced Cardiac Fructose 2,6 Bisphosphate Increases Hypertrophy and Decreases Glycolysis following Aortic Constriction

    PubMed Central

    Wang, Qianwen; Brainard, Robert E.; Watson, Lewis J.; Jones, Steven P.; Epstein, Paul N.

    2013-01-01

    This study was designed to test whether reduced levels of cardiac fructose-2,6-bisphosphate (F-2,6-P2) exacerbates cardiac damage in response to pressure overload. F-2,6-P2 is a positive regulator of the glycolytic enzyme phosphofructokinase. Normal and Mb transgenic mice were subject to transverse aortic constriction (TAC) or sham surgery. Mb transgenic mice have reduced F-2,6-P2 levels, due to cardiac expression of a transgene for a mutant, kinase deficient form of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) which controls the level of F-2,6-P2. Thirteen weeks following TAC surgery, glycolysis was elevated in FVB, but not in Mb, hearts. Mb hearts were markedly more sensitive to TAC induced damage. Echocardiography revealed lower fractional shortening in Mb-TAC mice as well as larger left ventricular end diastolic and end systolic diameters. Cardiac hypertrophy and pulmonary congestion were more severe in Mb-TAC mice as indicated by the ratios of heart and lung weight to tibia length. Expression of α-MHC RNA was reduced more in Mb-TAC hearts than in FVB-TAC hearts. TAC produced a much greater increase in fibrosis of Mb hearts and this was accompanied by 5-fold more collagen 1 RNA expression in Mb-TAC versus FVB-TAC hearts. Mb-TAC hearts had the lowest phosphocreatine to ATP ratio and the most oxidative stress as indicated by higher cardiac content of 4-hydroxynonenal protein adducts. These results indicate that the heart’s capacity to increase F-2,6-P2 during pressure overload elevates glycolysis which is beneficial for reducing pressure overload induced cardiac hypertrophy, dysfunction and fibrosis. PMID:23308291

  16. Wave reflection and central aortic pressure are increased in response to static and dynamic muscle contraction at comparable workloads.

    PubMed

    Edwards, David G; Mastin, Corey R; Kenefick, Robert W

    2008-02-01

    We determined the effects of static and dynamic muscle contraction at equivalent workloads on central aortic pressure and wave reflection. At random, 14 healthy men and women (23 +/- 5 yr of age) performed a static handgrip forearm contraction [90 s at 30% of maximal voluntary contraction (MVC)], dynamic handgrip contractions (1 contraction/s for 180 s at 30% MVC), and a control trial. During static and dynamic trials, tension-time index was controlled by holding peak tension constant. Measurements of brachial artery blood pressure and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) were conducted at baseline, during each trial, and during 1 min of postexercise ischemia (PEI). Aortic augmentation index (AI), an index of wave reflection, was calculated from the aortic pressure waveform. AI increased during both static and dynamic trials (static, 5.2 +/- 3.1 to 11.8 +/- 3.4%; dynamic, 5.8 +/- 3.0 to 13.3 +/- 3.4%; P < 0.05) and further increased during PEI (static, 18.5 +/- 3.1%; dynamic, 18.6 +/- 2.9%; P < 0.05). Peripheral and central systolic and diastolic pressures increased (P < 0.05) during both static and dynamic trials and remained elevated during PEI. AI and pressure responses did not differ between static and dynamic trials. Peripheral and central pressures increased similarly during static and dynamic contraction; however, the rise in central systolic pressure during both conditions was augmented by increased wave reflection. The present data suggest that wave reflection is an important determinant of the central blood pressure response during forearm muscle contractions.

  17. Influence of increased heart rate and aortic pressure on resting indices of functional coronary stenosis severity.

    PubMed

    Casadonte, Lorena; Verhoeff, Bart-Jan; Piek, Jan J; VanBavel, Ed; Spaan, Jos A E; Siebes, Maria

    2017-09-13

    Baseline assessment of functional stenosis severity has been proposed as a practical alternative to hyperemic indices. However, intact autoregulation mechanisms may affect intracoronary hemodynamics. The aim of this study was to investigate the effect of changes in aortic pressure (Pa) and heart rate (HR) on baseline coronary hemodynamics and functional stenosis assessment. In 15 patients (55 ± 3% diameter stenosis) Pa, intracoronary pressure (Pd) and flow velocity were obtained at control, and during atrial pacing at 120 bpm, increased Pa (+30 mmHg) with intravenous phenylephrine (PE), and elevated Pa while pacing at sinus heart rate (PE + sHR). We derived rate pressure product (RPP = systolic Pa × HR), baseline microvascular resistance (BMR = Pd/velocity), and stenosis resistance [BSR = (Pa - Pd)/velocity] as well as whole-cycle Pd/Pa. Tachycardia (120 ± 1 bpm) raised RPP by 74% vs. Accordingly, BMR decreased by 27% (p < 0.01) and velocity increased by 36% (p < 0.05), while Pd/Pa decreased by 0.05 ± 0.02 (p < 0.05) and BSR remained similar to control. Raising Pa to 121 ± 3 mmHg (PE) with concomitant reflex bradycardia increased BMR by 26% (p < 0.001) at essentially unchanged RPP and velocity. Consequently, BSR and Pd/Pa were only marginally affected. During PE + sHR, velocity increased by 21% (p < 0.01) attributable to a 46% higher RPP (p < 0.001). However, BMR, BSR, and Pd/Pa remained statistically unaffected. Nonetheless, the interventions tended to increase functional stenosis severity, causing Pd/Pa and BSR of borderline lesions to cross the diagnostic threshold. In conclusion, coronary microvascular adaptation to physiological conditions affecting metabolic demand at rest influences intracoronary hemodynamics, which may lead to altered basal stenosis indices used for clinical decision-making.

  18. 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.

  19. 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.

  20. 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

  1. Aortic Dissection

    MedlinePlus

    ... arteries (atherosclerosis) Weakened and bulging artery (pre-existing aortic aneurysm) An aortic valve defect (bicuspid aortic valve) A ... valve, tell your doctor. If you have an aortic aneurysm, find out how often you need monitoring and ...

  2. Aortic Arch Reconstruction in Neonates with Biventricular Morphology: Increased Risk for Development of Recoarctation by Use of Autologous Pericardium.

    PubMed

    Bechtold, Caroline; Purbojo, Ariawan; Schwitulla, Judith; Glöckler, Martin; Toka, Okan; Dittrich, Sven; Cesnjevar, Robert Anton; Rüffer, André

    2015-08-01

    The aim of this study was to analyze risk factors promoting development of recoarctation (Re-CoA) in neonates who survived aortic arch repair from an anterior approach. Fifty consecutive neonates with biventricular morphology and ductal-dependent lower body perfusion who were discharged home following aortic arch repair with cardiopulmonary bypass between 2000 and 2012 were retrospectively reviewed. Arch anatomy was either interruption (n = 10) or hypoplasia with coarctation (n = 40). Aortic arch reconstruction was performed by using patch material (bovine pericardium, n = 30, homograft, n = 10, or glutaraldehyde-treated autologous pericardium, n = 7), and three patients underwent direct end-to-side anastomosis. Antegrade cerebral and continuous myocardial perfusion was performed in 39 and 21 patients, respectively. Kaplan-Meier freedom from Re-CoA was calculated. Morphologic and perioperative data indicating increased risk of Re-CoA by univariate analysis were included in multivariate Cox regression analysis. Mean follow-up was 5.3 ± 4.1 years. Re-CoA occurred in 13 patients and was treated successfully by balloon dilatation (n = 6) or surgery (n = 7). Freedom from Re-CoA after 1 and 5 years was 83 ± 5 and 79 ± 6%, respectively. Two patients died early after surgical repair of Re-CoA. The use of autologous pericardium for aortic arch augmentation was the only independent risk factor for development of Re-CoA (hazard ratio: 4.3 [95% confidence interval: 1.2-16.1]; p = 0.028). Re-CoA following neonatal aortic arch surgery can be treated by balloon dilatation or surgery, if adequate. In this study, the risk for development of Re-CoA was independently increased by the use of autologous pericardium during initial arch repair. Georg Thieme Verlag KG Stuttgart · New York.

  3. Weather conditions and their effect on the increase of the risk of type A acute aortic dissection onset in Berlin.

    PubMed

    Taheri Shahraiyni, Hamid; Sodoudi, Sahar; Cubasch, Ulrich

    2016-08-01

    In this study, a minimum distance classification and forward feature selection technique are joined to determine the relationship between weather conditions and the increase of the risk of type A acute aortic dissection (AAD) events in Berlin. The results demonstrate that changes in the amount of cloudiness and air temperature are the most representative weather predictors among the studied parameters. A discrimination surface was developed for the prediction of AAD events 6 h ahead, and it is found that, under a specific amount of cloudiness and air temperature, the risk of AAD events in Berlin increases about 20 %.

  4. Perioperative Infections after Open Abdominal Aortic Aneurysm Repair Lead to Increased Risk of Subsequent Complications.

    PubMed

    Lee, Su Yeon; Peacock, Matthew R; Farber, Alik; Shah, Nishant K; Eslami, Mohammad H; Kalish, Jeffrey A; Rybin, Denis; Komshian, Sevan; Siracuse, Jeffrey J

    2017-10-01

    Patients undergoing open abdominal aortic aneurysm (AAA) repair are at risk of perioperative infections that can lead to subsequent complications. Our goal was to understand how an initial infectious complication influences the risk of subsequent complications in this cohort of patients. Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database (2005-2012), we evaluated the relationship between 3 index infectious complications after open elective AAA repair (pneumonia, deep/organ surgical site infection [SSI], and urinary tract infection [UTI]) and subsequent complications. We used 5:1 propensity matching and calculated propensity score to experience to establish matching cohorts for each index complication. This score was based on preoperative variables and number of event-free days. There were 3,991 patients who were identified to have undergone elective open AAA repair in the ACS-NSQIP database. Postoperative index pneumonia was associated with increased risk of unplanned intubation (28.6% vs. 3.5%; odds ratio [OR], 10.9; 95% confidence interval [CI]: 6.7-17.5; P < 0.001), prolonged ventilation (38.5% vs. 6.7%; OR, 8.7; 95% CI: 5.9-13.0; P < 0.001), sepsis (14.3% vs. 3.3%; OR, 4.8; 95% CI: 2.8-8.4; P < 0.001), acute renal failure (9.9% vs. 2.1%; OR, 5.1; 95% CI: 2.6-9.9; P < 0.001), deep vein thrombosis (DVT) (3.8% vs. 1.4%; OR, 2.7; 95% CI: 1.1-7.0; P = 0.035), and mortality (7.1% vs. 3.0%; OR, 2.5; 95% CI: 1.3-4.9; P = 0.009). Postoperative index UTI was associated with increased risk of sepsis (21.4% vs. 0%; OR, 49.2; 95% CI: 14.5-166.8; P < 0.001), pneumonia (10.7% vs. 2.9%; OR, 4.0; 95% CI: 1.8-8.6; P = 0.001), DVT (3.6% vs. 0.4%; OR, 10.0; 95% CI: 1.8-55.5; P = 0.008), and mortality (5.4% vs. 1.8%; OR, 3.0; 95% CI: 1.1-8.5; P = 0.02). Finally, postoperative index deep/organ SSI increased the risk of pneumonia (13.0% vs. 0.9%; OR, 16.7; 95% CI: 1.6-168.2; P = 0.017), prolonged ventilation

  5. Folic acid modulates eNOS activity via effects on posttranslational modifications and protein–protein interactions☆

    PubMed Central

    Taylor, Sarah Y.; Dixon, Hannah M.; Yoganayagam, Shobana; Price, Natalie; Lang, Derek

    2013-01-01

    Folic acid enhances endothelial function and improves outcome in primary prevention of cardiovascular disease. The exact intracellular signalling mechanisms involved remain elusive and were therefore the subject of this study. Particular focus was placed on folic acid-induced changes in posttranslational modifications of endothelial nitric oxide synthase (eNOS). Cultured endothelial cells were exposed to folic acid in the absence or presence of phosphatidylinositol-3' kinase/Akt (PI3K/Akt) inhibitors. The phosphorylation status of eNOS was determined via western blotting. The activities of eNOS and PI3K/Akt were evaluated. The interaction of eNOS with caveolin-1, Heat-Shock Protein 90 and calmodulin was studied using co-immunoprecipitation. Intracellular localisation of eNOS was investigated using sucrose gradient centrifugation and confocal microscopy. Folic acid promoted eNOS dephosphorylation at negative regulatory sites, and increased phosphorylation at positive regulatory sites. Modulation of phosphorylation status was concomitant with increased cGMP concentrations, and PI3K/Akt activity. Inhibition of PI3K/Akt revealed specific roles for this kinase pathway in folic acid-mediated eNOS phosphorylation. Regulatory protein and eNOS protein associations were altered in favour of a positive regulatory effect in the absence of bulk changes in intracellular eNOS localisation. Folic acid-mediated eNOS activation involves the modulation of eNOS phosphorylation status at multiple residues and positive changes in important protein–protein interactions. Such intracellular mechanisms may in part explain improvements in clinical vascular outcome following folic acid treatment. PMID:23796957

  6. [Aortic aneurysm].

    PubMed

    Villar, Fernando; Pedro-Botet, Juan; Vila, Ramón; Lahoz, Carlos

    2013-01-01

    Aortic aneurysm is one important cause of death in our country. The prevalence of abdominal aortic aneurism (AAA) is around 5% for men older than 50 years of age. Some factors are associated with increased risk for AAA: age, hypertension, hypercholesterolemia, cardiovascular disease and, in particular, smoking. The medical management of patients with an AAA includes cardiovascular risk treatment, particularly smoking cessation. Most of major societies guidelines recommend ultrasonography screening for AAA in men aged 65 to 75 years who have ever smoked because it leads to decreased AAA-specific mortality. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

  7. Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production

    PubMed Central

    2014-01-01

    Background It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). Methods We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. Results Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. Conclusions Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance. PMID:24693878

  8. Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele.

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Gabriel, Marcin; Zapalski, Stanisław; Pawlak, Andrzej L

    2003-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Several genetic, biochemical and environmental factors are recognized as relevant for the pathogenesis of AAA. We determined the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (C677T) in 63 patients with AAA and compared it to that in 75 subjects of the population sample. The frequencies of the C/C, C/T and T/T genotypes were 65%, 27%, and 8% in the population sample and 33%, 60%, and 6% in the patients. This corresponds to a 4.4-fold greater risk of AAA in subjects who have the 677C/T variant of MTHFR, as compared with those who are 677C/C (p < 0.0001; 95% CI=2.11-9.34). The frequency of allele MTHFR 677T in patients (0.37) was higher than in the population sample (0.21; p < 0.007). This association between the common allele of the MTHFR gene--MTHFR 677T--and the development of AAA suggests that elevated homocysteine (Hcy) may disturb the function of the aortic wall. The disturbance may involve enhancement of elastin degradation, the process enhanced by mild hyperhomocysteinemia in minipigs. The magnitude of this effect, which refers to the AAA patients unselected for familial occurrence, indicates that the disturbance of aortic wall physiology caused by the presence of the MTHFR 677T allele is greater than the effect of the earlier described allele disequilibrium at the polymorphic alleles of the PAI1 (plasminogen activator inhibitor 1) gene seen only in familial cases of AAA.

  9. Transcatheter aortic valve implantation.

    PubMed

    Oliemy, Ahmed; Al-Attar, Nawwar

    2014-01-01

    Transcatheter aortic valve implantation was developed to offer a therapeutic solution to patients with severe symptomatic aortic stenosis who are not candidates for conventional aortic valve replacement. The improvement in transcatheter aortic valve implantation outcomes is still of concern in the areas of stroke, vascular injury, heart block, paravalvular regurgitation and valve durability. Concomitantly, the progress, both technical and in terms of material advances of transcatheter valve systems, as well as in patient selection, renders transcatheter aortic valve implantation an increasingly viable treatment for more and more patients with structural heart disease.

  10. 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.

  11. Childhood Obesity Associates Haemodynamic and Vascular Changes That Result in Increased Central Aortic Pressure with Augmented Incident and Reflected Wave Components, without Changes in Peripheral Amplification

    PubMed Central

    Castro, Juan M.; García-Espinosa, Victoria; Curcio, Santiago; Arana, Maite; Chiesa, Pedro; Giachetto, Gustavo; Zócalo, Yanina; Bia, Daniel

    2016-01-01

    The aims were to determine if childhood obesity is associated with increased central aortic blood pressure (BP) and to characterize haemodynamic and vascular changes associated with BP changes in obese children and adolescents by means of analyzing changes in cardiac output (stroke volume, SV), arterial stiffness (aortic pulse wave velocity, PWV), peripheral vascular resistances (PVR), and net and relative contributions of reflected waves to the aortic pulse wave amplitude. We included 117 subjects (mean/range age: 10 (5–15) years, 49 females), who were obese (OB) or had normal weight (NW). Peripheral and central aortic BP, PWV, and pulse wave-derived parameters (augmentation index, amplitude of forward and backward components) were measured with tonometry (SphygmoCor) and oscillometry (Mobil-O-Graph). With independence of the presence of dyslipidemia, hypertension, or sedentarism, the aortic systolic and pulse BP were higher in OB than in NW subjects. The increase in central BP could not be explained by the elevation in the relative contribution of reflections to the aortic pressure wave and higher PVR or by an augmented peripheral reflection coefficient. Instead, the rise in central BP could be explained by an increase in the amplitude of both incident and reflect wave components associated to augmented SV and/or PWV. PMID:26881081

  12. Turbulence significantly increases pressure and fluid shear stress in an aortic aneurysm model under resting and exercise flow conditions.

    PubMed

    Khanafer, Khalil M; Bull, Joseph L; Upchurch, Gilbert R; Berguer, Ramon

    2007-01-01

    The numerical models of abdominal aortic aneurysm (AAA) in use do not take into account the non-Newtonian behavior of blood and the development of local turbulence. This study examines the influence of pulsatile, turbulent, non-Newtonian flow on fluid shear stresses and pressure changes under rest and exercise conditions. We numerically analyzed pulsatile turbulent flow, using simulated physiological rest and exercise waveforms, in axisymmetric-rigid aortic aneurysm models (AAMs). Discretization of governing equations was achieved using a finite element scheme. Maximum turbulence-induced shear stress was found at the distal end of an AAM. In large AAMs (dilated to undilated diameter ratio = 3.33) at peak systolic flow velocity, fluid shear stress during exercise is 70.4% higher than at rest. Our study provides a numerical, noninvasive method for obtaining detailed data on the forces generated by pulsatile turbulent flow in AAAs that are difficult to study in humans and in physical models. Our data suggest that increased flow turbulence results in increased shear stress in aneurysms. While pressure readings are fairly uniform along the length of an aneurysm, the kinetic energy generated by turbulence impacting on the wall of the distal half of the aneurysm increases fluid and wall shear stress at this site. If the increased fluid shear stress results in further dilation and hence further turbulence, wall stress may be a mechanism for aneurysmal growth and eventual rupture.

  13. Will our training programs meet the challenges of increasingly complex endovascular aortic surgery?

    PubMed

    Diethrich, Edward B

    2012-09-01

    It has been more than 2 decades since endovascular therapies appeared for the treatment of vascular disease. With each new enhancement in a therapeutic approach has come the demand for training to assure competence in the clinical setting. In the early days when the technology was relatively simple, training within the specific specialty through established training programs (eg, residencies, fellowships) was effective. However, today's endovascular treatment of complex aortic disease, as well as other vascular pathologies, is presenting demands that the current system cannot meet. New technologies will demand multispecialty collaboration, so current training programs must be altered if we are to meet the demands in education for future aortic interventions. This personal perspective reviews the evolution of endovascular therapy and the impact of product development's changing landscape on training. A new training paradigm must concentrate on centers of excellence with maximum flexibility to meet the needs and demands of our young trainees. It is vital that this approach be global, disease-focused, and linked to developments in epigenomics.

  14. eNOS uncoupling in the cerebellum after BBB disruption by exposure to Phoneutria nigriventer spider venom.

    PubMed

    Soares, Edilene Siqueira; Mendonça, Monique Culturato Padilha; da Cruz-Höfling, Maria Alice

    2015-09-15

    Numerous studies have shown that the venom of Phoneutria nigriventer (PNV) armed-spider causes excitotoxic signals and blood-brain barrier breakdown (BBBb) in rats. Nitric oxide (NO) is a signaling molecule which has a role in endothelium homeostasis and vascular health. The present study investigated the relevance of endothelial NO synthase (eNOS) uncoupling to clinical neurotoxic evolution induced by PNV. eNOS immunoblotting of cerebellum lysates processed through low-temperature SDS-PAGE revealed significant increased monomerization of the enzyme at critical periods of severe envenoming (1-2 h), whereas eNOS dimerization reversal paralleled to amelioration of animals condition (5-72 h). Moreover, eNOS uncoupling was accompanied by increased expression in calcium-sensing calmodulin protein and calcium-binding calbindin-D28 protein in cerebellar neurons. It is known that greater eNOS monomers than dimers implies the inability of eNOS to produce NO leading to superoxide production and endothelial/vascular barrier dysfunction. We suggest that transient eNOS deactivation and disturbances in calcium handling reduce NO production and enhance production of free radicals thus contributing to endothelial dysfunction in the cerebellum of envenomed rats. In addition, eNOS uncoupling compromises the enzyme capacity to respond to shear stress contributing to perivascular edema and it is one of the mechanisms involved in the BBBb promoted by PNV. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

    PubMed Central

    Serhatli, Muge; Kacar, Omer; Adiguzel, Zelal; Tuncer, Altug; Hayran, Mutlu; Baysal, Kemal

    2012-01-01

    Aortic aneurysms (AA) are characterized by structural deterioration leading to progressive dilation. During the development of AA, two key structural changes are pronounced, one being degradation of extracellular matrix and the other loss of smooth muscle cells (SMCs) through apoptosis. Reactive oxygen species (ROS) are produced above physiological levels in dilated (aneurismal) part of the aorta compared to the nondilated part and they are known to be associated with both the extracellular matrix degradation and the loss of SMCs. In this study, we hypothesized that aneurismal SMCs are more prone to apoptosis and that at least some cells undergo apoptosis due to elevated ROS in the aortic wall. To test this hypothesis, we first isolated SMCs from thoracic aneurismal tissue and compared their apoptotic tendency with normal SMCs in response to H2O2, oxidized sterol, or UV treatment. Exposed cells exhibited morphological changes characteristic of apoptosis, such as cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation. Terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) further confirmed the fragmentation of nuclear DNA in these cells. Vascular SMCs were analyzed for their micronuclei (MN) and binucleate (BN) frequency as indicators of genomic abnormality. These data were then compared to patient parameters, including age, gender, hypertension, or aortic diameter for existing correlations. While the tendency for apoptosis was not significantly different compared to normal cells, both the %MN and %BN were higher in aneurismal SMCs. The data suggest that there is increased DNA damage in TAA samples, which might play a pivotal role in disease development. PMID:22871164

  16. Active smoking increases microsomal PGE2-synthase-1/PGE-receptor-4 axis in human abdominal aortic aneurysms.

    PubMed

    Dilmé, Jaime-Félix; Solà-Villà, David; Bellmunt, Sergi; Romero, José-María; Escudero, José-Román; Camacho, Mercedes; Vila, Luis

    2014-01-01

    The cyclooxygenase- (COX-) 2/microsomal PGE-synthase- (mPGES-) 1/PGE-receptor- (EP-) 4 axis could play a key role in the physiopathology of abdominal aortic aneurysm (AAA) in humans. In this study, we investigated the influence of cardiovascular risk factors on the expression of the PGE2 pathway in human AAA. Aortic (n = 89) and plasma (n = 79) samples from patients who underwent AAA repair were collected. Patients were grouped according to risk factors. COX-isoenzymes, mPGES-1, EPs, α-actin, and CD45 and CD68 transcripts levels were quantified by QRT-PCR and plasma PGE2 metabolites by EIA. Current smoking (CS) patients compared to no-CS had significantly higher local levels of mPGES-1 (P = 0.009), EP-4 (P = 0.007), and PGE2 metabolites plasma levels (P = 0.008). In the multiple linear regression analysis, these parameters remained significantly enhanced in CS after adding confounding factors. Results from association studies with cell type markers suggested that the increased mPGES-1/EP-4 levels were mainly associated with microvascular endothelial cells. This study shows that elements of the PGE2 pathway, which play an important role in AAA development, are increased in CS. These results provide insight into the relevance of tobacco smoking in AAA development and reinforce the potential of mPGES-1 and EP-4 as targets for therapy in AAA patients.

  17. Presence of Renal Simple Cysts Is Associated With Increased Risk of Abdominal Aortic Aneurysms.

    PubMed

    Song, Bong Gun; Park, Yong Hwan

    2014-08-26

    We compared the incidence of renal simple cysts in 271 patients with abdominal aortic aneurysm (AAA) and 1387 patients without AAA (controls) using computed tomography (CT) angiography and abdominal CT, as a health screening program. The AAA group had significantly higher prevalence of renal simple cysts (55% vs 19%, P = .001) and chronic obstructive pulmonary disease (COPD; 12% vs 1%, P = .011) than the controls. After propensity score matching (n = 164), the prevalence of renal simple cysts was still significantly higher in the AAA group. In multivariate analysis, independent predictors of AAA were age, male gender, smoking history, hypertension, high-sensitivity C-reactive protein, creatinine, COPD, and renal simple cysts. The structural weakness predisposing for renal simple cysts may be associated with the initiation of AAA formation. More studies are needed to determine whether the presence of renal simple cysts can be considered as a risk factor for AAA. © The Author(s) 2014.

  18. Post-translational Regulation of Endothelial Nitric Oxide Synthase (eNOS) by Estrogens in the Rat Vagina

    PubMed Central

    Musicki, Biljana; Liu, Tongyun; Strong, Travis D.; Lagoda, Gwen A.; Bivalacqua, Trinity J.; Burnett, Arthur L.

    2010-01-01

    Introduction Estrogens control vaginal blood flow during female sexual arousal mostly through nitric oxide (NO). Although vascular effects of estrogens are attributed to an increase in endothelial NO production, the mechanisms of endothelial NO synthase (eNOS) regulation by estrogens in the vagina are largely unknown. Aims Our hypothesis was that estrogens regulate eNOS post-translationally in the vagina, providing a mechanism to affect NO bioavailability without changes in eNOS protein expression. Methods We measured eNOS phosphorylation and eNOS interaction with caveolin-1 and heat shock protein 90 (HSP90) in the distal and proximal vagina of female rats at diestrus, 7 days after ovariectomy and 2 days after replacement of ovariectomized rats with estradiol-17β (15 μg). Main Outcome Measures Molecular mechanisms of eNOS regulation by estrogen in the rat vagina. Results We localized phospho-eNOS (Ser-1177) immunohistochemically to the endothelium lining blood vessels and vaginal sinusoids. Estrogen withdrawal decreased phosphorylation of eNOS on its positive regulatory site (Ser-1177) and increased eNOS binding to its negative regulator caveolin-1 (without affecting eNOS/HSP90 interaction), and they were both normalized by estradiol replacement. Protein expressions of phosphorylated Akt (protein kinase B) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) were not affected by estrogen status, suggesting that the effect of estrogens on eNOS (Ser-1177) phosphorylation was not mediated by activated AKT or ERK1/2. eNOS phosphorylation on its negative regulatory site (Ser-114) was increased in the vagina by estrogen withdrawal and normalized by estradiol replacement, implying that the maintenance of low phosphorylation of eNOS on this site by estradiol may limit eNOS interaction with caveolin-1 and preserve the enzyme's activity. Total eNOS, inducible NOS, caveolin-1, and HSP90 protein expressions were not affected by ovariectomy or estradiol replacement

  19. Altered Endometrial Expression of Endothelial Nitric oxide Synthase (eNOS) in women with Unexplained Recurrent Miscarriage and Infertility

    PubMed Central

    Najafi, Tohid; Novin, Marefat Ghaffari; Ghazi, Reza; Khorram, Omid

    2012-01-01

    Background Endothelial nitric oxide synthase (eNOS) has diverse roles in the female reproductive system including a role in blastocyst implantation. Aberrant expression of eNOS could therefore be significant in the pathogenesis of disorders of implantation Materials and Methods eNOS protein and mRNA levels in the endometrium of women with recurrent miscarriages, unexplained infertility, and a control group was determined by compartmental quantitative immunohistochemistry and real time RT-PCR Results eNOS was immunolocalized to all layers of the endometrium and the vascular endothelium. eNOS protein expression was higher in glandular epithelium (P=0.004) and luminal epithelium (P=0.002) but not vascular endothelium and stroma (P=0.14) in women with recurrent miscarriage. Similarly, in women with unexplained infertility eNOS expression was significantly higher (P<0.03) in luminal epithelium but not in any other compartments compared with the control group. The levels of mRNA expression as determined by real time RT-PCR confirmed the protein data demonstrating higher eNOS mRNA expression In the endometrium of women with recurrent miscarriage and unexplained infertility compared with controls Conclusion Increased expression of eNOS in glandular and luminal epithelium of the endometrium in women with recurrent miscarriages and unexplained infertility suggests a detrimental effect of excess nitric oxide in endometrial receptivity and implantation PMID:22877939

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

    PubMed

    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

    2008-06-01

    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.

  1. 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

  2. Aortic dissection

    MedlinePlus

    Aortic aneurysm - dissecting; Chest pain - aortic dissection; Thoracic aortic aneurysm - dissection ... also cause abnormal widening or ballooning of the aorta ( aneurysm ). The exact cause is unknown, but more common ...

  3. Aortic Aneurysm

    MedlinePlus

    ... chest and abdomen. There are two types of aortic aneurysm: Thoracic aortic aneurysms (TAA) - these occur in the part of the aorta running through the chest Abdominal aortic aneurysms (AAA) - these occur in the part of the ...

  4. Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats.

    PubMed

    Sangüesa, Gemma; Shaligram, Sonali; Akther, Farjana; Roglans, Núria; Laguna, Juan C; Rahimian, Roshanak; Alegret, Marta

    2017-02-01

    High consumption of simple sugars causes adverse cardiometabolic effects. We investigated the mechanisms underlying the metabolic and vascular effects of glucose or fructose intake and determined whether these effects are exclusively related to increased calorie consumption. Female Sprague-Dawley rats were supplemented with 20% wt/vol glucose or fructose for 2 mo, and plasma analytes and aortic response to vasodilator and vasoconstrictor agents were determined. Expression of molecules associated with lipid metabolism, insulin signaling, and vascular response were evaluated in hepatic and/or aortic tissues. Caloric intake was increased in both sugar-supplemented groups vs. control and in glucose- vs. fructose-supplemented rats. Hepatic lipogenesis was induced in both groups. Plasma triglycerides were increased only in the fructose group, together with decreased expression of carnitine palmitoyltransferase-1A and increased microsomal triglyceride transfer protein expression in the liver. Plasma adiponectin and peroxisome proliferator-activated receptor (PPAR)-α expression was increased only by glucose supplementation. Insulin signaling in liver and aorta was impaired in both sugar-supplemented groups, but the effect was more pronounced in the fructose group. Fructose supplementation attenuated aortic relaxation response to a nitric oxide (NO) donor, whereas glucose potentiated it. Phenylephrine-induced maximal contractions were reduced in the glucose group, which could be related to increased endothelial NO synthase (eNOS) phosphorylation and subsequent elevated basal NO in the glucose group. In conclusion, despite higher caloric intake in glucose-supplemented rats, fructose caused worse metabolic and vascular responses. This may be because of the elevated adiponectin level and the subsequent enhancement of PPARα and eNOS phosphorylation in glucose-supplemented rats. This is the first study comparing the effects of glucose and fructose consumption on metabolic

  5. Aortic root stiffness affects the kinematics of bioprosthetic aortic valves.

    PubMed

    Jahren, Silje Ekroll; Winkler, Bernhard Michael; Heinisch, Paul Philipp; Wirz, Jessica; Carrel, Thierry; Obrist, Dominik

    2017-02-01

    In this study, the influence of aortic root distensibility on the haemodynamic parameters and valve kinematics of a bioprosthetic aortic valve was investigated in a controlled in vitro experiment. An Edwards INTUITY Elite 21 mm sutureless aortic valve (Edwards Lifesciences, Irvine, CA, USA) was inserted in three transparent aortic root phantoms with different wall thicknesses (0.55, 0.85 and 1.50 mm) mimicking different physiological distensibilities. Haemodynamic measurements were performed in an in vitro flow loop at heart rates of 60, 80 and 100 bpm with corresponding cardiac outputs of 3.5, 4.0 and 5.0 l/min and aortic pressures of 100/60, 120/90 and 145/110 mmHg, respectively. Aortic valve kinematics were assessed using a high-speed camera. The geometric orifice area (GOA) was measured by counting pixels in the lumen of the open aortic valve. The effective orifice area (EOA) was calculated from the root-mean-square value of the systolic aortic valve flow rate and the mean systolic trans-valvular pressure gradient. The tested aortic root phantoms reproduce physiological distensibilities of healthy individuals in age groups ranging from 40 to 70 years (±10 years). The haemodynamic results show only minor differences between the aortic root phantoms: the trans-valvular pressure gradient tends to increase for stiffer aortic roots, whereas the systolic aortic valve flow rate remains constant. As a consequence, the EOA decreased slightly for less distensible aortic roots. The GOA and the aortic valve opening and closing velocities increase significantly with reduced distensibility for all haemodynamic measurements. The resulting mean systolic flow velocity in the aortic valve orifice is lower for the stiffer aortic root. Aortic root distensibility may influence GOA and aortic valve kinematics, which affects the mechanical load on the aortic valve cusps. Whether these changes have a significant effect on the onset of structural valve deterioration of bioprosthetic

  6. Mg-supplementation Protects Against Ritonavir-mediated Endothelial Oxidative Stress and Hepatic eNOS Downregulation

    PubMed Central

    Chen, Xi; Mak, I.Tong

    2014-01-01

    Ritonavir (RTV), a prototypical protease inhibitor currently used as a key component for anti-HIV therapy, is known for its endothelial and hepatic toxicity. The effects of RTV and Mg-supplementation on cultured bovine endothelial cells (EC) and rat hepatic endothelial nitric oxide synthase (eNOS) status were investigated. RTV dose-dependently (5–30µM) decreased EC viability after 48hrs; high Mg (2 mM) significantly attenuated the lost viability. ECs incubated with 15 µM RTV for 6 to 24 hrs. resulted in 2–4-fold elevation of oxidized glutathione and a 25% loss of total glutathione. At 24 hrs., EC superoxide production due to RTV was detected by dihydroethidium staining, and increased 41% when quantified by flow cytometry; both altered glutathione status and superoxide levels were substantially reversed by 2 mM Mg. RTV reduced eNOS mRNA (−25% at 24 hrs.), and led to decreased eNOS dimer/monomer ratios; nitric oxide (NO)-derived products decreased 40%; both changes were attenuated by Mg-supplementation. In male LewXBrown-Norway rats, RTV administration (75 mg/kg/day, 5 weeks) resulted in an 85% increase in plasma 8-isoprostane, a 30% decrease of hepatic eNOS mRNA; concomitantly, eNOS protein decreased 72%, whereas plasma nitrite level was reduced 49%. Dietary Mg-supplementation (6-fold higher than control) prevented the eNOS mRNA decrease along with lowering 8-isoprostane, and restored the eNOS protein and plasma nitrite levels comparable to controls. Conclusion Mg attenuates RTV-mediated EC oxidative eNOS dysfunction, and down-regulation of hepatic eNOS expression; we suggest that Mg can serve as a beneficial adjunct therapeutic against RTV-mediated eNOS toxicity. PMID:24434120

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Increased 18F-FDG Uptake Is Predictive of Rupture in a Novel Rat Abdominal Aortic Aneurysm Rupture Model

    PubMed Central

    English, Sean J.; Piert, Morand R.; Diaz, Jose A.; Gordon, David; Ghosh, Abhijit; D'Alecy, Louis G.; Whitesall, Steven E.; Sharma, Ashish K.; DeRoo, Elise P.; Watt, Tessa; Su, Gang; Henke, Peter K.; Eliason, Jonathan L.; Ailawadi, Gorav; Upchurch, Gilbert R.

    2015-01-01

    Objective To determine whether 18F-fluorodeoxyglucose (18F-FDG) micro–positron emission tomography (micro-PET) can predict abdominal aortic aneurysm (AAA) rupture. Background An infrarenal AAA model is needed to study inflammatory mechanisms that drive rupture. 18F-FDG PET can detect vascular inflammation in animal models and patients. Methods After exposing Sprague-Dawley rats to intra-aortic porcine pancreatic elastase (PPE) (12 U/mL), AAA rupture was induced by daily, subcutaneous, β-aminopropionitrile (BAPN, 300 mg/kg, N = 24) administration. Negative control AAA animals (N = 15) underwent daily saline subcutaneous injection after PPE exposure. BAPN-exposed animals that did not rupture served as positive controls [nonruptured AAA (NRAAA) 14d, N = 9]. Rupture was witnessed using radiotelemetry. Maximum standard uptakes for 18F-FDG micro-PET studies were determined. Aortic wall PAI-1, uPA, and tPA concentrations were determined by western blot analyses. Interleukin (IL)-1β, IL-6, IL-10, and MIP-2 were determined by Bio-Plex bead array. Neutrophil and macrophage populations per high-power field were quantified. Matrix metalloproteinase (MMP) activities were determined by zymography. Results When comparing ruptured AAA (RAAA) to NRAAA 14d animals, increased focal 18F-FDG uptakes were detected at subsequent sites of rupture (P = 0.03). PAI-1 expression was significantly less in RAAA tissue (P = 0.01), with comparable uPA and decreased tPA levels (P = 0.02). IL-1β (P = 0.04), IL-6 (P = 0.001), IL-10 (P = 0.04), and MIP-2 (P = 0.02)expression, neutrophil (P = 0.02) and macrophage presence (P = 0.002), and MMP9 (P < 0.0001) activity were increased in RAAA tissue. Conclusions With this AAA rupture model, increased prerupture 18F-FDG uptake on micro-PET imaging was associated with increased inflammation in the ruptured AAA wall. 18F-FDG PET imaging may be used to monitor inflammatory changes before AAA rupture. PMID:24651130

  13. Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase

    PubMed Central

    El Accaoui, Ramzi N.; Gould, Sarah T.; Hajj, Georges P.; Chu, Yi; Davis, Melissa K.; Kraft, Diane C.; Lund, Donald D.; Brooks, Robert M.; Doshi, Hardik; Zimmerman, Kathy A.; Kutschke, William; Anseth, Kristi S.; Heistad, Donald D.

    2014-01-01

    Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS−/− mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by NG-nitro-l-arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS−/− mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS−/− aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS−/− and wild-type mice, but collagen-3 was preferentially increased in eNOS−/− mice. Calcification and apoptosis were significantly increased in BAV of eNOS−/− mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs. PMID:24610917

  14. Transient atrial fibrillation after open abdominal aortic revascularization surgery is associated with increased length of stay, mortality, and readmission rates.

    PubMed

    Blanco, Barbara A; Kothari, Anai N; Halandras, Pegge M; Blackwell, Robert H; Graunke, Dawn M; Kuo, Paul C; Cho, Jae S

    2017-08-01

    It is well established that transient postoperative atrial fibrillation (TPAF) is associated with adverse postoperative outcomes after major cardiac and noncardiac operations. The purpose of this study was to elucidate the incidence, impact, and risk factors associated with the development of TPAF in patients undergoing revascularization surgery for occlusive diseases of the abdominal aorta and its branches (AAB). By use of the Healthcare Cost and Utilization Project State Inpatient Database from Florida and California, patients who underwent open revascularization of AAB between 2006 and 2011 were identified. Patients diagnosed with aortic dissection or abdominal aortic aneurysm were excluded to limit the study cohort to include only patients with occlusive etiology. Also excluded were those with a pre-existing diagnosis of atrial fibrillation and those who underwent thoracic aortic repair and peripheral artery revascularization procedures. Multivariable logistic and linear regression analyses with treatment effects were conducted to analyze the association between TPAF and length of stay (LOS); the mortality rates at index admission, 1 month, and 1 year; and the readmission rates at 1 month and 1 year (adjusted for comorbidities and surgical and demographic factors). A backwards stepwise logistic regression model was built to identify predictors of TPAF. A total of 4462 patients were identified; 3253 underwent aortoiliac/femoral bypasses (72.9%), 1514 endarterectomies of AAB (33.9%), and 288 bypasses of AAB (6.5%). The incidence of TPAF was 2.4% (109 patients). Multivariate regression analysis with treatment effects showed that TPAF was associated with significantly increased LOS, mortality, and readmission rates. Factors identified as predictors of TPAF by backwards stepwise logistic regression modeling include electrolyte disorders, increasing age, and Charlson Comorbidity Index (C statistic = .69; accuracy = 58%). TPAF after revascularization of AAB is

  15. Editor's choice--Angulation of the C-arm during complex endovascular aortic procedures increases radiation exposure to the head.

    PubMed

    Albayati, M A; Kelly, S; Gallagher, D; Dourado, R; Patel, A S; Saha, P; Bajwa, A; El-Sayed, T; Salter, R; Gkoutzios, P; Gkoutzious, P; Carrell, T; Abisi, S; Modarai, B

    2015-04-01

    The increased complexity of endovascular aortic repair necessitates longer procedural time and higher radiation exposure to the operator, particularly to exposed body parts. The aims were to measure directly exposure to radiation of the bodies and heads of the operating team during endovascular repair of thoracoabdominal aortic aneurysms (TAAA), and to identify factors that may increase exposure. This was a single-centre prospective study. Between October 2013 and July 2014, consecutive elective branched and fenestrated TAAA repairs performed in a hybrid operating room were studied. Electronic dosimeters were used to measure directly radiation exposure to the primary (PO) and assistant (AO) operator in three different areas (under-lead, over-lead, and head). Fluoroscopy and digital subtraction angiography (DSA) acquisition times, C-arm angulation, and PO/AO height were recorded. Seventeen cases were analysed (Crawford II-IV), with a median operating time of 280 minutes (interquartile range 200-330 minutes). Median age was 76 years (range 71-81 years); median body mass index was 28 kg/m(2) (25-32 kg/m(2)). Stent-grafts incorporated branches only, fenestrations only, or a mixture of branches and fenestrations. A total of 21 branches and 38 fenestrations were cannulated and stented. Head dose was significantly higher in the PO compared with the AO (median 54 μSv [range 24-130 μSv] vs. 15 μSv [range 7-43 μSv], respectively; p = .022), as was over-lead body dose (median 80 μSv [range 37-163 μSv] vs. 32 μSv [range 6-48 μSv], respectively; p = .003). Corresponding under-lead doses were similar between operators (median 4 μSv [range 1-17 μSv] vs. 1 μSv [range 1-3 μSv], respectively; p = .222). Primary operator height, DSA acquisition time in left anterior oblique (LAO) position, and degrees of LAO angulation were independent predictors of PO head dose (p < .05). The head is an unprotected area receiving a significant radiation dose

  16. Early MT-1 MMP expression following elastase exposure is associated with increased cleaved MMP-2 activity in experimental rodent aortic aneurysms.

    PubMed

    Sinha, Indranil; Hannawa, Kevin K; Eliason, Jonathan L; Ailawadi, Gorav; Deogracias, Michael P; Bethi, Siddharth; Ford, John W; Roelofs, Karen J; Grigoryants, Vladimir; Henke, Peter K; Stanley, James C; Upchurch, Gilbert R

    2004-08-01

    The objective of this study was to determine the significance of membrane type 1 matrix metalloproteinase (MT1-MMP) activation of MMP-2 in experimental abdominal aortic aneurysms. Rat aortas were perfused with either saline as a control or elastase, and harvested on 2, 4, or 7 days after perfusion (n = 5 per treatment group/day). Aortic MT1-MMP and MMP-2 expression and protein were determined by real time polymerase chain reaction and Western blotting, respectively. Aortic explants were used to measure MMP-2 activity by zymography. Rat aortic smooth muscle cells in vitro were exposed to increasing doses of elastase and analyzed for MT-1 MMP expression. Aneurysms formed in 80% of the elastase-perfused aortas at 7 days, whereas none formed in the saline-perfused aortas. Significantly increased MT1-MMP expression was observed only on day 4, when levels were 6.5-fold higher in elastase-perfused aortas compared with saline-perfused aortas (P < .01). By day 7, MT1-MMP protein was present only in the elastase-perfused aortas (P = .02). By immunohistochemistry, MT1-MMP was detectable only in the elastase-perfused group at day 7. Cleaved MMP-2 activity (P = .045) was increased in elastase-perfused aortas compared with saline perfused aortas at day 7. In rat aortic smooth muscle cells, MT-1 MMP expression increased in response to elastase (P = .02). The rodent aortic aneurysm model exhibits upregulation of MT1-MMP expression and protein with subsequent increased conversion of MMP-2 from the latent to the cleaved form. Copyright 2004 Elsevier Inc.

  17. Bicuspid Aortic Valve

    DTIC Science & Technology

    2006-08-01

    Schnell E, Wollenek G, Maurer G, Baumgartner H, Lang IM. Mechanisms underlying aortic dilatation in congenital aortic valve malformation . Circulation...1999; 99(16):2138-2143. 10. Roberts CS, Roberts WC. Dissection of the aorta associated with congenital malformation of the aortic valve. J Am Coll... congenital heart defect, often diagnosed incidentally or as a consequence of an associated condition. Patients with this anomaly are at increased risk

  18. An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis.

    PubMed

    Barth, Rolf F; Maximilian Buja, L; Cao, Lei; Brodsky, Sergey V

    2017-07-01

    Brodsky et al. (Cardiovasc Pathol 25(6), 515-520, 2016) recently have reported that there was an unexpected and highly significant inverse correlation between body mass index (BMI) and atherosclerosis of the aortas of morbidly obese decedents (BMI >40 kg/m(2)). In a series of 304 decedents, 65 of whom were morbidly obese, minimal or no atherosclerosis was seen in 46 of them (70%) versus 20 (30%) who had severe atherosclerosis (P = 0.008). This obesity paradox was unexpected and raises important questions about the etiology and pathogenesis of atherosclerosis, which will be the subject of this commentary. The concept of healthy versus unhealthy adiposity may in part provide an explanation for the "obesity paradox." Another factor that will be considered is the possible role of adipokines and their genetic determinants that may significantly reduce the risk of developing aortic atherosclerosis in morbidly obese individuals. Considering the marked variability in the pattern and extent of atherosclerosis of the aorta, hemodynamic factors and endothelial cell shear stress may be the most important determinants that might explain the obesity paradox that we have observed. Finally, the possible role of gut microbiota and inflammation as factors in the etiopathogenesis of atherosclerosis will be considered, but their importance is less clear than that of hemodynamic factors. We conclude with the remarkable finding that a 5300-year-old, well-preserved mummy of the "Iceman," Ötzi had atherosclerotic disease of a number of major arteries and the interesting questions that this raises.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Short-term hyper-caloric diet induces blunted aortic vasoconstriction and enhanced vasorelaxation via increased NOS3 activity and expression in Dahl salt-sensitive rats

    PubMed Central

    Spradley, Frank T.; Kang, Kyu-Tae; Pollock, Jennifer S.

    2013-01-01

    Aim To test the hypothesis that hyper-caloric diet on mechanisms of angiotensin (Ang)II-induced vasoconstriction in Dahl salt-sensitive (SS) rats and genetic control SS-13BN rats. Methods Aortic function was assessed using wire myography in 16-week-old rats maintained on a normal diet or started on a 4-week hyper-caloric diet at 12-weeks-old. Results On normal diet, AngII vasoconstriction was greater in SS rats than SS-13BN rats. Intriguingly, the AngII response was reduced in aortic rings from SS rats on hyper-caloric diet versus normal diet, whereas this response was not altered by hyper-caloric diet in SS-13BN rats. We probed whether O2−, H2O2, or NO mediate the AngII response. PEG-SOD reduced the AngII response in all 4 groups. Catalase treatment of aortic rings did not alter aortic AngII response from SS rats on hyper-caloric but reduced the aortic AngII response of SS rats on normal diet; the exact opposite finding was observed with catalase in SS-13BN rats. L-NAME increased AngII response in SS rats on hyper-caloric but was without effect in the normal diet group. In stark contrast, L-NAME did not alter the AngII response in SS-13BN rats on hyper-caloric diet, yet L-NAME enhanced AngII responsiveness in the normal diet group. In SS rats, hyper-caloric diet increased aortic NOS3 activity and expression corresponding with increased endothelial-dependent vasorelaxation. Conclusion A short-term hyper-caloric diet elicits a vasodilatory phenotype in SS rats, but not in SS-13BN rats, by increasing NOS3 expression and function as well as reducing H2O2 function. PMID:23176108

  4. 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

  5. Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome.

    PubMed

    Olivieri, Laura J; Baba, Ridhwan Y; Arai, Andrew E; Bandettini, W Patricia; Rosing, Douglas R; Bakalov, Vladimir; Sachdev, Vandana; Bondy, Carolyn A

    2013-11-01

    Congenital aortic valve fusion is associated with aortic dilation, aneurysm, and rupture in girls and women with Turner syndrome. Our objective was to characterize aortic valve structure in subjects with Turner syndrome and to determine the prevalence of aortic dilation and valve dysfunction associated with different types of aortic valves. The aortic valve and thoracic aorta were characterized by cardiovascular MRI in 208 subjects with Turner syndrome in an institutional review board-approved natural history study. Echocardiography was used to measure peak velocities across the aortic valve and the degree of aortic regurgitation. Four distinct valve morphologies were identified: tricuspid aortic valve, 64% (n=133); partially fused aortic valve, 12% (n=25); bicuspid aortic valve, 23% (n=47); and unicuspid aortic valve, 1% (n=3). Age and body surface area were similar in the 4 valve morphology groups. There was a significant trend, independent of age, toward larger body surface area-indexed ascending aortic diameters with increasing valve fusion. Ascending aortic diameters were (mean±SD) 16.9±3.3, 18.3±3.3, and 19.8±3.9 mm/m(2) (P<0.0001) for tricuspid aortic valve, partially fused aortic valve, and bicuspid aortic valve+unicuspid aortic valve, respectively. Partially fused aortic valve, bicuspid aortic valve, and unicuspid aortic valve were significantly associated with mild aortic regurgitation and elevated peak velocities across the aortic valve. Aortic valve abnormalities in Turner syndrome occur with a spectrum of severity and are associated with aortic root dilation across age groups. Partial fusion of the aortic valve, traditionally regarded as an acquired valve problem, had an equal age distribution and was associated with an increased ascending aortic diameters.

  6. Atrial Fibrillation Is Associated With Increased Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: Insights from the PARTNER Trial

    PubMed Central

    Biviano, Angelo B.; Nazif, Tamim; Dizon, Jose; Garan, Hasan; Fleitman, Jessica; Hassan, Dua; Kapadia, Samir; Babaliaros, Vasilis; Xu, Ke; Parvataneni, Rupa; Rodes-Cabau, Josep; Szeto, Wilson Y.; Fearon, William F.; Dvir, Danny; Dewey, Todd; Williams, Mathew; Mack, Michael J.; Webb, John G.; Miller, D. Craig; Smith, Craig R.; Leon, Martin B.; Kodali, Susheel

    2015-01-01

    Background This study sought to evaluate the impact of atrial fibrillation (AF) on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). Methods and Results Data were evaluated in 1879 patients with baseline and discharge ECGs who underwent TAVR in the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial. A total of 1262 patients manifested sinus rhythm (SR) at baseline/SR at discharge, 113 SR baseline/AF discharge, and 470 AF baseline/AF discharge. Patients who converted from SR to AF by discharge had the highest rates of all-cause mortality at 30 days (p<0.0001 across all groups; 14.2% SR/AF vs. 2.6% SR/SR; adjusted HR=3.41 p=0.0002) and over two-fold difference at 1-year (p<0.0001 across all groups; 35.7% SR/AF vs. 15.8% SR/SR; adjusted HR=2.14, p<0.0001). The presence of AF on baseline and/or discharge ECG was a predictor of 1-year mortality (adjusted HR=2.14 for SR/AF group and HR=1.88 for AF/AF groups, p<0.0001 for both groups vs. SR/SR). For patients discharged in AF, those with lower ventricular response (i.e, <90 bpm) experienced less 1-year all-cause mortality (HR=0.74, p=0.04). Conclusions After TAVR, the presence of AF at discharge, and particularly the conversion to AF by discharge and higher ventricular response, are associated with increased mortality. These data underscore the deleterious impact of AF, as well as the need for targeted interventions to improve clinical outcomes, in patients undergoing TAVR. PMID:26733582

  7. Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement.

    PubMed

    Chen, Jiyuan; Peters, Andrew; Papke, Christina L; Villamizar, Carlos; Ringuette, Lea-Jeanne; Cao, Jiumei; Wang, Shanzhi; Ma, Shuangtao; Gong, Limin; Byanova, Katerina L; Xiong, Jian; Zhu, Michael X; Madonna, Rosalinda; Kee, Patrick; Geng, Yong-Jian; Brasier, Allan R; Davis, Elaine C; Prakash, Siddharth; Kwartler, Callie S; Milewicz, Dianna M

    2017-06-09

    Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Acta2(-/-) mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2(-/-) aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2(-/-) aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII. © 2017 American Heart Association, Inc.

  8. Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection.

    PubMed

    Xie, Lin; Talukder, M A Hassan; Sun, Jian; Varadharaj, Saradhadevi; Zweier, Jay L

    2015-09-01

    Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), and reduced BH4 availability leads to endothelial NOS (eNOS) uncoupling and increased reactive oxygen species (ROS) generation. Questions remain regarding the functional state of eNOS and role of BH4 availability in the process of in vivo myocardial ischemia-reperfusion (I/R) injury. Rats were subjected to 60min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic liposomal BH4 supplementation (1mg/kg, iv). Myocardial infarction was correlated with cardiac BH4 content, eNOS protein level, NOS enzyme activity, and ROS generation. In the vehicle group, 60-min ischemia drastically reduced myocardial BH4 content in the area at risk (AAR) compared to non-ischemic (NI) area and the level remained lower during early reperfusion followed by recovery after 24-h reperfusion. Total eNOS, activated eNOS protein level (eNOS Ser1177 phosphorylation) and NOS activity were also significantly reduced during ischemia and/or early reperfusion, but recovered after 24-h reperfusion. With liposomal BH4 treatment, BH4 levels were identical in the AAR and NI area during ischemia and/or early reperfusion, and were significantly higher than with vehicle. BH4 pre-treatment preserved eNOS Ser1177 phosphorylation and NOS activity in the AAR, and significantly reduced myocardial ROS generation and infarction compared to vehicle. These findings provide direct evidence that in vivo I/R induces eNOS dysfunction secondary to BH4 depletion, and that pre-ischemic liposomal BH4 administration preserves eNOS function conferring cardioprotection with reduced oxidative stress. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Increased galectin-3 levels are associated with abdominal aortic aneurysm progression and inhibition of galectin-3 decrease elastase-induced AAA development.

    PubMed

    Fernandez-García, Carlos-Ernesto; Tarin, Carlos; Roldan-Montero, Raquel; Martinez-Lopez, Diego; Torres-Fonseca, Monica; Lindhot, Jes S; Vega de Ceniga, Melina; Egido, Jesús; Lopez de Andres, Natalia; Blanco-Colio, Luis-Miguel; Martín-Ventura, Jose-Luis

    2017-10-05

    Abdominal aortic aneurysm (AAA) evolution is unpredictable. Moreover, no specific treatment exists for AAA, except surgery to prevent aortic rupture. Galectin-3 has been previously associated with CVD, but its potential role in AAA have not been addressed. Galectin-3 levels were increased in plasma of AAA patients (n=225) compared to controls (n=100). Moreover, galectin-3 concentrations were associated with need for surgical repair, independently of potential confounding factors. Galectin-3 mRNA and protein expression were increased in human AAA samples compared to healthy aortas. Experimental AAA in mice was induced by aortic elastase perfusion. Mice were treated i.v. with the galectin-3 inhibitor modified citrus pectin (MCP, 10mg/kg, every other day) or saline. Similar to humans, galectin-3 serum and aortic mRNA levels were also increased in elastase-induced AAA mice compared to control mice. Mice treated with MCP showed decreased aortic dilation, as well as elastin degradation, VSMC loss and macrophage content at day 14 post-elastase perfusion compared with control mice. The underlying mechanism(s) of the protective effect of MCP was associated to a decrease in galectin-3 and cytokine (mainly CCL5) mRNA and protein expression. Interestingly, galectin-3 induced CCL5 expression by a mechanism involving STAT3 activation in VSMC. Accordingly, MCP treatment decreased STAT3 phosphorylation in elastase-induced AAA. In conclusion, increased galectin-3 levels are associated with AAA progression, while galectin-3 inhibition decreased experimental AAA development. Our data suggest the potential role of galectin-3 as a therapeutic target in AAA. ©2017 The Author(s).

  10. 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

  11. Lithium increases PGC-1alpha expression and mitochondrial biogenesis in primary bovine aortic endothelial cells.

    PubMed

    Struewing, Ian T; Barnett, Corey D; Tang, Tao; Mao, Catherine D

    2007-06-01

    Lithium is a therapeutic agent commonly used to treat bipolar disorder and its beneficial effects are thought to be due to a combination of activation of the Wnt/beta-catenin pathway via inhibition of glycogen synthase kinase-3beta and depletion of the inositol pool via inhibition of the inositol monophosphatase-1. We demonstrated that lithium in primary endothelial cells induced an increase in mitochondrial mass leading to an increase in ATP production without any significant change in mitochondrial efficiency. This increase in mitochondrial mass was associated with an increase in the mRNA levels of mitochondrial biogenesis transcription factors: nuclear respiratory factor-1 and -2beta, as well as mitochondrial transcription factors A and B2, which lead to the coordinated upregulation of oxidative phosphorylation components encoded by either the nuclear or mitochondrial genome. These effects of lithium on mitochondrial biogenesis were independent of the inhibition of glycogen synthase kinase-3beta and independent of inositol depletion. Also, expression of the coactivator PGC-1alpha was increased, whereas expression of the coactivator PRC was not affected. Lithium treatment rapidly induced a decrease in activating Akt-Ser473 phosphorylation and inhibitory Forkhead box class O (FOXO1)-Thr24 phosphorylation, as well as an increase in activating c-AMP responsive element binding (CREB)-Ser133 phosphorylation, two mechanisms known to control PGC-1alpha expression. Together, our results show that lithium induces mitochondrial biogenesis via CREB/PGC-1alpha and FOXO1/PGC-1alpha cascades, which highlight the pleiotropic effects of lithium and reveal also novel beneficial effects via preservation of mitochondrial functions.

  12. Association Between Three eNOS Polymorphisms and Intracranial Aneurysms Risk

    PubMed Central

    Yang, Chao; Qi, Zhen-yu; Shao, Chuan; Xing, Wei-kang; Wang, Zhong

    2015-01-01

    Abstract Endothelial nitric oxide synthase (eNOS) is the catalyst of endothelial nitric oxide (NO) synthesis. Polymorphisms in the eNOS gene may influence the risk of intracranial aneurysm (IA), but the results of existing researches are still inconsistent. Thus, we performed the present meta-analysis to derive a more precise estimation between eNOS polymorphisms (T786C, G894T, 27-bp-variable number of tandem repeat [VNTR]) and IA risk. Case–control studies evaluating the association between the eNOS polymorphisms and IA risk were searched in PubMed, Ovid & Embase, Web of Science, and Chinese Wanfang datasets with the last search up to July 15, 2014. The pooled odds ratios (ORs) for the association between eNOS polymorphisms and IA and their corresponding 95% confidence intervals (CIs) were estimated using the random or fixed-effects model. Finally, 10 studies for T786C polymorphism (1819 cases and 1893 controls), 9 studies for G894T polymorphism (1393 cases and 1508 controls), and 7 studies for 27-bp-VNTR polymorphism (1281 cases and 1406 controls) were included in the meta-analyses. In the overall analysis, no evidence of association between eNOS polymorphisms and susceptibility of IA was found. When subgrouped by race descent, significantly increased risk was detected among Asians for T786C polymorphism (heterozygous comparison of codominant model: OR = 1.294, 95% CI = 1.025–1.634; dominant model: OR = 1.277, 95% CI = 1.019–1.600), but not in Caucasians or the other 2 polymorphisms. Our meta-analysis suggested that T786C polymorphism was associated with increased risk of IA among Asians, whereas G894T and 27-bp-VNTR polymorphisms might have no influence on the susceptibility of IA. PMID:25634184

  13. Pre-procedural dual antiplatelet therapy in patients undergoing transcatheter aortic valve implantation increases risk of bleeding.

    PubMed

    Hioki, Hirofumi; Watanabe, Yusuke; Kozuma, Ken; Nara, Yugo; Kawashima, Hideyuki; Kataoka, Akihisa; Yamamoto, Masanori; Takagi, Kensuke; Araki, Motoharu; Tada, Norio; Shirai, Shinichi; Yamanaka, Futoshi; Hayashida, Kentaro

    2017-03-01

    To evaluate the clinical benefit of pre-procedural antiplatelet therapy in patients undergoing transfemoral (TF) transcatheter aortic valve implantation (TAVI). OCEAN (Optimized transCathEter vAlvular interveNtion)-TAVI is a prospective, multicentre, observational cohort registry, enrolling 749 patients who underwent TAVI from October 2013 to August 2015 in Japan. We identified 540 patients (median age 85 years, 68.1% female) undergoing TF-TAVI; of these, 80 had no pre-procedural antiplatelet therapy and 460 had antiplatelet therapy. The endpoints were any bleeding (life-threatening, major, and minor bleeding) and thrombotic events (stroke, myocardial infarction, and valve thrombosis) during hospitalisation. Patients with dual antiplatelet therapy (DAPT) had a significantly higher incidence of any bleeding than those with single antiplatelet therapy (SAPT) (36.5% vs 27.5%, p=0.049) and no antiplatelet therapy (36.5% vs 21.3%, p=0.010). Patients without pre-procedural antiplatelet therapy did not experience an increased risk of thrombotic events. In multivariable logistic regression analysis, DAPT before TF-TAVI significantly increased any bleeding compared with SAPT (OR 2.05, 95% CI 1.16 to 3.65) and no antiplatelet therapy (OR 2.30, 95% CI 1.08 to 4.90). The current study demonstrated that DAPT before TF-TAVI increased the risk of bleeding compared with single or no antiplatelet therapy. Lower intensity antiplatelet therapy was not associated with thrombotic events. In modern practice, it might be reasonable to perform TAVI using single or no pre-procedural antiplatelet therapy with an expectation of no increase of adverse events. UMIN-ID; 000020423; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Knockdown of GSK3β increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells

    PubMed Central

    Weikel, Karen A.; Cacicedo, José M.; Ruderman, Neil B.; Ido, Yasuo

    2016-01-01

    High concentrations of glucose and palmitate increase endothelial cell inflammation and apoptosis, events that often precede atherogenesis. They may do so by decreasing basal autophagy and AMP-activated protein kinase (AMPK) activity, although the mechanisms by which this occurs are not clear. Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3β (GSK3β). To determine whether GSK3β affects nutrient-induced changes in autophagy and AMPK activity, we used a primary human aortic endothelial cell (HAEC) model of type 2 diabetes that we had previously characterized with impaired AMPK activity and autophagy [Weikel et al. (2015) Am. J. Phys. Cell Physiol. 308, C249–C263]. Presently, we found that incubation of HAECs with excess nutrients (25 mM glucose and 0.4 mM palmitate) increased GSK3β activity and impaired lysosome acidification. Suppression of GSK3β in these cells by treatment with a chemical inhibitor or overexpression of kinase-dead GSK3β attenuated these lysosomal changes. Under control and excess nutrient conditions, knockdown of GSK3β increased autophagosome formation, forkhead box protein O1 (FOXO1) activity and AMPK signalling and decreased Akt signalling. Similar changes in autophagy, AMPK and Akt signalling were observed in aortas from mice treated with the GSK3β inhibitor CHIR 99021. Thus, increasing basal autophagy and AMPK activity by inhibiting GSK3β may be an effective strategy in the setting of hyperglycaemia and dyslipidaemia for restoring endothelial cell health and reducing atherogenesis. PMID:27534430

  15. Knockdown of GSK3β increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells.

    PubMed

    Weikel, Karen A; Cacicedo, José M; Ruderman, Neil B; Ido, Yasuo

    2016-10-01

    High concentrations of glucose and palmitate increase endothelial cell inflammation and apoptosis, events that often precede atherogenesis. They may do so by decreasing basal autophagy and AMP-activated protein kinase (AMPK) activity, although the mechanisms by which this occurs are not clear. Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3β (GSK3β). To determine whether GSK3β affects nutrient-induced changes in autophagy and AMPK activity, we used a primary human aortic endothelial cell (HAEC) model of type 2 diabetes that we had previously characterized with impaired AMPK activity and autophagy [Weikel et al. (2015) Am. J. Phys. Cell Physiol. 308: , C249-C263]. Presently, we found that incubation of HAECs with excess nutrients (25 mM glucose and 0.4 mM palmitate) increased GSK3β activity and impaired lysosome acidification. Suppression of GSK3β in these cells by treatment with a chemical inhibitor or overexpression of kinase-dead GSK3β attenuated these lysosomal changes. Under control and excess nutrient conditions, knockdown of GSK3β increased autophagosome formation, forkhead box protein O1 (FOXO1) activity and AMPK signalling and decreased Akt signalling. Similar changes in autophagy, AMPK and Akt signalling were observed in aortas from mice treated with the GSK3β inhibitor CHIR 99021. Thus, increasing basal autophagy and AMPK activity by inhibiting GSK3β may be an effective strategy in the setting of hyperglycaemia and dyslipidaemia for restoring endothelial cell health and reducing atherogenesis.

  16. eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

    PubMed Central

    Yuen, Darren A.; Stead, Bailey E.; Zhang, Yanling; White, Kathryn E.; Kabir, M. Golam; Thai, Kerri; Advani, Suzanne L.; Connelly, Kim A.; Takano, Tomoko; Zhu, Lei; Cox, Alison J.; Kelly, Darren J.; Gibson, Ian W.; Takahashi, Takamune; Harris, Raymond C.

    2012-01-01

    Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS−/− mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS−/− mice, even though it inhibited glomerular capillary enlargement in both. In eNOS−/− mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS−/− mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS−/− glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes. PMID:22997257

  17. Radiation results in IL-8 mediated intercellular signaling that increases adhesion between monocytic cells and aortic endothelium

    NASA Astrophysics Data System (ADS)

    Kucik, Dennis; Babitz, Stephen; Dunaway, Chad; Steele, Chad

    Epidemiological evidence has established terrestrial radiation exposure as a risk factor for cardiovascular disease. For example, a major side effect of therapeutic radiation, especially for breast and head-and-neck cancers, is atherosclerosis, which can result in stroke years after treatment. Similarly, atomic bomb survivors were significantly more likely to die of cardiovascular disease than their countrymen. Even radiation technologists, prior to 1950 (when regulations governing shielding and occupational exposure were less rigorous) had an increased risk of clinically significant atherosclerosis. We have recently shown that 600 MeV (56) Fe similarly exacerbates plaque formation in the apoE mouse atherosclerosis model at doses 4-7 fold lower than required for x-rays to produce a similar pro-atherogenic effect. This raises concern that exposure to cosmic radiation might pose a similar risk for astronauts. Because so little is known about the mechanism of pro-atherogenic radiation effects, however, the current strategy to minimize risk from terrestrial radiation sources is to limit exposure. For astronauts on deep space missions, exposure to a significant amount of radiation will be unavoidable. Therefore, an understanding of the mechanism of radiation-induced atherosclerosis will be essential in order to develop countermeasures. Radiation can cause increased adhesiveness of vascular endothelium, leading to inappropriate accumulation of monocytes and other white blood cells, which can initiate a self-perpetuating inflammatory response. This vascular inflammation is an early event in atherosclerosis that can eventually lead to clinically significant cardiovascular events such as myocardial infarction and stroke. We showed earlier that x-rays, (56) Fe, and (28) Si all accelerate development of atherosclerosis in the apoE -/- mouse model. We also demonstrated that both x-rays and heavy ions increase adhesion of monocytic cells to vascular human aortic endothelial

  18. Functional significance of differential eNOS translocation

    PubMed Central

    Sánchez, Fabiola A.; Savalia, Nirav B.; Durán, Ricardo G.; Lal, Brajesh K.; Boric, Mauricio P.; Durán, Walter N.

    2006-01-01

    Nitric oxide (NO) regulates flow and permeability. ACh and platelet-activating factor (PAF) lead to endothelial NO synthase (eNOS) phosphorylation and NO release. While ACh causes only vasodilation, PAF induces vasoconstriction and hyperpermeability. The key differential signaling mechanisms for discriminating between vasodilation and hyperpermeability are unknown. We tested the hypothesis that differential translocation may serve as a regulatory mechanism of eNOS to determine specific vascular responses. We used ECV-304 cells permanently transfected with eNOS-green fluorescent protein (ECVeNOS-GFP) and demonstrated that the agonists activate eNOS and reproduce their characteristic endothelial permeability effects in these cells. We evaluated eNOS localization by lipid raft analysis and immunofluorescence microscopy. After PAF and ACh, eNOS moves away from caveolae. eNOS distributes both in the plasma membrane and Golgi in control cells. ACh (10−5 M, 10−4 M) translocated eNOS preferentially to the trans-Golgi network (TGN) and PAF (10−7 M) preferentially to the cytosol. We suggest that PAF-induced eNOS translocation preferentially to cytosol reflects a differential signaling mechanism related to changes in permeability, whereas ACh-induced eNOS translocation to the TGN is related to vasodilation. PMID:16679407

  19. 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.

  20. Narrowed Aortoseptal Angle Is Related to Increased Central Blood Pressure and Aortic Pressure Wave Reflection

    PubMed Central

    Olafiranye, Oladipupo; Ibrahim, Mediha; Kamran, Haroon; Venner-Jones, Kinda; McFarlane, Samy I.; Salciccioli, Louis; Lazar, Jason M.

    2012-01-01

    The left ventricular (LV) aortoseptal angle (ASA) decreases with age, and is associated with basal septal hypertrophy (septal bulge). Enhanced arterial pressure wave reflection is known to impact LV hypertrophy. We assessed whether ASA is related to central blood pressure (BP) and augmentation index (AI), a measure of the reflected pressure wave. We studied 75 subjects (age 62 ± 16 years; 66% female) who were referred for transthoracic echocardiography and had radial artery applanation tonometry within 24 h. Peripheral systolic BP (P-SBP), peripheral diastolic BP (P-DBP), and peripheral pulse pressure (P-PP) were obtained by sphygmomanometry. Central BPs (C-SBP, C-DBP, C-PP) and AI were derived from applanation tonometry. AI was corrected for heart rate (AI75). The basal septal wall thickness (SWT), mid SWT and ASA were measured using the parasternal long axis echocardiographic view. Mean ASA and AI75 were 117 ± 11° and 22 ± 11%, respectively. ASA correlated with AI75 (r = −0.31, p ≤ 0.01), C-SBP (r = −0.24, p = 0.04), C-PP (r = −0.29, p = 0.01), but only showed a trend towards significance with P-SBP (r = −0.2, p = 0.09) and P-PP (r = −0.21, p = 0.08). Interestingly, C-PP was correlated with basal SWT (r = 0.27, p = 0.02) but not with mid SWT (r = 0.19, p = 0.11). On multivariate linear regression analysis, adjusted for age, gender, weight, and mean arterial pressure, AI75 was an independent predictor of ASA (p = 0.02). Our results suggest that a narrowed ASA is related to increased pressure wave reflection and higher central BP. Further studies are needed to determine whether narrowed LV ASA is a cause or consequence of enhanced wave reflection and whether other factors are involved. PMID:22969773

  1. Liposomal Tetrahydrobiopterin Preserves eNOS Coupling in the Post-ischemic Heart Conferring in vivo Cardioprotection

    PubMed Central

    Xie, Lin; Talukder, M A Hassan; Sun, Jian; Varadharaj, Saradhadevi; Zweier, Jay L.

    2015-01-01

    Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), and reduced BH4 availability leads to endothelial NOS (eNOS) uncoupling and increased reactive oxygen species (ROS) generation. Questions remain regarding the functional state of eNOS and role of BH4 availability in the process of in vivo myocardial ischemia-reperfusion (I/R) injury. Rats were subjected to 60-minutes of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic liposomal BH4 supplementation (1 mg/kg, iv). Myocardial infarction was correlated with cardiac BH4 content, eNOS protein level, NOS enzyme activity, and ROS generation. In the vehicle group, 60-min ischemia drastically reduced myocardial BH4 content in the area at risk (AAR) compared to non-ischemic (NI) area and the level remained lower during early reperfusion followed by recovery after 24-hr reperfusion. Activated eNOS protein level (eNOS Ser1177 phosphorylation) and NOS activity were also significantly reduced during ischemia and/or early reperfusion, but recovered after 24-hr reperfusion. With liposomal BH4 treatment, BH4 levels were identical in the AAR and NI area during ischemia and/or early reperfusion, and were significantly higher than with vehicle. BH4 pre-treatment preserved eNOS Ser1177 phosphorylation and NOS activity in the AAR, and significantly reduced myocardial ROS generation and infarction compared to vehicle. These findings provide direct evidence that in vivo I/R induces eNOS dysfunction secondary to BH4 depletion, and that pre-ischemic liposomal BH4 administration preserves eNOS function conferring cardioprotection with reduced oxidative stress. PMID:26116866

  2. The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo.

    PubMed

    Schleicher, Michael; Yu, Jun; Murata, Takahisa; Derakhshan, Berhad; Atochin, Dimitriy; Qian, Li; Kashiwagi, Satoshi; Di Lorenzo, Annarita; Harrison, Kenneth D; Huang, Paul L; Sessa, William C

    2009-08-04

    Akt1 is critical for many in vivo functions; however, the cell-specific substrates responsible remain to be defined. Here, we examine the importance of endothelial nitric oxide synthase (eNOS) as an Akt1 substrate by generating Akt1-deficient mice (Akt1(-/-) mice) carrying knock-in mutations (serine to aspartate or serine to alanine substitutions) of the critical Akt1 phosphorylation site on eNOS (serine 1176) that render the enzyme "constitutively active" or "less active." The eNOS mutations did not influence several phenotypes in Akt1(-/-) mice; however, the defective postnatal angiogenesis characteristic of Akt1(-/-) mice was rescued by crossing the Akt1(-/-) mice with mice carrying the constitutively active form of eNOS, but not by crossing with mice carrying the less active eNOS mutant. This genetic rescue resulted in the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) and increased production of HIF-1alpha-responsive genes in vivo and in vitro. Thus, Akt1 regulates angiogenesis largely through phosphorylation of eNOS and NO-dependent signaling.

  3. 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.

  4. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet.

    PubMed

    Lau, Wei Ling; Leaf, Elizabeth M; Hu, Ming Chang; Takeno, Marc M; Kuro-o, Makoto; Moe, Orson W; Giachelli, Cecilia M

    2012-12-01

    Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

  5. Effects of Dietary Decosahexaenoic Acid (Dha) on eNOS in Human Coronary Artery Endothelial Cells

    PubMed Central

    Stebbins, Charles L.; Stice, James P.; Hart, C. Michael; Mbai, Fiona N.; Knowlton, Anne A.

    2015-01-01

    Endothelial dysfunction occurs in heart disease, and may reduce functional capacity via attenuations in peripheral blood flow. Dietary DHA may improve this dysfunction, but the mechanism is unknown. We determined if DHA enhances expression and activity of eNOS in cultured human coronary artery endothelial cells (HCAEC). HCAEC from 4 donors were treated with 5 nM, 50 nM, or 1 μM DHA for 7 days to model chronic DHA exposure. A trend for increased expression of eNOS and phospho-eNOS was observed with 5 and 50 nM DHA. DHA also enhanced expression of two proteins instrumental in activation of eNOS; phospho-Akt (5 and 50 nM) and HSP90 (50 nM and 1 μM). VEGF-induced activation of Akt increased NOx in treated (50 nM DHA) vs. untreated HCAEC (9.2±1.0 vs. 3.3±1.1 μmols/μg protein/μl). Findings suggest that DHA enhances eNOS and Akt activity, augments HSP90 expression, and increases NO bioavailability in response to Akt kinase activation PMID:18682551

  6. 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

  7. Contribution of backward and forward wave pressures to age-related increases in aortic pressure in a community sample not receiving antihypertensive therapy.

    PubMed

    Hodson, Bryan; Norton, Gavin R; Ballim, Imraan; Sareli, Pinhas; Woodiwiss, Angela J

    2017-08-24

    Reports on the contribution of aortic forward (Pf) and backward (Pb) wave pressures to age-related increases in central aortic pulse pressure (PPc) have been confounded by the use of participants receiving antihypertensive therapy. We assessed the relative contribution of Pf and Pb to age-related increases in PPc (radial applanation tonometry and SphygmoCor software using an assumed triangular wave for wave separation analysis) in 892 community participants not receiving antihypertensive therapy. We validated our results using aortic flow waves (echocardiography) for wave separation analysis in 254 of these participants. In multivariate regression models in those aged <50 years, adjustments for both Pb and a Pf-independent measure of reflected wave function (RM = Pb/Pf), but not Pf abolished the impact of age on PPc. However, in those aged >50 years, adjustments for Pf (β-coefficient: 0.25 ± 0.06 vs. 0.74 ± 0.08; P < .0001) and Pb (0.04 ± 0.04 vs. 0.74 ± 0.08; P < .0001), but not RM markedly decreased the relationship between age and PPc. On product of coefficient mediation analysis, whether assessed in men or in women, in those participants aged <50 years, independent of several confounders and mean arterial pressure, Pb (P < .005), but not Pf contributed to age-related increases in PPc. In contrast, in those participants aged ≥50 years, independent of several confounders and mean arterial pressure, Pb (P < .005) and Pf (P < .01) contributed to age-related increases in PPc, and Pb effects were markedly diminished by adjustments for Pf (0.26 ± 0.002 vs. 0.52 ± 0.003 mm Hg per year, P < .0001 for comparison). In conclusion, independent of the effects of antihypertensive therapy, aortic backward waves contribute to age-related increases in aortic PPc across the adult lifespan, but at an older age, this effect may be attributed in part to the impact of forward on backward wave pressures. Copyright © 2017 American Society of

  8. 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.

  9. Early ischaemic preconditioning requires Akt- and PKA-mediated activation of eNOS via serine1176 phosphorylation

    PubMed Central

    Yang, Changjun; Talukder, M.A. Hassan; Varadharaj, Saradhadevi; Velayutham, Murugesan; Zweier, Jay L.

    2013-01-01

    Aims The role of endothelial nitric oxide synthase (eNOS)/NO signalling is well documented in late ischaemic preconditioning (IPC); however, the role of eNOS and its activation in early IPC remains controversial. This study investigates the role of eNOS in early IPC and the signalling pathways and molecular interactions that regulate eNOS activation during early IPC. Methods and results Rat hearts were subjected to 30-min global ischaemia and reperfusion (I/R) with or without IPC (three cycles 5-min I and 5-min R) in the presence or absence of the NOS inhibitor l-NAME, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (LY), and protein kinase A (PKA) inhibitor H89 during IPC induction or prior endothelial permeablization. IPC improved post-ischaemic contractile function and reduced infarction compared with I/R with this being abrogated by l-NAME or endothelial permeablization. eNOSSer1176, AktSer473, and PKAThr197 phosphorylation was increased following IPC. I/R decreased eNOSSer1176 phosphorylation, whereas IPC increased it. Mass spectroscopy confirmed eNOSSer1176 phosphorylation and quantitative Western blots showed ∼24% modification of eNOSSer1176 following IPC. Immunoprecipitation demonstrated eNOS, Akt, and PKA complexation. Immunohistology showed IPC-induced Akt and PKA phosphorylation in cardiomyocytes and endothelium. With eNOS activation, IPC increased NO production as measured by electron paramagnetic resonance spin trapping and fluorescence microscopy. LY or H89 not only decreased AktSer473 or PKAThr197 phosphorylation, respectively, but also abolished IPC-induced preservation of eNOS and eNOSSer1176 phosphorylation as well as cardioprotection. Conclusion Thus, Akt- and PKA-mediated eNOS activation, with phosphorylation near the C-terminus, is critical for early IPC-induced cardioprotection, with eNOS-derived NO from the endothelium serving a critical role. PMID:22977010

  10. 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.

  11. SOD1 Overexpression Preserves Baroreflex Control of Heart Rate with an Increase of Aortic Depressor Nerve Function

    PubMed Central

    Hatcher, Jeffrey; Gu, He; Cheng, Zixi (Jack)

    2016-01-01

    Overproduction of reactive oxygen species (ROS), such as the superoxide radical (O2 ∙−), is associated with diseases which compromise cardiac autonomic function. Overexpression of SOD1 may offer protection against ROS damage to the cardiac autonomic nervous system, but reductions of O2 ∙− may interfere with normal cellular functions. We have selected the C57B6SJL-Tg (SOD1)2 Gur/J mouse as a model to determine whether SOD1 overexpression alters cardiac autonomic function, as measured by baroreflex sensitivity (BRS) and aortic depressor nerve (ADN) recordings, as well as evaluation of baseline heart rate (HR) and mean arterial pressure (MAP). Under isoflurane anesthesia, C57 wild-type and SOD1 mice were catheterized with an arterial pressure transducer and measurements of HR and MAP were taken. After establishing a baseline, hypotension and hypertension were induced by injection of sodium nitroprusside (SNP) and phenylephrine (PE), respectively, and ΔHR versus ΔMAP were recorded as a measure of baroreflex sensitivity (BRS). SNP and PE treatment were administered sequentially after a recovery period to measure arterial baroreceptor activation by recording aortic depressor nerve activity. Our findings show that overexpression of SOD1 in C57B6SJL-Tg (SOD1)2 Gur/J mouse preserved the normal HR, MAP, and BRS but enhanced aortic depressor nerve function. PMID:26823951

  12. Vascular dysfunctions in the isolated aorta of double-transgenic hypertensive mice developing aortic aneurysm.

    PubMed

    Waeckel, Ludovic; Badier-Commander, Cécile; Damery, Thibaut; Köhler, Ralf; Sansilvestri-Morel, Patricia; Simonet, Serge; Vayssettes-Courchay, Christine; Wulff, Heike; Félétou, Michel

    2015-09-01

    Angiotensin-II and oxidative stress are involved in the genesis of aortic aneurysms, a phenomenon exacerbated by endothelial nitric oxide synthase (eNOS) deletion or uncoupling. The purpose of this work was to study the endothelial function in wild-type C57BL/6 (BL) and transgenic mice expressing the h-angiotensinogen and h-renin genes (AR) subjected to either a control, or a high-salt diet plus a treatment with a NO-synthase inhibitor, N-ω-nitro-L-arginine-methyl-ester (L-NAME; BLSL and ARSL). BLSL showed a moderate increase in blood pressure, while ARSL became severely hypertensive. Seventy-five percent of ARSL developed aortic aneurysms, characterized by major histo-morphological changes and associated with an increase in NADP(H) oxidase-2 (NOX2) expression. Contractile responses (KCl, norepinephrine, U-46619) were similar in the four groups of mice, and relaxations were not affected in BLSL and AR. However, in ARSL, endothelium-dependent relaxations (acetylcholine, UK-14304) were significantly reduced, and this dysfunction was similar in aortae without or with aneurysms. The endothelial impairment was unaffected by catalase, superoxide-dismutase mimetic, radical scavengers, cyclooxygenase inhibition, or TP-receptor blockade and could not be attributed to sGC oxidation. Thus, ARSL is a severe hypertension model developing aortic aneurysm. A vascular dysfunction, involving both endothelial (reduced role of NO) and smooth muscle cells, precedes aneurysms formation and, paradoxically, does not appear to involve oxidative stress.

  13. Negligible effect of eNOS palmitoylation on fatty acid regulation of contraction in ventricular myocytes from healthy and hypertensive rats.

    PubMed

    Jin, Chun Li; Wu, Yu Na; Jang, Ji Hyun; Zhao, Zai Hao; Oh, Goo Taeg; Kim, Sung Joon; Zhang, Yin Hua

    2017-04-25

    S-palmitoylation is an important post-translational modification that affects the translocation and the activity of target proteins in a variety of cell types including cardiomyocytes. Since endothelial nitric oxide synthase (eNOS) is known to be palmitoylated and the activity of eNOS is essential in fatty acid-dependent β-oxidation in muscle, we aimed to test whether palmitoylation of eNOS is involved in palmitic acid (PA) regulation of left ventricular (LV) myocyte contraction from healthy (sham) and hypertensive (HTN) rats. Our results showed that PA, a predominant metabolic substrate for cardiac β-oxidation, significantly increased contraction and oxygen consumption rate (OCR) in LV myocytes from sham. Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) or eNOS gene deletion prevented PA regulation of the myocyte contraction or OCR, indicating the pivotal role of eNOS in mediating the effects of PA in cardiac myocytes. PA increased the palmitoylation of eNOS in LV myocytes and depalmitoylation with 2-bromopalmitate (2BP; 100 μM) abolished the increment. Furthermore, although PA did not increase eNOS-Ser(1177), 2BP reduced eNOS-Ser(1177) with and without PA. Intriguingly, PA-induced increases in contraction and OCR were unaffected by 2BP treatment. In HTN, PA did not affect eNOS palmitoylation, eNOS-Ser(1177), or myocyte contraction. However, 2BP diminished eNOS palmitoylation and eNOS-Ser(1177) in the presence and absence of PA but did not change myocyte contraction. Collectively, our results confirm eNOS palmitoylation in LV myocytes from sham and HTN rats and its upregulation by PA in sham. However, such post-transcriptional modification plays negligible role in PA regulation of myocyte contraction and mitochondrial activity in sham and HTN.

  14. Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat.

    PubMed

    Bunker, Aaron K; Arce-Esquivel, Arturo A; Rector, R Scott; Booth, Frank W; Ibdah, Jamal A; Laughlin, M Harold

    2010-06-01

    We tested the hypothesis that physical activity can attenuate the temporal decline of ACh-induced endothelium-dependent relaxation during type 2 diabetes mellitus progression in the Otsuka Long-Evans Tokushima fatty (OLETF) rat. Sedentary OLETF rats exhibited decreased ACh-induced abdominal aortic endothelium-dependent relaxation from 13 to 20 wk of age (20-35%) and from 13 to 40 wk of age (35-50%). ACh-induced endothelium-dependent relaxation was maintained in the physically active OLETF group and control sedentary Long-Evans Tokushima Otsuka (LETO) group from 13 to 40 wk of age. Aortic pretreatment with N(G)-nitro-l-arginine (l-NNA), indomethacin (Indo), and l-NNA + Indo did not alter the temporal decline in ACh-induced endothelium-dependent relaxation. Temporal changes in the protein expression of SOD isoforms in the aortic endothelium or smooth muscle did not contribute to the temporal decline in ACh-induced endothelium-dependent relaxation in sedentary OLETF rats. A significant increase in the 40-wk-old sedentary LETO and physically active OLETF rat aortic phosphorylated endothelial nitric oxide (p-eNOS)-to-eNOS ratio was observed versus 13- and 20-wk-old rats in each group that was not seen in the 40- versus 13- and 20-wk-old sedentary OLETF rats. These results suggest that temporal changes in the antioxidant system, EDHF, and cycloxygenase metabolite production in sedentary OLETF rat aortas do not contribute to the temporal decline in sedentary OLETF rat aortic ACh-induced endothelium-dependent relaxation seen with type 2 diabetes mellitus progression. We also report that physical activity in conjunction with aging in the OLETF rat results in a temporal increase in the aortic endothelial p-eNOS-to-eNOS ratio that was not seen in sedentary OLETF rats. These results suggest that the sustained aortic ACh-induced endothelium-dependent relaxation in aged physically active OLETF rats may be the result of an increase in active aortic eNOS.

  15. 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

  16. (−)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells

    PubMed Central

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

    2011-01-01

    The consumption of cacao-derived (i.e., cocoa) products provides beneficial cardiovascular effects in healthy subjects as well as individuals with endothelial dysfunction such as smokers, diabetics, and postmenopausal women. The vascular actions of cocoa are related to enhanced nitric oxide (NO) production. These actions can be reproduced by the administration of the cacao flavanol (−)-epicatechin (EPI). To further understand the mechanisms behind the vascular action of EPI, we investigated the effects of Ca2+ depletion on endothelial nitric oxide (NO) synthase (eNOS) activation/phosphorylation and translocation. Human coronary artery endothelial cells were treated with EPI or with bradykinin (BK), a well-known Ca2+-dependent eNOS activator. Results demonstrate that both EPI and BK induce increases in intracellular calcium and NO levels. However, under Ca2+-free conditions, EPI (but not BK) is still capable of inducing NO production through eNOS phosphorylation at serine 615, 633, and 1177. Interestingly, EPI-induced translocation of eNOS from the plasmalemma was abolished upon Ca2+ depletion. Thus, under Ca2+-free conditions, EPI can stimulate NO synthesis independent of calmodulin binding to eNOS and of its translocation into the cytoplasm. We also examined the effect of EPI on the NO/cGMP/vasodilator-stimulated phosphoprotein (VASP) pathway activation in isolated Ca2+-deprived canine mesenteric arteries. Results demonstrate that under these conditions, EPI induces the activation of this vasorelaxation-related pathway and that this effect is inhibited by pretreatment with nitro-l-arginine methyl ester, suggesting a functional relevance for this phenomenon. PMID:21209365

  17. 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.

  18. Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content

    PubMed Central

    Harvey, Nicholas C.; Lillycrop, Karen A.; Garratt, Emma; Sheppard, Allan; McLean, Cameron; Burdge, Graham; Slater-Jefferies, Jo; Rodford, Joanne; Crozier, Sarah; Inskip, Hazel; Emerald, Bright Starling; Gale, Catharine R; Hanson, Mark; Gluckman, Peter; Godfrey, Keith; Cooper, Cyrus

    2013-01-01

    Aim Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year old children. Methods We used Sequenom MassARRAY to assess the methylation status of 2 CpGs in the eNOS promoter, identified from our previous study, in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years (Lunar DPXL DXA instrument). Results Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553+, after taking account of age and sex there was a strong positive association between methylation status and the child’s whole body bone area (r=0.28,p=0.02), bone mineral content (r=0.34,p=0.005) and areal bone mineral density (r=0.34,p=0.005) at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass. Conclusions Our findings suggest an association between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. This supports a role for eNOS in bone growth and metabolism and implies that its contribution may at least in part occur during early skeletal development. PMID:22159788

  19. High Central Aortic Rather than Brachial Blood Pressure is Associated with Carotid Wall Remodeling and Increased Arterial Stiffness in Childhood.

    PubMed

    Peluso, Gonzalo; García-Espinosa, Victoria; Curcio, Santiago; Marota, Marco; Castro, Juan; Chiesa, Pedro; Giachetto, Gustavo; Bia, Daniel; Zócalo, Yanina

    2017-03-01

    In adults, central blood pressure (cBP) is reported to associate target organ damages (TODs) rather than peripheral blood pressure (pBP). However, data regarding the association of pre-clinical TODs with cBP and pBP in pediatric populations are scarce. To evaluate in children and adolescents the importance of cBP and pBP levels, in terms of their association with hemodynamic and vascular changes. 315 subjects [age (mean/range) 12/8-18 years] were included. pBP (oscillometry, Omron-HEM433INT and Mobil-O-Graph), cBP levels and waveforms (oscillometry, Mobil-O-Graph; applanation tonometry, SphygmoCor), aortic wave reflection-related parameters, carotid intima-media thickness (CIMT) and carotid (elastic modulus, stiffness-index) and aortic stiffness (carotid-femoral pulse wave velocity, PWV). Four groups were defined considering pBP and cBP percentiles (th): cBP ≥90th, cBP <90th, pBP ≥90th, pBP <90th. In each group, haemodynamic and vascular parameters were compared for subgroups defined considering the level of the remaining blood pressure (cBP or pBP). Subgroups were matched for anthropometric and cardiovascular risk factors (propensity matching-score). Subjects with high cBP showed a worse cardiovascular risk profile in addition to worse peripheral hemodynamic conditions. The CIMT, carotid and aortic stiffness levels were also higher in those subjects. CIMT and carotid stiffness remained statistically higher when subjects were matched for pBP and other cardiovascular risk factors. There were no differences in arterial properties when subjects were analyzed (compared) considering similar pBP levels, during normal and high cBP conditions. Compared with pBP, the cBP levels show a greater association with vascular alterations (high CIMT and arterial stiffness), in children and adolescents.

  20. 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

  1. Aortic compressor for aortic occlusion in hemorrhagic shock.

    PubMed

    Mahoney, B D; Gerdes, D; Roller, B; Ruiz, E

    1984-01-01

    The aortic compressor is a device that allows rapid, simple, immediately reversible occlusion of the thoracic aorta, without the aortic dissection required to use an aortic cross-clamp. We evaluated the aortic compressor in a controlled study using a canine hemorrhagic shock model. Twelve mongrel dogs were exsanguinated to a mean arterial pressure (MAP) of 47 mm Hg and maintained at that level for 20 minutes. At that point, all animals had a left lateral thoracotomy. Six study animals had the thoracic aorta occluded at the diaphragm using the compressor. Five minutes after thoracotomy, with or without occlusion, the shed blood was reinfused. Application of the aortic compressor was the only variable. Use of the aortic compressor led to an immediate and statistically significant doubling of the study animals' MAP. The increased afterload of aortic occlusion did not impair cardiac output. The cardiac index of the study animals rose slightly, while that of the control animals fell. At the same time the compressor prevented blood flow to the abdominal aorta. If the canine model can be extrapolated to human application, then the aortic compressor would be expected to enhance perfusion of the heart and brain during hemorrhagic shock, prevent further arterial blood loss from intra-abdominal injury or ruptured abdominal aortic aneurysm, and preserve already diminished cardiac output. Because the aorta does not need to be dissected out to use the compressor, there is no risk of injury to nearby vascular structures.

  2. 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.

  3. 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.

  4. Increased Epicardial Fat Thickness Correlates with Aortic Stiffness and N-Terminal Pro-Brain Natriuretic Peptide Levels in Acute Ischemic Stroke Patients

    PubMed Central

    Unal, Yasemin; Basaran, Ozcan; Akin, Fatih; Emir, Gulser Karadaban; Kutlu, Gulnihal; Biteker, Murat

    2016-01-01

    Epicardial fat, a metabolically active tissue, has emerged as a risk factor and active player in metabolic and cardiovascular diseases. We investigated epicardial fat thickness in patients who had sustained an acute ischemic stroke, and we evaluated the relationship of epicardial fat thickness with other prognostic factors. We enrolled 61 consecutive patients (age, ≥18 yr) who had sustained a first acute ischemic stroke and had been admitted to our hospital within 24 hours of the onset of stroke symptoms. The control group comprised 82 consecutive sex- and age-matched patients free of past or current stroke who had been admitted to our cardiology clinics. Blood samples were taken for measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at admission. Aortic stiffness indices and epicardial fat thickness were measured by means of transthoracic echocardiography within the first 48 hours. In comparison with the control group, the patients with acute ischemic stroke had significantly higher epicardial fat thickness (4.8 ± 0.9 vs 3.8 ± 0.7 mm; P <0.001), lower aortic distensibility (2.5 ± 0.8 vs 3.4 ± 0.9 cm2·dyn−1; P <0.001) and lower aortic strain (5.5% ± 1.9% vs 6.4% ± 1.8%; P=0.003). We found a significant association between epicardial fat thickness, NT-proBNP levels, and arterial dysfunction in patients who had sustained acute ischemic stroke. Increased epicardial fat thickness might be a novel risk factor and might enable evaluation of subclinical target-organ damage in these patients. PMID:27303237

  5. eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE−/− Mice

    PubMed Central

    Ponnuswamy, Padmapriya; Schröttle, Angelika; Ostermeier, Eva; Grüner, Sabine; Huang, Paul L.; Ertl, Georg; Hoffmann, Ulrich; Nieswandt, Bernhard; Kuhlencordt, Peter J.

    2012-01-01

    Background All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial- (L/E) and platelet/endothelial- (P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. Principal Findings Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE−/−/eNOS−/−), while P/E-interactions did not differ, compared to apoE−/−. eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE−/− vessels. Conclusion Overt plaque formation, increased vascular inflammation and L/E- interactions are associated with significant reduction of superoxide production in apoE−/−/eNOS−/− vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE−/− atherosclerosis but does not negate the enzyme's strong protective effects. PMID:22291917

  6. 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.

  7. 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

  8. Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells.

    PubMed

    Klinge, Carolyn M; Wickramasinghe, Nalinie S; Ivanova, Margarita M; Dougherty, Susan M

    2008-07-01

    Epidemiological studies correlate moderate red wine consumption to reduced incidence of cardiovascular disease. Resveratrol is a polyphenolic compound in red wine that has cardioprotective effects in rodents. Although endothelial cell (EC) studies indicate that micromolar resveratrol has diverse biological activities, these concentrations are not physiologically relevant because human oral ingestion provides only brief exposure to nanomolar plasma levels. Previously, we reported that nanomolar resveratrol activated ERK1/2 signaling in bovine aortic ECs (BAECs). The goal of this study was to determine the mechanisms by which nanomolar resveratrol rapidly activates endothelial nitric oxide synthase (eNOS) in human umbilical vein ECs (HUVECs). We report for the first time that resveratrol increased interaction between estrogen receptor alpha (ER alpha), caveolin-1 (Cav-1) and c-Src, and increased phosphorylation of Cav-1, c-Src, and eNOS. Pretreatment with the lipid raft disruptor beta-methyl cyclodextrin or G alpha inhibitor pertussis toxin blocked resveratrol- and E(2)-induced eNOS activation and NO production. Depletion of endogenous ER alpha, not ERbeta, by siRNA attenuated resveratrol- and E(2)-induced ERK1/2, Src, and eNOS phosphorylation. Our data demonstrate that nanomolar resveratrol induces ER alpha-Cav-1-c-SRC interaction, resulting in NO production through a G alpha-protein-coupled mechanism. This study provides important new insights into mechanisms for the beneficial effects of resveratrol in ECs.

  9. 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

  10. Prognostic significance of mild aortic regurgitation in predicting mortality after transcatheter aortic valve replacement.

    PubMed

    Jones, Brandon M; Tuzcu, E Murat; Krishnaswamy, Amar; Popovic, Zoran; Mick, Stephanie; Roselli, Eric E; Gul, Sajjad; Devgun, Jasneet; Mistry, Sohi; Jaber, Wael A; Svensson, Lars G; Kapadia, Samir R

    2016-09-01

    Moderate to severe aortic regurgitation after transcatheter aortic valve replacement is associated with worse outcomes. The impact of mild aortic regurgitation has been less clear, possibly because of the broad categories that have been used in clinical trials, but holds increasing importance in the study of next-generation devices in low- and intermediate-risk cohorts. A more granular scheme, which is common in clinical practice and proposed for future trials, may add prognostic value. We evaluated all patients undergoing transfemoral transcatheter aortic valve replacement at the Cleveland Clinic from 2006 to 2012. The degree of aortic regurgitation after transcatheter aortic valve replacement was reported from the echocardiography database based on a clinical, transthoracic echocardiogram performed within 30 days of the procedure. Aortic regurgitation was finely discriminated on the basis of a multiwindow, multiparametric, integrative approach using our usual clinical scale: none, trivial to 1+, 1+, 1 to 2+, 2+, 2 to 3+, 3+, 3 to 4+, or 4+. There were 237 patients included in the analysis. By controlling for age, gender, Society of Thoracic Surgeons score, baseline ejection fraction, and aortic regurgitation before transcatheter aortic valve replacement, there was a significant increase in mortality for each half grade of aortic regurgitation compared with the complete absence of aortic regurgitation after transcatheter aortic valve replacement. The unit hazard ratio for each 1+ increase in aortic regurgitation after transcatheter aortic valve replacement was 2.26 (95% confidence interval, 1.48-3.43; P < .001) considering aortic regurgitation as a continuous variable. Other clinical variables did not significantly affect mortality. Even mild aortic regurgitation after transcatheter aortic valve replacement is associated with worse long-term mortality. There may be prognostic value in reporting milder categories of aortic regurgitation with more granular

  11. 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.

  12. 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

  13. Participation of oleic acid in the formation of the aortic aneurysm in Marfan syndrome patients.

    PubMed

    Soto, María Elena; Iturriaga Hernández, Alejandra Valeria; Guarner Lans, Verónica; Zuñiga-Muñoz, Alejandra; Aranda Fraustro, Alberto; Velázquez Espejel, Rodrigo; Pérez-Torres, Israel

    2016-03-01

    Marfan syndrome (MFS) is associated with progressive aortic dilatation and endothelial dysfunction that lead to early acute dissection and rupture of the aorta and sudden death. Alteration in fatty acid (FA) metabolism can stimulate nitric oxide (NO) overproduction which increases the activity of the inducible form of NO synthase (iNOS) that is involved in endothelial dysfunction. We evaluated the participation of FA in the formation of thoracic aneurysms in MFS and its relation to the iNOS. Oleic acid (OA), iNOS, citrulline, nitrates and nitrites, TGF-β1, TNF-α, monounsaturated FA and NO synthase activity were significantly increased (p<0.05) in tissue from the aortas of MFS. Saturated FA, eNOS and HDL were significantly decreased (p<0.05). Arachidonic acid, delta-9 desaturase tended to increase and histological examination showed an increase in cystic necrosis, elastic fibers and collagen in MFS. The increase in OA contributes to the altered pathway of iNOS, which favors endothelial dysfunction and formation of the aortic aneurysms in MFS. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. 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.

  15. 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.

  16. Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis.

    PubMed

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

    2014-02-01

    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. 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. 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. Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. 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. 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. © 2013 International Society for Sexual Medicine.

  17. 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

  18. 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.

  19. Decreased expression of fibulin-4 in aortic wall of aortic dissection.

    PubMed

    Huawei, P; Qian, C; Chuan, T; Lei, L; Laing, W; Wenlong, X; Wenzhi, L

    2014-02-01

    In this research, we will examine the expression of Fibulin-4 in aortic wall to find out its role in aortic dissection development. The samples of aortic wall were obtained from 10 patients operated for acute ascending aortic dissection and five patients for chronic ascending aortic dissection. Another 15 pieces of samples from patients who had coronary artery bypass were as controls. The aortic samples were stained with aldehyde magenta dyeing to evaluate the arrangement of elastic fibers. The Fibulin-4 protein and mRNA expression were both determined by Western blot and realtime quantitative polymerase chain reaction. Compared with the control group, both in acute and chronic ascending aortic dissection, elastic fiber fragments increased and the expression of fibulin-4 protein significantly decreased (P= 0.045 < 0.05). The level of fibulin-4 mRNA decreased in acute ascending aortic dissection (P= 0.034 < 0.05), while it increased in chronic ascending aortic dissection (P=0.004 < 0.05). The increased amounts of elastic fiber fragments were negatively correlated with the expression of fibulin-4 mRNA in acute ascending aortic dissection. In conclusion, in aortic wall of ascending aortic dissection, the expression of fibulin-4 protein decreased and the expression of fibulin-4 mRNA was abnormal. Fibulin-4 may play an important role in the pathogenesis of aortic dissection.

  20. Exercise restriction is not associated with increasing body mass index over time in patients with anomalous aortic origin of the coronary arteries.

    PubMed

    Meza, James M; Elias, Matthew D; Wilder, Travis J; O'Brien, James E; Kim, Richard W; Mavroudis, Constantine; Williams, William G; Brothers, Julie; Cohen, Meryl S; McCrindle, Brian W

    2017-10-01

    Anomalous aortic origin of the coronary arteries is associated with exercise-induced ischaemia, leading some physicians to restrict exercise in patients with this condition. We sought to determine whether exercise restriction was associated with increasing body mass index over time. From 1998 to 2015, 440 patients ⩽30 years old were enrolled into an inception cohort. Exercise-restriction status was documented in 143 patients. Using linear mixed model repeated-measures regression, factors associated with increasing body mass index z-score over time, including exercise restriction and surgical intervention as time-varying covariates, were investigated. The 143 patients attended 558 clinic visits for which exercise-restriction status was recorded. The mean number of clinic visits per patient was 4, and the median duration of follow-up was 1.7 years (interquartile range (IQR) 0.5-4.4). The median age at first clinic visit was 10.3 years (IQR 7.1-13.9), and 71% (101/143) were males. All patients were alive at their most recent follow-up. At the first clinic visit, 54% (78/143) were exercise restricted, and restriction status changed in 34% (48/143) during follow-up. The median baseline body mass index z-score was 0.2 (IQR 0.3-0.9). In repeated-measures analysis, neither time-related exercise restriction nor its interaction with time was associated with increasing body mass index z-score. Surgical intervention and its interaction with time were associated with decreasing body mass index z-score. Although exercise restriction was not associated with increasing body mass index over time, surgical intervention was associated with decreasing body mass index z-score over time in patients with anomalous aortic origin of the coronary arteries.

  1. [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.

  2. [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.

  3. 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.

  4. 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).

  5. 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.

  6. Geranylgeranylacetone protects against cerebral ischemia and reperfusion injury: HSP90 and eNOS phosphorylation involved.

    PubMed

    He, Dake; Song, Xiaoqing; Li, Ling

    2015-03-02

    Cerebral ischemia and reperfusion (I/R) can trigger a cytotoxic cascade with overflow of reactive oxygen species, paradoxically causing neurological dysfunction, redox imbalance, inflammation and apoptosis. The present study aims to investigate the effect of geranylgeranylacetone(GGA) on cerebral I/R injury and the underlying mechanism. The results demonstrated that cerebral I/R increased the neurological function abnormality, brain edema, inflammation and oxidative injury in rats as well as the cognitive impairment, which was significantly reversed by GGA in a dose-dependent manner. GGA also suppressed the cell injury and apoptosis caused by cerebral I/R. Moreover, the protective effect of GGA was found to involve heat shock protein 90 (HSP90) and phosphorylated endothelial nitric oxide synthase (eNOS) expression and activity. Both the HSP90 and eNOS inhibitor abolished the effect of GGA. The data showed that GGA could protect rats against cerebral I/R injury, which may be related to the induction of HSP90 and activation of eNOS. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Predictive risk models for proximal aortic surgery

    PubMed Central

    Díaz, Rocío; Pascual, Isaac; Álvarez, Rubén; Alperi, Alberto; Rozado, Jose; Morales, Carlos; Silva, Jacobo; Morís, César

    2017-01-01

    Predictive risk models help improve decision making, information to our patients and quality control comparing results between surgeons and between institutions. The use of these models promotes competitiveness and led to increasingly better results. All these virtues are of utmost importance when the surgical operation entails high-risk. Although proximal aortic surgery is less frequent than other cardiac surgery operations, this procedure itself is more challenging and technically demanding than other common cardiac surgery techniques. The aim of this study is to review the current status of predictive risk models for patients who undergo proximal aortic surgery, which means aortic root replacement, supracoronary ascending aortic replacement or aortic arch surgery. PMID:28616348

  8. Predictive risk models for proximal aortic surgery.

    PubMed

    Hernandez-Vaquero, Daniel; Díaz, Rocío; Pascual, Isaac; Álvarez, Rubén; Alperi, Alberto; Rozado, Jose; Morales, Carlos; Silva, Jacobo; Morís, César

    2017-05-01

    Predictive risk models help improve decision making, information to our patients and quality control comparing results between surgeons and between institutions. The use of these models promotes competitiveness and led to increasingly better results. All these virtues are of utmost importance when the surgical operation entails high-risk. Although proximal aortic surgery is less frequent than other cardiac surgery operations, this procedure itself is more challenging and technically demanding than other common cardiac surgery techniques. The aim of this study is to review the current status of predictive risk models for patients who undergo proximal aortic surgery, which means aortic root replacement, supracoronary ascending aortic replacement or aortic arch surgery.

  9. Is aortic atherothrombotic disease detected using multidetector-row CT associated with an increased risk of early ischemic lesion recurrence after acute ischemic stroke?

    PubMed

    Ko, Youngchai; Kim, Wook-Joo; Jang, Myung Suk; Yang, Mi Hwa; Park, Jung Hyun; Choi, Sang Il; Chun, Eun Ju; Lee, Soo Joo; Han, Moon-Ku; Bae, Hee-Joon

    2012-03-01

    Multidetector-row CT (MDCT) is emerging as a new tool for diagnosing aortic atherothrombotic disease (AAD). We elucidated whether MDCT-detected AAD is associated with an increased risk of early ischemic lesion recurrence on diffusion-weighted MRI after ischemic stroke. A consecutive series of patients with acute ischemic stroke confirmed using diffusion-weighted MRI who were hospitalized within 48 hours after symptom onset and underwent MDCT were identified in a prospective stroke registry database. AAD on MDCT was defined as the presence of plaque formation that was noncalcified and ≥4 mm thick, ulcerative, or soft and thrombosed (vulnerable) in the proximal aortic arch. Ischemic lesion recurrence on diffusion-weighted MRI was defined as the occurrence of any new lesion separate from the index lesion on follow-up diffusion-weighted MRI performed within 14 days after symptom onset. A total of 138 patients was selected. MDCT detected AAD in 24 of 138 (17.4%); ≥4 mm thickness in 17 of 138 (12.3%); ulcerated plaque in 20 of 138 (14.5%); and vulnerable plaque in 16 of 138 (11.6%). With respect to diffusion-weighted MRI lesion recurrence, the crude ORs (95% CIs) were as follows: AAD, 3.56 (1.43-8.89); vulnerable plaque, 3.21 (1.11-9.30); ulcerated plaque, 3.37 (1.27-8.95); and ≥4 mm thickness of the noncalcified plaque, 4.23 (1.11-16.19). These results remained significant after adjustments for potential confounders were made. This study shows that AAD detected by MDCT increases the risk of early ischemic lesion recurrence after acute ischemic stroke, thus supporting the role of MDCT in diagnosing AAD and assessing its contribution to recurrence.

  10. 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

  11. Unplanned return to operating room after endovascular repair of abdominal aortic aneurysm (EVAR) is associated with increased risk of hospital readmission.

    PubMed

    Aziz, Faisal; Ferranti, Katelynn; Lehman, Erik B

    2017-01-01

    Objectives Hospital readmissions after surgical operations are considered serious events. Centers for Medicare and Medicaid (CMS) consider surgical readmissions as preventable and hold hospitals responsible for them. Endovascular abdominal aortic aneurysm (EVAR) has become the first line modality of treatment for suitable patients with abdominal aortic aneurysm (AAA). The purpose of this study is to retrospectively review the factors associated with hospital readmission after EVAR. Methods The 2013 EVAR targeted American College of Surgeons (ACS-NSQIP) database and generalized 2013 general and vascular surgery ACS-NSQIP participant use files were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing EVAR surgery were assessed. Multivariate logistic regression analysis was used to determine independent risk factors for hospital readmission within 30 days after surgery. Results A total of 2277 patients (81% males, 19% females) underwent EVAR operations in the year 2013. Indications for operations included: asymptomatic large diameter (79%), symptomatic (5.7%), rupture without hypotension (4.3%), and rupture with hypotension (2.8%). Among these patients, 178 (7.8%) were readmitted to the hospital within 30 days after surgery. About 53% of all readmissions were within two weeks after the discharge. Risk factors, associated with readmission included: body mass index (per 5-units, OR 1.23, CI 1.06-1.42, p < 0.05), days from admission to operation (per 1 day, OR 1.26, CI 1.12-1.41, p < 0.05), prior abdominal aortic surgery (OR 1.60, CI 1.10-2.31, p < 0.05), urinary tract infection (OR 5.93, CI 2.09-16.88, p < 0.05), superficial surgical site infection (OR 6.57, CI 2.53-17.09, p < 0.05), unplanned return to the operating room (OR 11.29, CI 6.29-20.28, p < 0.05), myocardial infarction (OR 11.30, CI 4.42-28.89, p < 0.05), deep venous thrombosis (OR 11.52, CI 2.89-45.86, p < 0.05 and deep incisional

  12. 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.

  13. Risk of rupture or dissection in descending thoracic aortic aneurysm.

    PubMed

    Kim, Joon Bum; Kim, Kibeom; Lindsay, Mark E; MacGillivray, Thomas; Isselbacher, Eric M; Cambria, Richard P; Sundt, Thoralf M

    2015-10-27

    Current practice guidelines recommend surgical repair of large thoracic aortic aneurysms to prevent fatal aortic dissection or rupture, but limited natural history data exist to support clinical criteria for timely intervention. Of 3247 patients with thoracic aortic aneurysm registered in our institutional Thoracic Aortic Center Database, we identified and reviewed 257 nonsyndromic patients (age, 72.4±10.5 years; 143 female) with descending thoracic or thoracoabdominal aortic aneurysm without a history of aortic dissection in whom surgical intervention was not undertaken. The primary end point was a composite of aortic dissection/rupture and sudden death. Baseline mean maximal aortic diameter was 52.4±10.8 mm, with 103 patients having diameters ≥55 mm. During a median follow-up of 25.1 months (quartiles 1-3, 8.3-56.4 months), definite and possible aortic events occurred in 19 (7.4%) and 31 (12.1%) patients, respectively. On multivariable analyses, maximal aortic diameter at baseline emerged as the only significant predictor of aortic events (hazard ratio=1.12; 95% confidence interval, 1.08-1.15). Estimated rates of definite aortic events within 1 year were 5.5%, 7.2%, and 9.3% for aortic diameters of 50, 55, and 60 mm, respectively. Receiver-operating characteristic curves for discriminating aortic events were higher for indexed aortic sizes referenced by body size (area under the curve=0.832-0.889) but not significantly different from absolute maximal aortic diameter (area under the curve=0.805). Aortic size was the principal factor related to aortic events in unrepaired descending thoracic or thoracoabdominal aortic aneurysm. Although the risk of aortic events started to increase with a diameter >5.0 to 5.5 cm, it is uncertain whether repair of thoracic aortic aneurysms in this range leads to overall benefit, and the threshold for repair requires further evaluation. © 2015 American Heart Association, Inc.

  14. 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

  15. 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

  16. Effect of increasing heart rate in patients with aortic regurgitation. Effect of incremental atrial pacing on scintigraphic, hemodynamic and thermodilution measurements

    SciTech Connect

    Firth, B.G.; Dehmer, G.J.; Nicod, P.; Willerson, J.T.; Hillis, L.D.

    1982-06-01

    This study was performed to assess the effect of pacing-induced tachycardia in patients with aortic regurgitation. In 12 patients (5 men and 7 women with a mean age of 53 years) with aortic regurgitation, left ventricular end-diastolic and end-systolic volume indexes were measured with multigated equilibrium blood pool imaging, and forward cardiac index was determined with thermodilution, both at rest (mean heart rate +/- standard deviation 72 +/- 8 beats/min) and during atrial pacing at 100 and 120 beats/min. Pacing caused a decremental reduction in left ventricular end-diastolic and end-systolic volume indexes and radionuclide-determined stroke volume index but no change in radionuclide-determined cardiac index or left ventricular ejection fraction. Forward cardiac index increased incrementally from the baseline value at rest to that at 120 beats/min despite a decremental reduction in stroke volume index. There was a stepwise decrease in regurgitant volume/stroke (46 +/- 20 ml/m2 at baseline, 27 +/- 15 at 120 beats/min; p less than 0.05) but no change in regurgitant volume/min (3.38 +/- 1.80 liters/min per m2 at baseline, 3.22 +/- 1.78 at 120 beats/min; difference not significant (NS)) or regurgitant fraction (0.54 +/- 0.13 at baseline, 0.49 +/- 0.13 at 120 beats/min; NS). Mean femoral arterial, pulmonary arterial and pulmonary capillary wedge pressures did not change with pacing.

  17. An increased frequency of the 5A allele in the promoter region of the MMP3 gene is associated with abdominal aortic aneurysms.

    PubMed

    Deguara, Jean; Burnand, Kevin G; Berg, Jonathan; Green, Peter; Lewis, Cathryn M; Chinien, Ganesh; Waltham, Matthew; Taylor, Peter; Stern, Rowena F; Stern, Rachel F; Solomon, Ellen; Smith, Alberto

    2007-12-15

    Matrix metalloproteinase 3 (MMP3), is over expressed in the wall of abdominal aortic aneurysms (AAA), while inactivation of the gene expressing this enzyme is associated with reduced aneurysm formation in an experimental model. The 5A allele of the 5A/6A polymorphism in the promoter region of the MMP3 gene is associated with enhanced MMP3 expression. This study aimed to determine whether the presence of the 5A allele in the MMP3 promoter is a risk factor for AAA, and if this allele is associated with an increased expression of MMP3 in the aneurysm wall. We compared the frequencies of the 5A and 6A alleles in AAA (n = 405), aortic occlusive disease (AOD) (n = 123) and controls (n = 405). The 5A allele frequency was higher in AAA compared with controls (odds ratio - OR 1.32, P = 0.005) and AOD (OR 1.684, P = 0.0004), but was similar in AOD compared to controls (OR 0.78, P = 0.1). The ORs of the 5A/6A and the 5A/5A genotypes were 1.35 and 1.79, compared with 6A homozygotes. Although wall from 5A homozygotes contained 17% more MMP3 mRNA than homozygotes (P = 0.049) the significance of this was lost when adjusted for age and sex (P = 0.069), and size (P = 0.30). Wall from 5A homozygotes did however contain over 45% more MMP3 protein than heterozygotes (P = 0.009 when corrected for age and sex and P = 0.043 when corrected for aneurysm size). It appears that an abnormality in the MMP3 gene is part of the genetic profile that predisposes to aneurysmal disease.

  18. 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

  19. Effects of hyperbaric oxygen therapy in enhancing expressions of e-NOS, TNF-α and VEGF in wound healing

    NASA Astrophysics Data System (ADS)

    Susilo, Imam; Devi, Anita; Purwandhono, Azham; Hadi Warsito, Sunaryo

    2017-05-01

    Wound healing is a physiological process that occurs progressively through overlapping phases. Tissue oxygenation is an important part of the complex regulation for wound healing. Hyperbaric Oxygen (HBO) therapy is a method of increasing oxygen delivery to tissues. The therapy improves tissue oxygenation and stimulates the formation of H2O2 as a secondary messenger for Tumour Necrosis Factor alpha (TNF α), e-NOS, VEGF and Nuclear Factor Kappa Beta phosphorylation (NF-Kb) which play an important role in the rapid transcription of a wide variety of genes in response to extracellular stimuli. This study aims to determine the effects of Hyperbaric Oxygen therapy in enhancing the expressions of e-NOS, TNF-α, VEGF and wound healing. This study is an animal study with a ‘randomized control group of pre-test and post test design’ on 28 Wistar rats. Randomly, the rats were divided into 4 groups with 7 rats in each group. The HBO treatment group 1 received 5 sessions of HBO 2.4 ATA in 3 × 30 minutes; the HBO treatment group 2 received 10 sessions of HBO 2.4 ATA in 3 × 30 minutes; and each of the control groups were without HBO. Each of the 28 male rats were given a full thickness excisional wound of 1 × 1cm. Examinations of e-NOS, TNF-α, VEGF expressions and wound healing were performed on day-0 (pre-HBO) and day-5 HBO or on day-0 (pre-HBO) and day-10 HBO. The resultsshowthat the Hyperbaric Oxygen therapy can improve e-NOS (p=0.02), TNF-α (p= 0.02), VEGF expression (p=0.02) and wound healing (p=0.002) significantly in the provision of HBO 2.4 ATA for 3 × 30 minutes in 5 sessions over 5 consecutive days. While the 10 sessions of HBO 2.4 ATA for 3 × 30 minutes over 10 consecutive days only increase e-NOS (p=0.02), TNF-α (p=0.04), VEGF expression significantly (p=0.03) but do not improve wound healing significantly (p=0.3) compared with no HBO. The study concludes that HBO can improve the expressions of e-NOS, TNF-α, VEGF and wound healing in the provision of HBO

  20. 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

  1. Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction.

    PubMed

    Chen, Leilei; Zhang, Yuan; Tao, Liangliang; Yang, Zhijian; Wang, Liansheng

    2017-02-01

    Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic option for patients with acute myocardial infarction. We show here that the ectopic overexpression of endothelial nitric oxide synthases (eNOS), an endothelial form of NOS, could enhance the ability of MSCs in treating ischemic heart damage after the occlusion of the coronary artery. Adenoviral delivery of human eNOS gene into mouse bone marrow-derived MSCs (BM-MSCs) conferred resistance to oxygen glucose deprivation (OGD)-induced cell death in vitro, and elevated the bioavailability of nitric oxide when injected into the myocardium in vivo. In a rat model of acute myocardial infarction, the transplantation of eNOS-overexpressing BM-MSCs significantly reduced myocardial infarct size, corrected hemodynamic parameters and increased capillary density. We also found that the synergistic effects were consistently better than either treatment alone. These findings reveal a positive role of elevated eNOS expression in cardiac repair, and suggest the combination of eNOS and MSC transplant therapy as a potential approach for treating myocardial infarction.

  2. 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 ( ...

  3. Thoracic aortic aneurysm

    MedlinePlus

    Aortic aneurysm - thoracic; Syphilitic aneurysm; Aneurysm - thoracic aortic ... The most common cause of a thoracic aortic aneurysm is hardening of ... high cholesterol, long-term high blood pressure, or who smoke. ...

  4. Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke.

    PubMed

    Wei, Loo Keat; Au, Anthony; Menon, Saras; Gan, Siew Hua; Griffiths, Lyn R

    2015-09-01

    The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks. Polymorphisms of these genes were analyzed in age-, sex-, and ethnicity-matched case-controls (n = 594); serum vitamin profiles were determined using immunoassays. The MTHFR 677C>T, 1298A>C, eNOS intron 4a/b, and ApoE polymorphisms were significantly associated with the increased risk of ischemic stroke. Elevated serum homocysteine and vitamin B12 levels were associated with MTHFR 677C>T and eNOS intron 4a/b polymorphisms. The ApoE and eNOS -786T>C polymorphisms were associated with increased serum vitamin B12 levels. However, none of the polymorphisms influenced serum folate levels except for the MTHFR 1298A>C. Different patterns of MTHFR and eNOS haplotypes tend to affect serum vitamin profiles to different degrees, which contribute to either different susceptibility risk or protective effect on ischemic stroke. Overall, increased levels of serum homocysteine and vitamin B12 levels were associated with higher risk of ischemic stroke in the investigated population. The present study suggests that the genotypes and haplotypes of MTHFR 677C>T and eNOS intron 4a/b polymorphisms are potential serum biomarkers in the pathophysiological processes of ischemic stroke, by modulating homocysteine and vitamin B12 levels. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. The role of eNOS on the compensatory regulation of vascular tonus by H2S in mouse carotid arteries.

    PubMed

    Ertuna, Elif; Loot, Annemarieke E; Fleming, Ingrid; Yetik-Anacak, Gunay

    2017-09-30

    The gasotransmitter nitric oxide (NO) has an important role in vascular function and a decrease in its bioavailability is accepted as a main pathological mechanism for cardiovascular diseases. However, other gasotransmitters such as hydrogen sulfide (H2S) are also generated by the endothelium and can also affect vascular tone and a crosstalk may exist between H2S and NO. We therefore investigated the consequences of deficiency, replacement or overexpression of endothelial nitric oxide synthase (eNOS) on H2S-induced vascular responses in murine carotid arteries. In pre-contracted carotid arteries from wild-type (WT) mice, l-cysteine elicited relaxation that was inhibited by the H2S synthesis inhibitor amino-oxyacetic acid (AOAA). Genetic deletion of eNOS increased l-cysteine-induced relaxation compared to WT, but the replacement of eNOS by adenoviral transfection or H2S synthesis inhibition by AOAA reversed it. Furthermore, eNOS deletion did not alter NaHS-induced relaxation in carotid arteries while eNOS overexpression/replacement increased NaHS-induced relaxation responses in carotid arteries from WT or eNOS(-/-). We suggest that, endogenously produced H2S can compensate for impaired vasodilatory responses in the absence of NO to maintain vascular patency; while, eNOS abundance can limit endogenous H2S-induced vascular responses in mice carotid arteries. Our result suggests that endogenous vs. exogenous H2S-induced relaxation are reciprocally regulated by NO in mice carotid arteries. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. 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.

  11. Myxomavirus anti-inflammatory chemokine binding protein reduces the increased plaque growth induced by chronic Porphyromonas gingivalis oral infection after balloon angioplasty aortic injury in mice.

    PubMed

    Lucas, Alexandra R; Verma, Raj K; Dai, Erbin; Liu, Liying; Chen, Hao; Kesavalu, Sheela; Rivera, Mercedes; Velsko, Irina; Ambadapadi, Sriram; Chukkapalli, Sasanka; Kesavalu, Lakshmyya

    2014-01-01

    Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase restenosis. Two virus-derived anti-inflammatory proteins, M-T7 and Serp-1, reduce inflammation and plaque growth after BA and transplant in animal models through separate pathways. M-T7 is a broad spectrum C, CC and CXC chemokine-binding protein. Serp-1 is a serine protease inhibitor (serpin) inhibiting thrombotic and thrombolytic pathways. Serp-1 also reduces arterial inflammation and improves survival in a mouse herpes virus (MHV68) model of lethal vasculitis. In addition, Serp-1 demonstrated safety and efficacy in patients with unstable coronary disease and stent implant, reducing markers of myocardial damage. We investigate here the effects of Porphyromonas gingivalis, a periodontal pathogen, on restenosis after BA and the effects of blocking chemokine and protease pathways with M-T7 and Serp-1. ApoE-/- mice had aortic BA and oral P. gingivalis infection. Arterial plaque growth was examined at 24 weeks with and without anti-inflammatory protein treatment. Dental plaques from mice infected with P. gingivalis tested positive for infection. Neither Serp-1 nor M-T7 treatment reduced infection, but IgG antibody levels in mice treated with Serp-1 and M-T7 were reduced. P. gingivalis significantly increased monocyte invasion and arterial plaque growth after BA (P<0.025). Monocyte invasion and plaque growth were blocked by M-T7 treatment (P<0.023), whereas Serp-1 produced only a trend toward reductions. Both proteins modified expression of TLR4 and MyD88. In conclusion, aortic plaque growth in ApoE-/- mice increased after angioplasty in mice with chronic oral P. gingivalis infection. Blockade of chemokines, but not serine

  12. Myxomavirus Anti-Inflammatory Chemokine Binding Protein Reduces the Increased Plaque Growth Induced by Chronic Porphyromonas gingivalis Oral Infection after Balloon Angioplasty Aortic Injury in Mice

    PubMed Central

    Lucas, Alexandra R.; Verma, Raj K.; Dai, Erbin; Liu, Liying; Chen, Hao; Kesavalu, Sheela; Rivera, Mercedes; Velsko, Irina; Ambadapadi, Sriram; Chukkapalli, Sasanka; Kesavalu, Lakshmyya

    2014-01-01

    Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase restenosis. Two virus-derived anti-inflammatory proteins, M-T7 and Serp-1, reduce inflammation and plaque growth after BA and transplant in animal models through separate pathways. M-T7 is a broad spectrum C, CC and CXC chemokine-binding protein. Serp-1 is a serine protease inhibitor (serpin) inhibiting thrombotic and thrombolytic pathways. Serp-1 also reduces arterial inflammation and improves survival in a mouse herpes virus (MHV68) model of lethal vasculitis. In addition, Serp-1 demonstrated safety and efficacy in patients with unstable coronary disease and stent implant, reducing markers of myocardial damage. We investigate here the effects of Porphyromonas gingivalis, a periodontal pathogen, on restenosis after BA and the effects of blocking chemokine and protease pathways with M-T7 and Serp-1. ApoE−/− mice had aortic BA and oral P. gingivalis infection. Arterial plaque growth was examined at 24 weeks with and without anti-inflammatory protein treatment. Dental plaques from mice infected with P. gingivalis tested positive for infection. Neither Serp-1 nor M-T7 treatment reduced infection, but IgG antibody levels in mice treated with Serp-1 and M-T7 were reduced. P. gingivalis significantly increased monocyte invasion and arterial plaque growth after BA (P<0.025). Monocyte invasion and plaque growth were blocked by M-T7 treatment (P<0.023), whereas Serp-1 produced only a trend toward reductions. Both proteins modified expression of TLR4 and MyD88. In conclusion, aortic plaque growth in ApoE−/− mice increased after angioplasty in mice with chronic oral P. gingivalis infection. Blockade of chemokines, but not serine

  13. 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

  14. The concept of aortic replacement based on computational fluid dynamic analysis: patient-directed aortic replacement†

    PubMed Central

    Heim, Laurant; Poole, Robert J.; Warwick, Richard; Poullis, Michael

    2013-01-01

    OBJECTIVES Aortic replacement is based on the aortic diameter in the absence of dissection or connective tissue diseases. Frequently, a number of different aortic-to-prosthetic anastomotic positions are possible depending on patient factors and surgeon preferences. High stress on residual aortic tissue may result in aneurysm formation or aneurysmal dilatation. Utilizing a computational fluid dynamic evaluation, we aimed to define possible optimal operative interventions with regard to the extent of aortic replacement. METHODS For proof of principle, a computational fluid dynamic (CFD) analysis, using Fluent 6.2 (Ansys UK Ltd, Sheffield, UK), was performed on a simplified ascending arch and descending aortic geometry. Wall shear stress in three dimensions was assessed for the standard operations: ascending aortic replacement, arch replacement and proximal descending aortic replacement. RESULTS Hermiarch replacement is superior to isolated ascending aortic replacement with regard to residual stress analysis on tissues (up to a 10-fold reduction). Aortic arch replacement with island implantation of the supra-aortic vessels may potentially result in high stress on the residual aorta (10-fold increase). Aortic arch replacement with individual supra-aortic vessel implantation may result in areas of high stress (10-fold increase) on native vessels if an inadequate length of supra-aortic tissue is not resected, regardless of it being aneurysmal. CONCLUSIONS Computational fluid dynamic evaluation, which will have to be patient-specific, 3D anatomical and physiological, potentially has enormous implications for operative strategy in aortic replacement surgery. CFD analysis may direct the replacement of normal-diameter aortas in the future. PMID:23407695

  15. Jujuboside B Reduces Vascular Tension by Increasing Ca2+ Influx and Activating Endothelial Nitric Oxide Synthase.

    PubMed

    Zhao, Yixiu; Zhang, Xin; Li, Jiannan; Bian, Yu; Sheng, Miaomiao; Liu, Bin; Fu, Zidong; Zhang, Yan; Yang, Baofeng

    2016-01-01

    Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved

  16. Jujuboside B Reduces Vascular Tension by Increasing Ca2+ Influx and Activating Endothelial Nitric Oxide Synthase

    PubMed Central

    Zhao, Yixiu; Zhang, Xin; Li, Jiannan; Bian, Yu; Sheng, Miaomiao; Liu, Bin; Fu, Zidong; Zhang, Yan; Yang, Baofeng

    2016-01-01

    Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved

  17. Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment.

    PubMed

    Denimal, Damien; Monier, Serge; Brindisi, Marie-Claude; Petit, Jean-Michel; Bouillet, Benjamin; Nguyen, Amandine; Demizieux, Laurent; Simoneau, Isabelle; Pais de Barros, Jean-Paul; Vergès, Bruno; Duvillard, Laurence

    2017-05-01

    High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[(3)H]arginine to L-[(3)H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients. © 2017 American Heart Association, Inc.

  18. The role of the eNOS G894T and T-786C gene polymorphism in the development of ascites in cirrhosis.

    PubMed

    Yildirim, O; Yigit, A; Seckin, Y; Yesilada, E; Gulbay, G; Cagin, Y F; Aksungur, Z; Bilgic, Y; Türkoz, Y; Yologlu, S

    2016-11-01

    Increased nitric oxide (NO) production in cirrhotic patients causes splanchnic vasodilation, leading to the development of the hyperdynamic circulatory syndrome. One factor that influences plasma NO concentration is eNOS gene polymorphism; consequently, the aim of this study was to investigate whether the eNOS gene G894T and T-786C polymorphisms play any role in the development of ascites in such patients. Three groups were created: 70 cirrhotic patients with ascites, 69 cirrhotic participants without ascites (stable cirrhosis), and 60 healthy controls. Polymorphisms were determined using polymerase chain reaction (PCR) and melting curve analysis. The plasma nitrite (NO marker) level was measured by deploying the spectrophotometric Griess reaction. Plasma nitrite levels in the cirrhosis with ascites and stable cirrhosis groups were significantly higher than in the controls (p < 0.0001). The frequency of GG, GT, and TT genotypes for the eNOS G894T polymorphism in the cirrhosis with ascites group was 55.7%, 38.6%, and 5.7% respectively, while in the stable cirrhosis group these figures were 60.9%, 36.2%, and 2.9%. In the controls, the distribution was 63.3%, 33.3%, and 3.3%, respectively. The frequency of TT, TC, and CC genotypes for the eNOS-786C polymorphism in the first group was 52.9%, 34.2%, and 12.9% respectively; in the second group, this was 46.4%, 42%, and 11.6%, and in the controls, 48.3%, 46.7%, and 5%. There were no significant differences in genotype and allele distributions of the eNOS-786C and eNOS G894T polymorphisms among the groups. Plasma nitrite concentration is enhanced in cirrhotic patients, and there is no relationship between the G894T and eNOS-786C polymorphisms and the development of ascites.

  19. 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

  20. 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.

  1. 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

  2. Fo Shou San, an ancient Chinese herbal decoction, protects endothelial function through increasing endothelial nitric oxide synthase activity.

    PubMed

    Bi, Cathy W C; Xu, Li; Tian, Xiao Yu; Liu, Jian; Zheng, Ken Y Z; Lau, Chi Wai; Lau, David T W; Choi, Roy C Y; Dong, Tina T X; Huang, Yu; Tsim, Karl W K

    2012-01-01

    Fo Shou San (FSS) is an ancient herbal decoction comprised of Chuanxiong Rhizoma (CR; Chuanxiong) and Angelicae Sinensis Radix (ASR; Danggui) in a ratio of 2:3. Previous studies indicate that FSS promotes blood circulation and dissipates blood stasis, thus which is being used widely to treat vascular diseases. Here, we aim to determine the cellular mechanism for the vascular benefit of FSS. The treatment of FSS reversed homocysteine-induced impairment of acetylcholine (ACh)-evoked endothelium-dependent relaxation in aortic rings, isolated from rats. Like radical oxygen species (ROS) scavenger tempol, FSS attenuated homocysteine-stimulated ROS generation in cultured human umbilical vein endothelial cells (HUVECs), and it also stimulated the production of nitric oxide (NO) as measured by fluorescence dye and biochemical assay. In addition, the phosphorylation levels of both Akt kinase and endothelial NO synthases (eNOS) were markedly increased by FSS treatment, which was abolished by an Akt inhibitor triciribine. Likewise, triciribine reversed FSS-induced NO production in HUVECs. Finally, FSS elevated intracellular Ca(2+) levels in HUVECs, and the Ca(2+) chelator BAPTA-AM inhibited the FSS-stimulated eNOS phosphorylation. The present results show that this ancient herbal decoction benefits endothelial function through increased activity of Akt kinase and eNOS; this effect is causally via a rise of intracellular Ca(2+) and a reduction of ROS.

  3. 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.

  4. Increased MMP-9 expression and activity by aortic smooth muscle cells after nitric oxide synthase inhibition is associated with increased nuclear factor-kappaB and activator protein-1 activity.

    PubMed

    Knipp, Brian S; Ailawadi, Gorav; Ford, John W; Peterson, David A; Eagleton, Matthew J; Roelofs, Karen J; Hannawa, Kevin K; Deogracias, Michael P; Ji, Baoan; Logsdon, Craig; Graziano, Kathleen D; Simeone, Diane M; Thompson, Robert W; Henke, Peter K; Stanley, James C; Upchurch, Gilbert R

    2004-01-01

    To determine the mechanism underlying increased expression and activity of matrix metalloproteinase 9 (MMP-9) by rat aortic smooth muscle cells (RA-SMC) after inhibition of inducible nitric oxide synthase (iNOS). Treatment of interleukin-1beta-stimulated RA-SMC with aminoguanidine led to an increase of 96% in MMP-9 activity (P = 0.003) by gelatin zymography, a 40% increase in pro-MMP-9 protein (P = 0.018) by Western blot, and a 155% increase in MMP-9 mRNA (P = 0.06) by reverse transcription polymerase chain reaction. Aminoguanidine also caused a 26% decrease in cytosolic IkappaB levels (P = 0.014) by Western blot, as well as a 97% increase in nuclear factor-kappaB binding and a 216% increase in activator protein-1 binding as measured by electrophoretic mobility shift assay. No significant changes were noted in MMP-2 or TIMP-1 expression, protein levels, or activity after aminoguanidine administration. MMP-9 expression and activity is increased in cytokine stimulated RA-SMCs after iNOS inhibition, coincident with activation of the nuclear factor-kappaB and activator protein-1 pathways. We speculate that local derangements in iNOS may favor MMP-9-dependent vessel wall damage in vivo via an inflammatory cascade mechanism.

  5. Effects of aldosterone and related steroids on LPS-induced increased expression of inducible NOS in rat aortic smooth muscle cells

    PubMed Central

    Godfrey, V; Martin, AL; Struthers, AD; Lyles, GA

    2011-01-01

    BACKGROUND AND PURPOSE Expression of inducible NOS (iNOS) is important in certain inflammatory diseases. We determined if the hormone aldosterone, a mineralocorticoid receptor (MR) agonist, affects LPS activation of iNOS expression in rat aortic smooth muscle cells (RASMC). EXPERIMENTAL APPROACH Cultured RASMC were treated with LPS, with or without agonists/antagonists of steroid receptors. iNOS expression was determined by nitrite assays on culture medium removed from treated cells and by immunoblotting of cell protein extracts. KEY RESULTS LPS (1 µg·mL−1) increased nitrite and iNOS protein above that in control (untreated) cells. These effects of LPS were reduced by aldosterone (0.1–10 µM). The MR antagonists, eplerenone (10 µM) and spironolactone (10 or 50 µM), did not inhibit these actions of 1 µM aldosterone, but the latter were prevented by 10 µM mifepristone, a glucocorticoid (GR) and progestogen receptor (PR) antagonist. Mifepristone also prevented the reduction of LPS-induced nitrite increase produced by 1 µM dexamethasone (GR agonist) and 10 µM progesterone (PR agonist). Spironolactone (10–50 µM) by itself decreased LPS-induced increases in nitrite and iNOS protein. Mifepristone (10 µM) partially reversed these effects of 10 µM spironolactone, but not those of 50 µM; the effects of 50 µM spironolactone were also unchanged when mifepristone was increased to 50 µM. CONCLUSIONS AND IMPLICATIONS This pharmacological profile suggests that aldosterone, and possibly 10 µM spironolactone, use mechanisms that are dependent on PR and/or GR, but not MR, to inhibit iNOS induction in RASMC. With 50 µM spironolactone, other inhibitory mechanisms requiring further investigation may become predominant. PMID:21649641

  6. 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.

  7. 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.

  8. 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

  9. High fat diet increases and the polyphenol, S17834, decreases acetylation of the SirT1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice

    PubMed Central

    Xu, Shanqin; Jiang, Bingbing; Hou, Xiuyun; Shi, Chaomei; Bachschmid, Markus; Zang, Mengwei; Verbeuren, Tony J.; Cohen, Richard A.

    2011-01-01

    Our purpose was to determine if high fat diet and treatment with a polyphenol regulates acetylation of lysine-382 of p53, the site regulated by sirtuin-1, and apoptosis in the endothelium of the atherosclerotic lesion-prone mouse aortic arch. In cultured endothelial cells two atherogenic stimuli, hydrogen peroxide and tumor necrosis factor-α, increased acetylation of p53 lysine-382, as well as caspase-3 cleavage, an indicator of apoptotic signaling. The polyphenol, S17834, significantly prevented these changes. In LDL receptor-deficient mice, a high fat diet increased, and treatment with S17834 attenuated early atherosclerotic lesions on the lesser curvature of the aortic arch. In wild type C57BL6 mice fed the same diet, no atherosclerotic lesions were observed in this lesion-prone area, but p53 acetylation and caspase-3 cleavage increased in the endothelium. In high fat fed mice, S17834 increased sirtuin-1 protein in the lesion-prone endothelium and prevented both the increase in p53 acetylation and caspase-3 cleavage without affecting blood lipids. These results indicate that high fat diet increases and S17834 decreases acetylation of p53 in lesion-prone aortic endothelial cells of normal mice independently of blood lipids, suggesting that the polyphenol may regulate endothelial cell p53 acetylation and apoptosis via local actions. PMID:21654327

  10. Endovascular Repair for Type A Aortic Dissection After Transcatheter Aortic Valve Replacement With a Medtronic CoreValve.

    PubMed

    Berfield, Kathleen K S; Sweet, Matthew P; McCabe, James M; Reisman, Mark; Mackensen, G Burkhard; Mokadam, Nahush A; Dean, Larry S; Smith, Jason W

    2015-10-01

    Transcatheter aortic valve replacement is being used with increasing frequency in patients with severe aortic stenosis who are otherwise deemed to be at high surgical risk. Aortic dissection is a rare complication of transcatheter aortic valve replacement and poses a unique management dilemma. We describe the treatment of an acute Stanford type A aortic dissection after transcatheter aortic valve replacement with a modified thoracic endovascular stent graft in a 95-year-old woman. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  11. Measurement of effective aortic valve area using three-dimensional echocardiography in children undergoing aortic balloon valvuloplasty for aortic stenosis.

    PubMed

    Bharucha, Tara; Fernandes, Fernanda; Slorach, Cameron; Mertens, Luc; Friedberg, Mark Kevin

    2012-04-01

    Pressure gradient is used for timing of balloon aortic valvuloplasty for aortic stenosis (AS) in children, but does not correlate well with outcome and is limited if ventricular function is poor. In adults, effective orifice area (EOA) is used to assess AS severity, but EOA by continuity equation or 2D echo is unreliable in children. Three-dimensional echocardiography (3DE) may reliably assess EOA but has not been studied in children. We assessed measurement of aortic valve EOA by 3DE in children with AS before and after balloon aortic valvuloplasty and compared results with change in aortic valve gradient. 3DE was performed at time of catheterization before and after balloon aortic valvuloplasty. Using 3DE multiplanar review mode, valve annulus diameter, area, and EOA were measured and compared with change in aortic gradient and degree of aortic insufficiency. Twenty-four 3DE studies in 12 children (mean age 4.4 ± 5.0 years) were analyzed. EOA was measurable in all. Catheter peak gradient decreased from 45 ± 10 to 26 ± 17 mmHg (P = 0.0018). 3DE EOA increased after balloon aortic valvuloplasty (0.59 ± 0.52 cm(2) vs 0.80 ± 0.70 cm(2) ; P = 0.03), without change in valve diameter. EOA change correlated with change in peak (r = 0.77; P = 0.005) and mean (r = 0.60; P = 0.03) aortic valve gradient post balloon aortic valvuloplasty. 3DE facilitates EOA measurement in pediatric AS and correlates with change in aortic valve gradient after balloon valvuloplasty. © 2011, Wiley Periodicals, Inc.

  12. Increased transcript level of poly(ADP-ribose) polymerase (PARP-1) in human tricuspid compared with bicuspid aortic valves correlates with the stenosis severity

    SciTech Connect

    Nagy, Edit; Caidahl, Kenneth; Franco-Cereceda, Anders; Baeck, Magnus

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer Oxidative stress has been implicated in the pathomechanism of calcific aortic valve stenosis. Black-Right-Pointing-Pointer We assessed the transcript levels for PARP-1 (poly(ADP-ribose) polymerase), acts as a DNA damage nick sensor in stenotic valves. Black-Right-Pointing-Pointer Early stage of diseased tricuspid valves exhibited higher mRNA levels for PARP-1 compared to bicuspid valves. Black-Right-Pointing-Pointer The mRNA levels for PARP-1 inversely correlated with the clinical stenosis severity in tricuspid valves. Black-Right-Pointing-Pointer Our data demonstrated that DNA damage pathways might be associated with stenosis severity only in tricuspid valves. -- Abstract: Oxidative stress may contribute to the hemodynamic progression of aortic valve stenosis, and is associated with activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) 1. The aim of the present study was to assess the transcriptional profile and the topological distribution of PARP-1 in human aortic valves, and its relation to the stenosis severity. Human stenotic aortic valves were obtained from 46 patients undergoing aortic valve replacement surgery and used for mRNA extraction followed by quantitative real-time PCR to correlate the PARP-1 expression levels with the non invasive hemodynamic parameters quantifying the stenosis severity. Primary isolated valvular interstitial cells (VICs) were used to explore the effects of cytokines and leukotriene C{sub 4} (LTC{sub 4}) on valvular PARP-1 expression. The thickened areas of stenotic valves with tricuspid morphology expressed significantly higher levels of PARP-1 mRNA compared with the corresponding part of bicuspid valves (0.501 vs 0.243, P = 0.01). Furthermore, the quantitative gene expression levels of PARP-1 were inversely correlated with the aortic valve area (AVA) (r = -0.46, P = 0.0469) and AVA indexed for body surface area (BSA) (r = -0.498; P = 0.0298) only in tricuspid aortic valves

  13. Effect of exercise training on eNOS expression, NO production and oxygen metabolism in human placenta.

    PubMed

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

    2013-01-01

    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. 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. 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). 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 exercise on the vascular and antioxidant system and in turn

  14. MicroRNA-19b is a potential biomarker of increased myocardial collagen cross-linking in patients with aortic stenosis and heart failure

    PubMed Central

    Beaumont, Javier; López, Begoña; Ravassa, Susana; Hermida, Nerea; José, Gorka San; Gallego, Idoia; Valencia, Félix; Gómez-Doblas, Juan José; de Teresa, Eduardo; Díez, Javier; González, Arantxa

    2017-01-01

    This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF. PMID:28091585

  15. CD16(+) monocyte subsets are increased in large abdominal aortic aneurysms and are differentially related with circulating and cell-associated biochemical and inflammatory biomarkers.

    PubMed

    Ghigliotti, Giorgio; Barisione, Chiara; Garibaldi, Silvano; Brunelli, Claudio; Palmieri, Daniela; Spinella, Giovanni; Pane, Bianca; Spallarossa, Paolo; Altieri, Paola; Fabbi, Patrizia; Sambuceti, Gianmario; Palombo, Domenico

    2013-01-01

    Proinflammatory components are present in abdominal aortic aneurysm (AAA). Circulating monocytes display heterogeneity, and three subsets have been identified, based on the differential expression for CD14 and CD16 receptors: CD14(+)CD16(−), classical, CD14(+)CD16(+), intermediate and CD14(dim)CD16(+), non-classical monocytes. Increased proinflammatory CD16+ monocytes with high expression of CD143 are present in CKD patients. D-dimer is increased in AAA patients, and might contribute to the pro-inflammatory response associated to circulating monocytes. We aimed to investigate the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and monocyte CD143 expression in AAA patients, and their relationship with Ddimer, eGFR and other inflammatory parameters. Blood from 74 AAA patients and 30 healthy controls was analyzed to determine the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and the monocyte CD143 expression by means of flow-cytometry. AAA patients had expanded CD16+ subsets (CD14(+)CD16(+): 7.66 ± 0.31% vs 5.42 ± 0.27%; CD14(dim)CD16(+): 7.43 ± 0.48% vs 5.54 ± 0.38%, AAA vs controls, mean ± SE, both p < 0.05). CD14(+)CD16(+) cells were associated to D-dimer and age, and to reduced eGFR. CD14(dim)CD16(+) cells were associated to uric acid, surface CD143, and reduced count of total leukocytes and neutrophils. Within AAA patients, the two CD16(+) subsets and the monocyte CD143 expression display different relationships with D-dimer, parameters of renal function and circulating biochemical and inflammatory biomarkers.

  16. MicroRNA-19b is a potential biomarker of increased myocardial collagen cross-linking in patients with aortic stenosis and heart failure.

    PubMed

    Beaumont, Javier; López, Begoña; Ravassa, Susana; Hermida, Nerea; José, Gorka San; Gallego, Idoia; Valencia, Félix; Gómez-Doblas, Juan José; de Teresa, Eduardo; Díez, Javier; González, Arantxa

    2017-01-16

    This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF.

  17. Aortic Valve Adaptation to Aortic Root Dilatation

    PubMed Central

    Kim, Dae-Hee; Handschumacher, Mark D.; Levine, Robert A.; Sun, Byung Joo; Jang, Jeong Yoon; Yang, Dong Hyun; Kang, Joon-Won; Song, Jong-Min; Kang, Duk-Hyun; Lim, Tae-Hwan; Song, Jae-Kwan

    2015-01-01

    Background The 3-dimensional relationship between aortic root and cusp is essential to understand the mechanism of aortic regurgitation (AR) because of aortic root dilatation (ARD). We sought to test the hypothesis that the stretched cusps in ARD enlarge to compensate for ARD. Methods and Results Computed tomography imaged 92 patients (57 with ARD, 29 with moderate to severe AR, 28 without significant AR) and 35 normal controls. Specialized 3-dimensional software measured individual cusp surface areas relative to maximal mid-sinus cross-sectional area and minimal 3-dimensional annular area, coaptation area fraction, and asymmetry of sinus volumes and intercommissural distances. Total open cusp surface area increased (P<0.001) from 7.6±1.4 cm2/m2 in normals to 12.9±2.2 cm2/m2 in AR-negative and 15.2±3.3 cm2/m2 in AR-positive patients. However, the ratio of closed cusp surface area to maximal mid-sinus area, reflecting cusp adaptation, decreased from normals to AR-negative to AR-positive patients (1.38±0.20, 1.15±0.15, 0.88±0.15; P<0.001), creating the lowest coaptation area fraction. Cusp distensibility (closed diastolic versus open area) decreased from 20% in controls and AR-negative patients to 5% in AR-positive patients (P<0.001). Multivariate determinants of AR and coaptation area fraction reflected both sinus size and cusp-to-annular adaptation. ARD was also progressively asymmetrical with root size, and individual cusp surface areas failed to match this asymmetry. Conclusions Aortic cusp enlargement occurs in ARD, but cusp adaptation and distensibility become limited in prominent, asymmetrical ARD, leading to AR. Optimal AR repair tailored to individual patient anatomy can benefit from appreciating valve adaptation and 3-dimensional relationships; understanding cusp adaptation mechanisms may ultimately provide therapeutic opportunities to improve such compensation. PMID:25051951

  18. Beneficial effects of the active principle component of Korean cabbage kimchi via increasing nitric oxide production and suppressing inflammation in the aorta of apoE knockout mice.

    PubMed

    Noh, Jeong Sook; Choi, Yung Hyun; Song, Yeong Ok

    2013-01-14

    The present study investigated the effects of 3'-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), the active principle compound of kimchi, on vascular damage in the experimental atherosclerotic animal. HDMPPA was administrated by an intraperitoneal injection of 10 mg/kg per d for 8 weeks to apoE knockout (KO) mice with an atherogenic diet containing 1 % cholesterol, and its effects were compared with vehicle-treated control mice. HDMPPA increased NO content in the aorta, accompanied by a decrease in reactive oxygen species (ROS) concentration. Furthermore, in the HDMPPA-treated group, aortic endothelial NO synthase (eNOS) expression was up-regulated compared with the control group. These results suggested that HDMPPA could maintain NO bioavailability through an increasing eNOS expression and preventing NO degradation by ROS. Furthermore, HDMPPA treatment in apoE KO mice inhibited eNOS uncoupling through an increase in vascular tetrahydrobiopterin content and a decrease in serum asymmetric dimethylarginine levels. Moreover, HDMPPA ameliorates inflammatory-related protein expression in the aorta of apoE KO mice. Therefore, the present study suggests that HDMPPA, the active compound of kimchi, a Korean functional food, may exert its vascular protective effect through the preservation of NO bioavailability and suppression of the inflammatory response.

  19. Surgeon leadership in the coding, billing, and contractual negotiations for fenestrated endovascular aortic aneurysm repair increases medical center contribution margin and physician reimbursement.

    PubMed

    Aiello, Francesco; Durgin, Jonathan; Daniel, Vijaya; Messina, Louis; Doucet, Danielle; Simons, Jessica; Jenkins, James; Schanzer, Andres

    2017-10-01

    Fenestrated endovascular aneurysm repair (FEVAR) allows endovascular treatment of thoracoabdominal and juxtarenal aneurysms previously outside the indications of use for standard devices. However, because of considerable device costs and increased procedure time, FEVAR is thought to result in financial losses for medical centers and physicians. We hypothesized that surgeon leadership in the coding, billing, and contractual negotiations for FEVAR procedures will increase medical center contribution margin (CM) and physician reimbursement. At the UMass Memorial Center for Complex Aortic Disease, a vascular surgeon with experience in medical finances is supported to manage the billing and coding of FEVAR procedures for medical center and physician reimbursement. A comprehensive financial analysis was performed for all FEVAR procedures (2011-2015), independent of insurance status, patient presentation, or type of device used. Medical center CM (actual reimbursement minus direct costs) was determined for each index FEVAR procedure and for all related subsequent procedures, inpatient or outpatient, 3 months before and 1 year subsequent to the index FEVAR procedure. Medical center CM for outpatient clinic visits, radiology examinations, vascular laboratory studies, and cardiology and pulmonary evaluations related to FEVAR were also determined. Surgeon reimbursement for index FEVAR procedure, related adjunct procedures, and assistant surgeon reimbursement were also calculated. All financial analyses were performed and adjudicated by the UMass Department of Finance. The index hospitalization for 63 FEVAR procedures incurred $2,776,726 of direct costs and generated $3,027,887 in reimbursement, resulting in a positive CM of $251,160. Subsequent related hospital procedures (n = 26) generated a CM of $144,473. Outpatient clinic visits, radiologic examinations, and vascular laboratory studies generated an additional CM of $96,888. Direct cost analysis revealed that grafts

  20. 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.

  1. 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

  2. Chronic high-fat diet-induced obesity decreased survival and increased hypertrophy of rats with experimental eccentric hypertrophy from chronic aortic regurgitation.

    PubMed

    Dhahri, Wahiba; Drolet, Marie-Claude; Roussel, Elise; Couet, Jacques; Arsenault, Marie

    2014-09-24

    The composition of a diet can influence myocardial metabolism and development of left ventricular hypertrophy (LVH). The impact of a high-fat diet in chronic left ventricular volume overload (VO) causing eccentric LVH is unknown. This study examined the effects of chronic ingestion of a high-fat diet in rats with chronic VO caused by severe aortic valve regurgitation (AR) on LVH, function and on myocardial energetics and survival. Male Wistar rats were divided in four groups: Shams on control or high-fat (HF) diet (15 rats/group) and AR rats fed with the same diets (ARC (n = 56) and ARHF (n = 32)). HF diet was started one week before AR induction and the protocol was stopped 30 weeks later. As expected, AR caused significant LV dilation and hypertrophy and this was exacerbated in the ARHF group. Moreover, survival in the ARHF group was significantly decreased compared the ARC group. Although the sham animals on HF also developed significant obesity compared to those on control diet, this was not associated with heart hypertrophy. The HF diet in AR rats partially countered the expected shift in myocardial energy substrate preference usually observed in heart hypertrophy (from fatty acids towards glucose). Systolic function was decreased in AR rats but HF diet had no impact on this parameter. The response to HF diet of different fatty acid oxidation markers as well as the increase in glucose transporter-4 translocation to the plasma membrane compared to ARC was blunted in AR animals compared to those on control diet. HF diet for 30 weeks decreased survival of AR rats and worsened eccentric hypertrophy without affecting systolic function. The expected adaptation of myocardial energetics to volume-overload left ventricle hypertrophy in AR animals seemed to be impaired by the high-fat diet suggesting less metabolic flexibility.

  3. An ethanolic extract of Lindera obtusiloba stems causes NO-mediated endothelium-dependent relaxations in rat aortic rings and prevents angiotensin II-induced hypertension and endothelial dysfunction in rats.

    PubMed

    Lee, Jung-Ok; Oak, Min-Ho; Jung, Sang Hoon; Park, Dong Hyun; Auger, Cyril; Kim, Kyoung Rak; Lee, Seung-Woo; Schini-Kerth, Valérie B

    2011-06-01

    Lindera obtusiloba is a medical herb traditionally used in Asia for the improvement of blood circulation, treatment of inflammation, and prevention of liver damage. The possibility that L. obtusiloba affects vascular reactivity remains to be examined. Therefore, the aim of the present study was to evaluate both the in vitro and in vivo vascular effects of an ethanolic extract of L. obtusiloba stems (LOE). Vascular reactivity was assessed in organ chambers using rat aortic rings and the activation of endothelial NO synthase (eNOS) in cultured bovine aortic endothelial cells. LOE induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (N (ω)-nitro-L: -arginine) and guanylyl cyclase (1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-L-one), significantly reduced by inhibitors of PI3 kinase (wortmannin and LY294002), and not affected by inhibitors of cyclooxygenase (indomethacin) and endothelium-derived hyperpolarizing factor-mediated responses (charybdotoxin plus apamin). LOE prevented contractile responses to phenylephrine and angiotensin II in rings with endothelium, but not in those without endothelium. LOE caused a concentration-dependent phosphorylation of Akt at Serine473 and eNOS at Serine1177 in endothelial cells. Thereafter, the vasoprotective effect of LOE was investigated in an experimental model of hypertension in rats. Intake of LOE prevented the angiotensin II-induced increase in systolic blood pressure, and endothelial dysfunction to acetylcholine and oxidative stress as assessed using dihydroethidine in aortic rings. The present findings indicate that LOE has vasoprotective and antihypertensive properties most likely by stimulating the endothelial formation of NO and inhibiting oxidative stress.

  4. 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

  5. Melatonin and vitamin C ameliorate alcohol-induced oxidative stress and eNOS expression in rat kidney.

    PubMed

    Sönmez, Mehmet Fatih; Narin, Figen; Akkuş, Derya; Türkmen, Ayşegül Burçin

    2012-01-01

    The aim of this study was to investigate the preventive effects of melatonin and vitamin C as antioxidants on renal injury in chronic alcohol consumption. A total of 24 adult male Wistar rats weighing 200-250 g were used in the study. Rats were divided into four equal groups. Group I (control): rats were not fed on alcohol; Group II: rats were fed on alcohol; Group III: rats were fed on alcohol and 40 mg/kg vitamin C; and Group IV: rats were fed on alcohol and 4 mg/kg melatonin. Light microscopic examination revealed atrophic renal corpuscles, dilatation and congestion of the peritubular vessels, and renal corpuscles with obscure Bowman's space and a few foamy-appearing tubules due to alcohol consumption were observed. Expression of endothelial nitric oxide synthase (eNOS) was localized to glomerulus, distal, and collector tubules. eNOS staining decreased in alcohol treatment group and melatonin and vitamin C encore increased expression pattern of eNOS. Alcohol consumption increased malondialdehyde (MDA) level and superoxide dismutase (SOD) and catalase (CAT) activities significantly in the alcohol consumption groups compared with that in the control group, while in melatonin give group just MDA level was decreased statistically significant and SOD and CAT activities were also decreased numerically compared with the alcohol consumption groups. These results indicated that chronic alcohol consumption caused renal damage by increased lipid peroxidation and melatonin and vitamin C administration produced in some degree protection against alcohol-induced damage.

  6. Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction.

    PubMed

    He, Zhihui; Chen, Yan; Hou, Can; He, Wenfang; Chen, Ping

    2017-07-02

    BACKGROUND Endothelial dysfunction is an important pathophysiologic feature in many smoke-related diseases. Endothelial progenitor cells (EPCs) are the precursors of endothelial cells and play a fundamental role in the maintenance of endothelial integrity and function. Endothelial nitric oxide synthase (eNOS) is the dominant NOS isoform in the vasculature and plays a central role in the maintenance of endothelial homeostasis. p16(INK4a) is a cyclin-dependent kinase inhibitor and could be regarded as a major dominant senescence gene. The present study aimed to determine whether the expression of eNOS and p16(INK4a) in EPCs is related to EPCs function and the possible epigenetic mechanism, if any. MATERIAL AND METHODS We investigated EPCs capacity for proliferation, adhesion, and secretion, and the expression of eNOS and p16(INK4a) in EPCs which were altered by cigarette smoke extract (CSE) in vitro. Furthermore, Decitabine (Dec), an agent of demethylation, was used to examine whether it could alter the changes induced by CSE. RESULTS The present study demonstrated that EPCs altered by CSE in vitro displayed decreased capacities of proliferation, adhesion, and secretion, which was accompanied by decreased eNOS expression and increased p16(INK4a) expression in EPCs. Furthermore, Dec could alleviate the changes in the expression of eNOS and p16(INK4a), and protect against the EPCs dysfunction caused by CSE. CONCLUSIONS The decreased eNOS expression and increased p16(INK4a) expression was associated with dysfunction of EPCs caused by CSE. The mechanism of methylation, one of the most common epigenetic mechanism, may be involved in the EPCs dysfunction caused by CSE.

  7. 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.

  8. 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

  9. 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.

  10. The association between aortic regurgitation and undetermined embolic infarction with aortic complex plaque.

    PubMed

    Kim, Dae-Won; Cho, Jung Sun; Cho, Jae Yeong; Kim, Kye Hun; Sun, Byung Joo; Park, Jae-Hyeong

    2017-01-01

    Background Retrograde embolism from the descending thoracic aorta is one possible cause of undetermined ischemic stroke. Significant aortic regurgitation can increase the amount of reversed flow in the thoracic aorta and thus is associated with an increased incidence of stroke. Aims This study aimed to examine the association between significant aortic regurgitation and undetermined embolic infarction with aortic complex plaques. Methods This study included 380 patients with undetermined embolic stroke who did not have abnormal flow such as atrial septal defect, patent foramen ovale determined by agitated saline bubble test, intracardiac thrombi on transesophageal echocardiography, atrial fibrillation, or small vessel stroke, cerebral artery, and carotid stenosis on the brain magnetic resonance imaging. The patients were divided into the complex aortic plaques group (n = 63), which was defined as having plaque with >4 mm in thickness, ulceration, or high mobility, and the no complex aortic plaques group (n = 317). Results Transesophageal echocardiography with a bubble study, brain MRI, and laboratory tests were performed for all subjects. Significant aortic regurgitation was more prevalent in patients with undetermined embolic stroke and complex aortic plaques than in patients without complex aortic plaques (adjusted OR = 4.981; 95% CI = 1.323-18.876, P = 0.028). In addition, the distribution of complex aortic plaques according to the severity of aortic regurgitation in patients with undetermined embolic stroke had a tendency toward the ascending thoracic aorta and proximal aortic arch. Conclusions Significant aortic regurgitation may affect undetermined embolic stroke in patients with complex aortic plaques.

  11. Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance.

    PubMed

    den Hartog, Alexander W; Franken, Romy; de Witte, Piet; Radonic, Teodora; Marquering, Henk A; van der Steen, Wessel E; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Zwinderman, Aeilko H; Mulder, Barbara J M; Groenink, Maarten

    2013-11-01

    To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome. The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated. Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13). Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1. RSNA, 2013

  12. Ketamine upregulates eNOS expression in human astroglial A172 cells: Possible role in its antidepressive properties.

    PubMed

    Yuhas, Yael; Ashkenazi, Shai; Berent, Eva; Weizman, Abraham

    2017-04-15

    Ketamine is a potent anti-depressive agent. Nitric oxide plays an essential role in neuronal transmission and cerebral blood flow and has been implicated in the pathophysiology of major depressive disorder as well as cardiovascular functioning. We investigated the effect of ketamine on eNOS expression in human A172 astroglial cells. Ketamine (50-500μM) increased eNOS expression at 4-24h in a concentration-dependent manner. This effect was mediated by NMDA receptor, Akt inhibition and ERK1/2 activation and was synergistically augmented by rapamycin. The combined effect on the vascular, immune and neuronal systems may be relevant to the rapid antidepressive effect of ketamine. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. 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…

  14. 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

  15. Current aortic endografts for the treatment of abdominal aortic aneurysms.

    PubMed

    Colvard, Benjamin; Georg, Yannick; Chakfe, Nabil; Swanstrom, Lee

    2016-05-01

    Endovascular Aneurysm Repair is a widely adopted method of treatment for patients with abdominal aortic aneurysms. The minimally invasive approach offered with EVAR has become popular not only among physicians and patients, but in the medical device industry as well. Over the past 25 years the global market for aortic endografts has increased rapidly, resulting in a wide range of devices from various companies. Currently, there are seven endografts approved by the FDA for the treatment of abdominal aortic aneurysms. These devices offer a wide range of designs intended to increase inclusion criteria while decreasing technical complications such as endoleak and migration. Despite advances in device design, secondary interventions and follow-up requirements remain a significant issue. New devices are currently being studied in the U.S. and abroad and may significantly reduce complications and secondary interventions.

  16. Aortic valve replacement in rheumatoid aortic incompetence.

    PubMed Central

    Devlin, A B; Goldstraw, P; Caves, P K

    1978-01-01

    Rheumatoid aortic valve disease is uncommon. and there are few reports of valve replacement in this condition. Aortic valve replacement and partial pericardiectomy was performed in a patient with acute rheumatoid aortitis and aortic incompetence. Previous reports suggest that any patient with rheumatoid arthritis who develops cardiac symptoms should be carefully assessed for surgically treatable involvement of the pericardium or heart valves. Images PMID:725829

  17. eNOS gene haplotype is indirectly associated with the recovery of cardiovascular autonomic modulation from exercise.

    PubMed

    Silva, Bruno M; Barbosa, Thales C; Neves, Fabricia J; Sales, Allan K; Rocha, Natalia G; Medeiros, Renata F; Pereira, Felipe S; Garcia, Vinicius P; Cardoso, Fabiane T; Nobrega, Antonio C L

    2014-12-01

    Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene decrease expression and activation of eNOS in vitro, which is associated with lower post-exercise increase in vasodilator reactivity in vivo. However, it is unknown whether such polymorphisms are associated with other eNOS-related phenotypes during recovery from exercise. Therefore, we investigated the impact of an eNOS haplotype containing polymorphic alleles at loci -786 and 894 on the recovery of cardiovascular autonomic function from exercise. Sedentary, non-obese, healthy subjects were enrolled [n = 107, age 32 ± 1 years (mean ± SEM)]. Resting autonomic modulation (heart rate variability, systolic blood pressure variability, and spontaneous baroreflex sensitivity) and vascular reactivity (forearm hyperemic response post-ischemia) were assessed at baseline, 10, 60, and 120 min after a maximal cardiopulmonary exercise test. Besides, autonomic function was assessed by heart rate recovery (HRR) immediately after peak exercise. Haplotype analysis showed that vagal modulation (i.e., HF n.u.) was significantly higher, combined sympathetic and vagal modulation (i.e., LF/HF) was significantly lower and total blood pressure variability was significantly lower post-exercise in a haplotype containing polymorphic alleles (H2) compared to a haplotype with wild type alleles (H1). HRR was similar between groups. Corroborating previous evidence, H2 had significantly lower post-exercise increase in vasodilator reactivity than H1. In conclusion, a haplotype containing polymorphic alleles at loci -786 and 894 had enhanced recovery of autonomic modulation from exercise, along with unchanged HRR, and attenuated vasodilator reactivity. Then, these results suggest an autonomic compensatory response of a direct deleterious effect of eNOS polymorphisms on the vascular function. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Hypercholesterolemia-induced erectile dysfunction: endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase

    PubMed Central

    Musicki, Biljana; Liu, Tongyun; Lagoda, Gwen A.; Strong, Travis D.; Sezen, Sena F.; Johnson, Justin M.; Burnett, Arthur L.

    2010-01-01

    INTRODUCTION Hypercholesterolemia induces erectile dysfunction (ED) mostly by increasing oxidative stress and impairing endothelial function in the penis, but the mechanisms regulating reactive oxygen species (ROS) production in the penis are not understood. AIMS We evaluated whether hypercholesterolemia activates nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the penis, providing an initial source of ROS to induce endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction resulting in ED. METHODS Low-density-lipoprotein receptor (LDLR)–null mice were fed Western diet for 4 weeks to induce early-stage hyperlipidemia. Wild type (WT) mice fed regular chow served as controls. Mice received NAD(P)H oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Erectile function was assessed in response to cavernous nerve electrical stimulation. Markers of endothelial function (phospho [P]-vasodilator-stimulated-protein [VASP]-Ser-239), oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NAD[P]H oxidase subunits p67phox, p47phox, and gp91phox), P-eNOS-Ser-1177, and eNOS were measured by Western blot in penes. MAIN OUTCOME MEASURES Molecular mechanisms of ROS generation and endothelial dysfunction in hypercholesterolemia-induced ED. RESULTS Erectile response was significantly (P<0.05) reduced in hypercholesterolemic LDLR-null mice compared to WT mice. Relative to WT mice, hypercholesterolemia increased (P<0.05) protein expressions of NAD(P)H oxidase subunits p67phox, p47phox and gp91phox, eNOS uncoupling, and 4-HNE-modified proteins, and reduced (P<0.05) P-VASP-Ser-239 expression in the penis. Apocynin treatment of LDLR-null mice preserved (P<0.05) maximal intracavernosal pressure, and reversed (P < 0.05) the abnormalities in protein expressions of gp67phox and gp47phox, 4-HNE, P-VASP-Ser-239, and eNOS uncoupling in the penis. Apocynin treatment of WT mice did not affect any of these parameters

  19. Aortic aneurysm repair - endovascular

    MedlinePlus

    ... Endovascular aneurysm repair - aorta; AAA repair - endovascular; Repair - aortic aneurysm - endovascular ... leaking or bleeding. You may have an abdominal aortic aneurysm that is not causing any symptoms or problems. ...

  20. Abdominal aortic aneurysm

    MedlinePlus

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

  1. CT in aortic trauma

    SciTech Connect

    Heiberg, E.; Wolverson, M.K.; Sundaram, M.; Shields, J.B.

    1983-06-01

    A diagnosis of aortic transection was made at computed tomography (CT) in four of 10 patients with acute multiple trauma suspected of having thoracic aortic injuries. There were no false-negative or false-positive examinations. The CT findings of an injured aorta were (1) false aneurysm, (2) linear lucency within the opacified aortic lumen caused by the torn edge of the aortic wall, (3) marginal irregularity of the opacified aortic lumen, (4) periaortic or intramural aortic hematoma, and (5) dissection. The extent of associated mediastinal hemorrhage and the amount of blood in the pleural space were not useful as indicators of aortic injury. Similarly, shift of the trachea and esophagus or absence thereof was found in patients with or without aortic tear.

  2. Aortic dissection (image)

    MedlinePlus

    Aortic dissection is a condition in which there is bleeding into and along the wall of the aorta (the ... the inner wall of the artery. Although aortic dissection can affect anybody, it is most often seen ...

  3. 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 ...

  4. Increasing Incidence of Midterm and Long-Term Complications After Endovascular Graft Repair of Abdominal Aortic Aneurysms: A Note of Caution Based on a 9-Year Experience

    PubMed Central

    Ohki, Takao; Veith, Frank J.; Shaw, Palma; Lipsitz, Evan; Suggs, William D.; Wain, Reese A.; Bade, Maseer; Mehta, Manish; Cayne, Neal; Cynamon, Jacob; Valldares, Jennifer; McKay, Jamie

    2001-01-01

    Objective To analyze the late complications after endovascular graft repair of elective abdominal aortic aneurysms (AAAs) at the authors’ institution since November 1992. Summary Background Data Recently, the use of endovascular grafts for the treatment of AAAs has increased dramatically. However, there is little midterm or long-term proof of their efficacy. Methods During the past 9 years, 239 endovascular graft repairs were performed for nonruptured AAAs, many (86%) in high-risk patients or in those with complex anatomy. The grafts used were Montefiore (n = 97), Ancure/EVT (n = 14), Vanguard (n = 16), Talent (n = 47), Excluder (n = 20), AneuRx (n = 29), and Zenith (n = 16). All but the AneuRx and Ancure repairs were performed as part of a U.S. phase 1 or phase 2 clinical trial under a Food and Drug Administration investigational device exemption. Procedural outcomes and follow-up results were prospectively recorded. Results The major complication and death rates within 30 days of endovascular graft repair were 17.6% and 8.5%, respectively. The technical success rate with complete AAA exclusion was 88.7%. During follow-up to 75 months (mean ± standard deviation, 15.7 ± 6.3 months), 53 patients (22%) died of unrelated causes. Two AAAs treated with endovascular grafts ruptured and were surgically repaired, with one death. Other late complications included type 1 endoleak (n = 7), aortoduodenal fistula (n = 2), graft thrombosis/stenosis (n = 7), limb separation or fabric tear with a subsequent type 3 endoleak (n = 1), and a persistent type 2 endoleak (n = 13). Secondary intervention or surgery was required in 23 patients (10%). These included deployment of a second graft (n = 4), open AAA repair (n = 5), coil embolization (n = 6), extraanatomic bypass (n = 4), and stent placement (n = 3). Conclusion With longer follow-up, complications occurred with increasing frequency. Although most could be managed with some form of endovascular reintervention, some

  5. Betaxolol stimulates eNOS production associated with LOX-1 and VEGF in Dahl salt-sensitive rats.

    PubMed

    Kobayashi, Naohiko; Yoshida, Kohtaro; Mita, Shin-ichiro; Honda, Takeaki; Hara, Kazuyoshi; Nakano, Shigefumi; Tsubokou, Yusuke; Matsuoka, Hiroaki

    2004-07-01

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor (VEGF) may play key roles in atherosclerosis, and have been shown to regulate nitric oxide (NO) production. However, the molecular mechanisms by which betaxolol, a specific beta 1-antagonist, stimulates endothelial NO synthase (eNOS) expression associated with LOX-1 and VEGF are unclear. We hypothesized that in the left ventricle of Dahl salt-sensitive (DS) rats, betaxolol reduces production of LOX-1 by suppressing NAD(P)H oxidase p47phox expression; betaxolol stimulates eNOS production associated with expression of VEGF and LOX-1; and betaxolol inhibits adhesion molecule and signal transduction, which may be involved in cardiovascular remodeling. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e. at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy was noted. Betaxolol (0.9 mg/kg per day) was administered to 6-week-old DS rats for 5 weeks until the onset of left ventricular hypertrophy stage. Decreased expression of eNOS and VEGF in DS rats was increased by betaxolol. Upregulated LOX-1, NAD(P)H oxidase p47phox, intercellular and vascular cell adhesion molecule-1 expression and phosphorylations of p38 mitogen-activated protein kinase and p65 nuclear factor-kappa B activity were inhibited by betaxolol. Betaxolol administration resulted in significant improvement of cardiovascular remodeling and suppression of transforming growth factor-beta 1 and type I collagen expression. These results suggest that cardioprotective effects of betaxolol may stimulate eNOS production associated with VEGF and LOX-1, and inhibit adhesion molecule and signal transduction in DS rats.

  6. 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

  7. High salt medium activates RhoA/ROCK and downregulates eNOS expression via the upregulation of ADMA.

    PubMed

    Cao, Yu; Fang, Yuan; Mu, Jianjun; Liu, Xiaohong

    2016-07-01

    Endothelial dysfunction has an important role in the development and progression of salt-sensitive hypertension. Asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS), has been demonstrated to be involved in the pathophysiological processes of endothelial dysfunction and salt‑sensitive hypertension. However, it is currently unclear how high salt intake may induce these processes. The present study investigated the effects of high salt medium on ADMA, endothelial NOS (eNOS) and the Ras homolog gene family, member A (RhoA)/Rho-associated protein kinase (ROCK) pathway in the EA.hy926 umbilical vein cell line. The results demonstrated that high salt medium significantly increased the concentration of ADMA, the expression of protein arginine methyltransferase 1 (PRMT‑1) and RhoA, and the activity of ROCK, and downregulated the expression of eNOS. Knockdown of PRMT-1 with small interfering RNA (siRNA) significantly abrogated the aforementioned effects. These results indicated that ADMA has a key role in high salt‑mediated activation of the RhoA/ROCK pathway and inhibition of eNOS biosynthesis. siRNA‑PRMT‑1 may be considered a novel remedy for the treatment of endothelial dysfunction.

  8. Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice.

    PubMed

    Buday, Anna; Orsy, Petra; Godó, Mária; Mózes, Miklós; Kökény, Gábor; Lacza, Zsombor; Koller, Akos; Ungvári, Zoltán; Gross, Marie-Luise; Benyó, Zoltán; Hamar, Péter

    2010-08-01

    The role of circulating, systemic TGF-beta levels in endothelial function is not clear. TGF-beta(1) may cause endothelial dysfunction in apolipoprotein E-deficient (apoE(-/-)) mice via stimulation of reactive oxygen species (ROS) production by the NADPH oxidase (NOX) system and aggravate aortic and heart remodeling and hypertension. Thoracic aorta (TA) were isolated from 4-mo-old control (C57Bl/6), apoE(-/-), TGF-beta(1)-overexpressing (TGFbeta(1)), and crossbred apoE(-/-) x TGFbeta(1) mice. Endothelium-dependent relaxation was measured before and after incubation with apocynin (NOX inhibitor) or superoxide dismutase (SOD; ROS scavenger). Superoxide production within the vessel wall was determined by dihydroethidine staining under confocal microscope. In 8-mo-old mice, aortic and myocardial morphometric changes, plaque formation by en face fat staining, and blood pressure were determined. Serum TGF-beta(1) levels (ELISA) were elevated in TGFbeta(1) mice without downregulation of TGF-beta-I receptor (immunohistochemistry). In the aortic wall, superoxide production was enhanced and NO-dependent relaxation diminished in apoE(-/-) x TGFbeta(1) mice but improved significantly after apocynin or SOD. Myocardial capillary density was reduced, fibrocyte density increased, aortic wall was thicker, combined lesion area was greater, and blood pressure was higher in the apoE(-/-) x TGFbeta vs. C57Bl/6 mice. Our results demonstrate that elevated circulating TGF-beta(1) causes endothelial dysfunction through NOX activation-induced oxidative stress, accelerating atherosclerosis and hypertension in apoE(-/-) mice. These findings may provide a mechanism explaining accelerated atherosclerosis in patients with elevated plasma TGFbeta(1).

  9. Identification of chicken eNOS gene and differential expression in highland versus lowland chicken breeds.

    PubMed

    Peng, J F; Ling, Y; Gou, W Y; Zhang, H; Wu, C X

    2012-09-01

    Nitric oxide (NO), an endothelium-derived relaxing factor, is synthesized from l-arginine by endothelial nitric oxide synthase (eNOS) in the endothelium. The objective of the present study was to preliminarily illuminate the expression of the eNOS gene in hypoxic adaptation of chicken embryonic development. The eNOS expression profiles between the Tibet and Shouguang chickens incubated under both normoxic and hypoxic conditions were detected by TaqMan real-time PCR. In this study, the chicken eNOS gene was found by both in silico cloning and RACE approaches. From the eNOS gene, we obtained a 3,310-bp mRNA sequence and a 10,666-bp DNA sequence and discovered that it was located on chicken chromosome 2 and had 7 unique transcripts. eNOS mRNA was detected in abundant amounts in some chick embryo organs (i.e., heart, liver, chorio-allantoic membrane, and lung), and expressed stably with the lowest levels in the brain. We observed that when exposed to hypoxia (13% O(2)) different embryo organ tissues had various sensitivities to hypoxia as determined by their eNOS expression profiles. Compared with the Shouguang chicken, the eNOS expression in the Tibet chicken was higher in the lung and liver, lower in the heart, and similar in the brain. In chorio-allantoic membranes, eNOS expression was higher in the Shouguang chicken than the Tibet chicken under hypoxic conditions, but not markedly different under normoxic conditions. The differences of eNOS expression between the 2 breeds may be relative to the hypoxic adaptation ability in Tibet chickens during embryonic development. This work will provide reference for future studies on the role of eNOS in hypoxic adaptation and response.

  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. 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

  12. The significance of aortic valve calcification in patients with bicuspid aortic valve disease.

    PubMed

    Ren, Xinshuang; Zhang, Minghui; Liu, Kun; Hou, Zhihui; Gao, Yang; Yin, Weihua; Wang, Zhiqiang; Li, Zhennan; Lu, Bin

    2016-03-01

    Bicuspid aortic valve (BAV) is a common congenital heart disease. Our study was to analyze clinical features of BAV and evaluate whether aortic valve calcium score (AVCS) was a reliable marker for aortic stenosis (AS) in patients with BAV. 101 patients with BAV who both underwent echocardiology and cardiac computed tomography (CT) scan in our institution were included. Basic clinical data, haemodynamic feature, aortic valve and coronary calcium score were collected and compared among patients with different valve function and different degree of AS. Risk factors related to severe AS were evaluated by logistic regression, and a receiver operative characteristic curve was used to determine the cutoff calcium score greater than which the diagnosis of severe AS was optimized. Patients with aortic regurgitation (AR) were younger and demonstrated larger aortic annulus and sinus compared with patients with other valve dysfunction. Aortic valve calcium score was higher in patients with AS than with AR. For patients with different degree of AS, there were statistical significances in the value of age, aortic valve calcium score and coronary calcium score. AVCS was positively related to severe AS with an odd ratio of 1.286 (95% CI 1.099-1.504) by every 300 points increase. AVCS was also a strong predictor for severe AS with area under the curve 0.855 with a cutoff value of 897 (sensitivity 86.7%, specificity 72.2%). Conclusively, aortic calcium score calculated by quantitative CT is a reliable marker in evaluating severity of AS.

  13. High pacing rates for management of aortic insufficiency after balloon aortic valvuloplasty or transcatheter aortic valve replacement.

    PubMed

    Ali, Omar; Salinger, Michael H; Levisay, Justin P; Feldman, Ted

    2014-01-01

    Aortic insufficiency (AI) after transcatheter aortic valve replacement (TAVR) is difficult to manage when associated with congestive heart failure. AI after balloon aortic valvuloplasty (BAV) may be catastrophic, especially in patients who are not candidates for TAVR. We describe the use of urgent temporary pacing, followed by permanent pacing, to increase the heart rate to diminish diastolic filling time for the short term management of AI after BAV or TAVR. The strategy is particularly useful in patients who already have permanent pacemakers, which are common in this population.

  14. Increased superoxide dismutase and Na+, K+-ATPase activities in aortic strips from potassium-adapted rats: implication for altered vascular reactivity.

    PubMed

    Ozolua, Raymond I; Omogbai, Eric K I; Ebeigbe, Anthony B; Asagba, Samuel O

    2003-05-01

    The contributions of superoxide dismutase (SOD) and Na(+), K(+)-ATPase to the altered vascular reactivity in potassium-adapted rats were investigated to test the hypothesis that smooth muscle hyperpolarisation may be involved. Isometric contractions to noradrenaline (NA), 5-hydroxytryptamine (5-HT), and relaxations to acetylcholine (ACh), levcromakalim (LEV) and sodium nitroprusside (SNP), were measured in aortic rings from potassium-adapted rats. Pieces of the aortae were also excised from the animals and assayed for SOD and Na(+), K(+)-ATPase. Maximum contractile responses were significantly attenuated (P<0.05) in aortic rings from the potassium-adapted rats to NA and 5-HT, while relaxations were also significantly augmented (P<0.05) in the same rings to LEV and SNP, but not to ACh. Both SOD and Na(+), K(+)-ATPase activities were significantly higher (P<0.05) in the aortae from the potassium-adapted rats compared to controls. It is concluded that the alteration in vascular smooth muscle reactivity may be due to hyperpolarisation caused by the activities of SOD and Na(+), K(+)-ATPase.

  15. 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

  16. Morphometric evaluation of the aortic root in stillborns.

    PubMed

    da Fonseca Ferraz, Mara Lúcia; Franco, Calline Alves; Juliano, Gabriela Ribeiro; Juliano, Guilherme Ribeiro; de Almeida, João Antônio; Soares, Maria Helena; Oliveira, Lívia Ferreira; Ramalho, Luciana Santos; Cavellani, Camila Lourencini; Espindula, Ana Paula; Corrêa, Rosana Rosa Miranda; de Oliveira, Flávia Aparecida; Dos Reis, Marlene Antônia; de Paula Antunes Teixeira, Vicente

    2016-08-01

    To describe the dimensions and amount of collagen in the aortic root of autopsied fetuses at different gestational ages. 40 samples of aortic roots were selected from autopsied fetuses with gestational ages ranging between 20 and 40 weeks. The thickness and the area of the aortic wall were analyzed on slides stained with Hematoxylin and Eosin, and the collagen was quantified on slides stained with Picrosirius, by using an image analyzing system. A positive correlation was observed between the thickness of the media layer of the aortic wall and the gestational age. There was a positive and significant correlation between the percentage of collagen in the aortic wall with gestational age and fetal weight. The correlation between gestational age and the area of the aortic root circumference was positive and significant. And the correlation between the aortic diameter and the gestational age as well as fetal length was positive and significant. The thickness of the media layer, the amount of collagen in the aortic wall, the area of the aortic root circumference and the aortic diameter rose with the increase of the gestational age. Thus, the morphological analysis of the aortic root may help as a parameter during the follow-up of inter-uterine growth and fetal development. Copyright © 2016 Elsevier GmbH. All rights reserved.

  17. 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

  18. 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.

  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. Chlorogenic acid improves ex vivo vessel function and protects endothelial cells against HOCl-induced oxidative damage, via increased production of nitric oxide and induction of Hmox-1.

    PubMed

    Jiang, Rujia; Hodgson, Jonathan M; Mas, Emilie; Croft, Kevin D; Ward, Natalie C

    2016-01-01

    Dietary polyphenols are potential contributors toward improved cardiovascular health. Coffee is one of the richest sources of dietary polyphenols in a coffee-drinking population, the most abundant form being chlorogenic acid (CGA). Endothelial dysfunction is an early and major risk factor for cardiovascular disease. Nitric oxide (NO) is a key factor in regulation of endothelial function. Heme oxygenase-1 (Hmox-1), an inducible isoform of heme oxygenase that is produced in response to stressors such as oxidative stress, may also play a role in vascular protection. The aim of this study was to investigate the effect of CGA on endothelial function with oxidant-induced damage in isolated aortic rings from C57BL mice. We further examine the mechanism by investigating cell viability, activation of eNOS and induction of Hmox-1 in human aortic endothelial cells (HAECs). We found that pretreatment of isolated aortic rings with 10-μM CGA-protected vessels against HOCl-induced endothelial dysfunction (P<0.05). Pretreatment of cultured HAECs with 10-μM CGA increased endothelial cell viability following exposure to HOCl (P<0.05). Moreover, CGA increased NO production in HAECs in a dose-dependent manner, peaking at 6 h (P<0.05). CGA at 5 μM and 10 μM increased eNOS dimerization at 6 h and induced Hmox-1 protein expression at 6 h and 24 h in HAECs. These results are consistent with the cardiovascular protective effects of coffee polyphenols and demonstrate that CGA can protect vessels and cultured endothelial cells against oxidant-induced damage. The mechanism behind the beneficial effect of CGA appears to be in part via increased production of NO and induction of Hmox-1. Copyright © 2015 Elsevier Inc. All rights reserved.

  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. 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

  3. 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.

  4. 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

  5. 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.

  6. Pharmacological characterization of mechanisms involved in the vasorelaxation produced by rosuvastatin in aortic rings from rats with a cafeteria-style diet

    PubMed Central

    López-Canales, Jorge Skiold; Lozano-Cuenca, Jair; López-Canales, Oscar Alberto; Aguilar-Carrasco, José Carlos; Aranda-Zepeda, Lidia; López-Sánchez, Pedro; Castillo-Henkel, Enrique Fernando; López-Mayorga, Ruth Mery; Valencia-Hernández, Ignacio

    2015-01-01

    The present study aimed to investigate the possible influence of several inhibitors and blockers on the vascular effect produced by the acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a semi-solid, cafeteria-style (CAF) diet. It also aimed to examine the effects of rosuvastatin on the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase in aortic rings from rats with a CAF diet. From comparisons of the effect on phenylephrine-precontracted aortic rings extracted from rats with two different diets (a standard and a CAF diet), it was found that 10−9–10−5-mol/L rosuvastatin produced lower concentration-dependent vasorelaxation on rings from the CAF diet group. The vasorelaxant effect was unaffected by the vehicle, but it was significantly attenuated by 10−5-mol/L NG-nitro-l-arginine methyl ester, 10−2-mol/L tetraethylammonium, 10−3-mol/L 4-aminopyridine, 10−7-mol/L apamin plus 10−7-mol/L charybdotoxin, 10−5-mol/L indomethacin, or 10−5-mol/L cycloheximide. Moreover, in aortic rings from rats with a CAF diet, rosuvastatin enhanced the expression of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase. The acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a CAF diet had a vasorelaxant effect. Overall, the present results suggest that the stimulation of eNOS, the opening of Ca2+-activated and voltage-activated K+ channels, the stimulation of prostaglandin synthesis and enhanced protein levels of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase are involved in this relaxant effect. PMID:25881486

  7. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis.

    PubMed

    Makkar, Raj R; Fontana, Gregory P; Jilaihawi, Hasan; Kapadia, Samir; Pichard, Augusto D; Douglas, Pamela S; Thourani, Vinod H; Babaliaros, Vasilis C; Webb, John G; Herrmann, Howard C; Bavaria, Joseph E; Kodali, Susheel; Brown, David L; Bowers, Bruce; Dewey, Todd M; Svensson, Lars G; Tuzcu, Murat; Moses, Jeffrey W; Williams, Matthew R; Siegel, Robert J; Akin, Jodi J; Anderson, William N; Pocock, Stuart; Smith, Craig R; Leon, Martin B

    2012-05-03

    Transcatheter aortic-valve replacement (TAVR) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The outcomes beyond 1 year in such patients are not known. We randomly assigned patients to transfemoral TAVR or to standard therapy (which often included balloon aortic valvuloplasty). Data on 2-year outcomes were analyzed. A total of 358 patients underwent randomization at 21 centers. The rates of death at 2 years were 43.3% in the TAVR group and 68.0% in the standard-therapy group (P<0.001), and the corresponding rates of cardiac death were 31.0% and 62.4% (P<0.001). The survival advantage associated with TAVR that was seen at 1 year remained significant among patients who survived beyond the first year (hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.92; P=0.02 with the use of the log-rank test). The rate of stroke was higher after TAVR than with standard therapy (13.8% vs. 5.5%, P=0.01), owing, in the first 30 days, to the occurrence of more ischemic events in the TAVR group (6.7% vs. 1.7%, P=0.02) and, beyond 30 days, to the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, P=0.16). At 2 years, the rate of rehospitalization was 35.0% in the TAVR group and 72.5% in the standard-therapy group (P<0.001). TAVR, as compared with standard therapy, was also associated with improved functional status (P<0.001). The data suggest that the mortality benefit after TAVR may be limited to patients who do not have extensive coexisting conditions. Echocardiographic analysis showed a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of paravalvular aortic regurgitation. Among appropriately selected patients with severe aortic stenosis who were not suitable candidates for surgery, TAVR reduced the rates of death and hospitalization, with a decrease in symptoms and an improvement in valve hemodynamics that were sustained at 2 years of

  8. Serological proteome analysis approach-based identification of ENO1 as a tumor-associated antigen and its autoantibody could enhance the sensitivity of CEA and CYFRA 21-1 in the detection of non-small cell lung cancer

    PubMed Central

    Dai, Liping; Qu, Yanhong; Li, Jitian; Wang, Xiao; Wang, Kaijuan; Wang, Peng; Jiang, Bing-Hua; Zhang, Jianying

    2017-01-01

    Purpose Lung cancer (LC) is the leading cause of cancer-related deaths for both male and female worldwide. Early detection of LC could improve five-year survival rate up to 48.8% compared to 3.3% of late/distant stage. Autoantibodies to tumor-associated antigens (TAAs) have been described as being present before clinical symptoms in lung and other cancers. We aimed to identify more TAAs to improve the performance for discovering non-small cell lung cancer (NSCLC) patients from healthy individuals. Methods Two independent sets were included in this study. Serological proteome analysis (SERPA) was used to identify TAAs from NSCLC cell line H1299 in a discovery set. In validation study, anti-ENO1 autoantibody was examined by immunoassay in sera from 242 patients with NSCLC and 270 normal individuals. Results A 47 KDa protein was identified to be alpha-enolase (ENO1) by using SERPA. Analysis of sera from 512 participants by ELISA showed significantly higher frequency of anti-ENO1 autoantibodies in NSCLC sera compared with the sera from normal individuals, with AUC (95%CI) of 0.589 (0.539-0.638, P=0.001). There was no significant difference in frequency of anti-ENO1 in different stages, histological or metastasis status of NSCLC. When anti-ENO1 detection was combined with other two tumor protein biomarkers (CEA and CYFRA 21-1), the sensitivity of NSCLC increased to 84%. Conclusions ENO1 can elicit humoral immune response in NSCLC and its autoantibody has association with the tumorigenesis of NSCLC. Furthermore, these intriguing results suggest the possibility of autoantibody against ENO1 serving as a potential diagnostic biomarker in NSCLC and have implications for defining novel histological determinants of NSCLC. PMID:28456790

  9. Far-infrared radiation acutely increases nitric oxide production by increasing Ca(2+) mobilization and Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of endothelial nitric oxide synthase at serine 1179.

    PubMed

    Park, Jung-Hyun; Lee, Sangmi; Cho, Du-Hyong; Park, Young Mi; Kang, Duk-Hee; Jo, Inho

    2013-07-12

    Repeated thermal therapy manifested by far-infrared (FIR) radiation improves vascular function in both patients and mouse model with coronary heart disease, but its underlying mechanism is not fully understood. Using FIR as a thermal therapy agent, we investigate the molecular mechanism of its effect on endothelial nitric oxide synthase (eNOS) activity and NO production. FIR increased the phosphorylation of eNOS at serine 1179 (eNOS-Ser(1179)) in a time-dependent manner (up to 40min of FIR radiation) in bovine aortic endothelial cells (BAEC) without alterations in eNOS expression. This increase was accompanied by increases in NO production and intracellular Ca(2+) levels. Treatment with KN-93, a selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and H-89, a protein kinase A inhibitor, inhibited FIR radiation-stimulated eNOS-Ser(1179) phosphorylation. FIR radiation itself also increased the temperature of culture medium. As transient receptors potential vanilloid (TRPV) ion channels are known to be temperature-sensitive calcium channels, we explore whether TRPV channels mediate these observed effects. Reverse transcription-PCR assay revealed two TRPV isoforms in BAEC, TRPV2 and TRPV4. Although ruthenium red, a pan-TRPV inhibitor, completely reversed the observed effect of FIR radiation, a partial attenuation (∼20%) was found in cells treated with Tranilast, TRPV2 inhibitor. However, ectopic expression of siRNA of TRPV2 showed no significant alteration in FIR radiation-stimulated eNOS-Ser(1179) phosphorylation. This study suggests that FIR radiation increases NO production via increasing CaMKII-mediated eNOS-Ser(1179) phosphorylation but TRPV channels may not be involved in this pathway. Our results may provide the molecular mechanism by which FIR radiation improves endothelial function.

  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. 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

  12. 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

  13. 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

  14. Aortic assessment of bicuspid aortic valve patients and their first-degree relatives.

    PubMed

    Straneo, Pablo; Parma, Gabriel; Lluberas, Natalia; Marichal, Alvaro; Soca, Gerardo; Cura, Leandro; Paganini, Juan J; Brusich, Daniel; Florio, Lucia; Dayan, Victor

    2017-03-01

    Background Bicuspid aortic valve patients have an increased risk of aortic dilatation. A deficit of nitric oxide synthase has been proposed as the causative factor. No correlation between flow-mediated dilation and aortic diameter has been performed in patients with bicuspid aortic valves and normal aortic diameters. Being a hereditary disease, we compared echocardiographic features and endothelial function in these patients and their first-degree relatives. Methods Comprehensive physical examinations, routine laboratory tests, transthoracic echocardiography, and measurements of endothelium-dependent and non-dependent flow-mediated vasodilatation were performed in 18 bicuspid aortic valve patients (14 type 1 and 4 type 2) and 19 of their first-degree relatives. Results The first-degree relatives were younger (36.7 ± 18.8 vs. 50.5 ± 13.9 years, p = 0.019) with higher ejection fractions (64.6% ± 1.7% vs. 58.4% ± 9.5%, p = 0.015). Aortic diameters indexed to body surface area were similar in both groups, the except the tubular aorta which was larger in bicuspid aortic valve patients (19.3 ± 2.7 vs. 17.4 ± 2.2 mm·m(-2), p = 0.033). Flow-dependent vasodilation was similar in both groups. A significant inverse correlation was found between non-flow-dependent vasodilation and aortic root diameter in patients with bicuspid aortic valve ( R = -0.57, p = 0.05). Conclusions Bicuspid aortic valve patients without aortopathy have larger ascending aortic diameters than their first-degree relatives. Endothelial function is similar in both groups, and there is no correlation with ascending aorta diameter. Nonetheless, an inverse correlation exists between non-endothelial-dependent dilation and aortic root diameter in bicuspid aortic valve patients.

  15. Transcatheter aortic valve implantation in aortic coarctation.

    PubMed

    Schramm, René; Kupatt, Christian; Becker, Christoph; Bombien, René; Reichart, Bruno; Sodian, Ralf; Schmitz, Christoph

    2013-06-01

    A 77-year-old male patient was scheduled for transcatheter aortic valve implantation for symptomatic and severe aortic valve stenosis. Severe multidirectional kinking of the aorta based on aortic coarctation did not allow for the transfemoral, but only for the transapical approach. The procedure was complicated because of the technically challenging retrograde passage of the transfemorally inserted pig-tail catheter required for intraoperative angiography of the aortic root. Correct positioning of the pig-tail catheter into the ascending aorta was accomplished by use of a loop snare, which was advanced into the descending aorta via the antegrade route, passing the cardiac apex, the stenotic aortic valve, and the coarctation-associated kinking. The pig-tail catheter tip was manipulated into the loop snare, pulled traverse the coarctation, and released within the proximal ascending aorta. Subsequent procedures were uneventful and followed the standardized protocol. A 29 mm Edwards Lifescience transcatheter Sapien bioprosthesis was successfully implanted. Georg Thieme Verlag KG Stuttgart · New York.

  16. Lack of progress in valvular heart disease in the pre-transcatheter aortic valve replacement era: increasing deaths and minimal change in mortality rate over the past three decades.

    PubMed

    Coffey, Sean; Cox, Brian; Williams, Michael J A

    2014-04-01

    Valvular heart disease (VHD) is an increasingly common problem in clinical practice. With the development of new but expensive therapeutic options, health care systems require timely epidemiological information on VHD. We sought to determine the mortality burden of VHD and how it has changed over time. Population level data from the United States (US) from 1979 to 2009 were used to examine trends in VHD mortality rates over time. Our outcome measure was death, where the primary cause of death was valvular heart disease. The annual number of VHD deaths increased from 15,054 in 1979 to 26,663 in 2009, an increase of on average 2.8% in the US each year (R(2) = 0.97, P < .001). The total VHD mortality rate increased with older age and male sex. There was little overall change in age- and sex-adjusted total VHD mortality rate over time (mortality rate ratio per year 0.999, 95% confidence interval 0.999 to 0.999, P < .001). Non-rheumatic aortic valve disease accounted for 45.2% of all VHD deaths. Adjusted mortality rates for aortic valve disease, mitral valve disease and endocarditis increased (P < .001), while that for rheumatic heart disease decreased (P < .001). If VHD mortality rates remain stable, deaths due to VHD are projected to double over the next 25 years. Despite improvements in mortality rates for other major conditions and in surgical outcomes for VHD, adjusted VHD mortality rates showed minimal change over the 31 years examined. The ageing population is driving a marked increase in the number of deaths due to VHD. Copyright © 2014 Mosby, Inc. All rights reserved.

  17. Aortic Valve Disease

    MedlinePlus

    ... body Watch the video below as Dr. Robbin Cohen describes aortic stenosis Video of Robbin G. Cohen, MD on Aortic Stenosis Causes and Symptoms Causes ... when having dental work. Reviewed by: Robbin G. Cohen, MD, with assistance from John Hallsten and Travis ...

  18. 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

  19. Myocardial remodeling with aortic stenosis and after aortic valve replacement: mechanisms and future prognostic implications.

    PubMed

    Yarbrough, William M; Mukherjee, Rupak; Ikonomidis, John S; Zile, Michael R; Spinale, Francis G

    2012-03-01

    Aortic valve stenosis is a common cause of left ventricular pressure overload, a pathologic process that elicits myocyte hypertrophy and alterations in extracellular matrix composition, both of which contribute to increases in left ventricular stiffness. However, clinical and animal studies suggest that increased myocardial extracellular matrix fibrillar collagen content occurs later in the time course of left ventricular pressure overload at a time coincident with severe abnormalities in diastolic function followed by the development of symptomatic heart failure. Aortic valve replacement remains the most effective treatment for elimination of chronic pressure overload secondary to aortic stenosis but has traditionally been recommended only after the onset of clinical symptoms. Long-term follow-up of patients with symptomatic aortic stenosis after aortic valve replacement suggests that valve replacement may not result in complete reversal of the maladaptive changes that occur within the myocardial extracellular matrix secondary to the pressure overload state. To the contrary, residual left ventricular extracellular matrix abnormalities such as these are likely responsible for persistent abnormalities in diastolic function and increased morbidity and mortality after aortic valve replacement. Defining the mechanisms and pathways responsible for regulating the myocardial extracellular matrix during the natural history of aortic stenosis may provide a means by which to detect crucial structural milestones and thereby permit more precise identification of the development of maladaptive left ventricular remodeling. Published by Mosby, Inc.

  20. 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

  1. 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

  2. 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

  3. Pulmonary hypertension and vascular oxidative damage in cigarette smoke exposed eNOS(-/-) mice and human smokers.

    PubMed

    Wright, J L; Zhou, S; Churg, A

    2012-09-01

    Cigarette smoke is known to be associated with pulmonary hypertension in humans and in animal models. Although the etiology of pulmonary hypertension in smokers is not understood, recent work has suggested a role for inducible nitric oxide synthase (iNOS) in inducing oxidative stress. To further evaluate this question, we assessed eNOS-/- mice exposed to air or cigarette smoke for the presence of pulmonary hypertension and examined vascular remodeling and expression of nitrotyrosine, a marker of reactive nitrogen species-induced oxidative damage, using immunohistochemistry. To ascertain whether oxidants may play a role in humans, we also examined lung tissue from nonsmokers, and patients with chronic obstructive pulmonary disease (COPD) with and without pulmonary hypertension. We found that eNOS(-/-) mice developed increased pulmonary arterial pressure after six months cigarette smoke exposure, and this was associated with vascular remodeling and increased vascular nitrotyrosine staining. iNOS gene expression was decreased in the pulmonary arteries of the smoke exposed animals, and no protein was detectable by immunohistochemistry. In humans, vascular nitrotyrosine staining intensity was increased in smokers with COPD compared to nonsmokers, and further increased in smokers with combined COPD and pulmonary hypertension. We conclude that cigarette smoke-induced pulmonary hypertension is associated with evidence of oxidative vascular damage by reactive nitrogen species, but that iNOS does not appear to be the major contributor to such damage. Most likely the source of reactive nitrogen species is the cigarette smoke itself.

  4. 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.

  5. eNOS is required for acute in vivo ischemic preconditioning of the heart: effects of ischemic duration and sex

    PubMed Central

    Talukder, M. A. Hassan; Yang, Fuchun; Shimokawa, Hiroaki

    2010-01-01

    Ischemic preconditioning (IPC) is a powerful phenomenon that provides potent cardioprotection in mammalian hearts; however, the role of endothelial nitric oxide (NO) synthase (eNOS)-mediated NO in this process remains highly controversial. Questions also remain regarding this pathway as a function of sex and ischemic duration. Therefore, we performed extensive experiments in wild-type (WT) and eNOS knockout (eNOS−/−) mice to evaluate whether the infarct-limiting effect of IPC depends on eNOS, ischemic periods, and sex. Classical IPC was induced by three cycles of 5 min of regional coronary ischemia separated by 5 min of reperfusion and was followed by 30 or 60 min of sustained ischemia and 24 h of reperfusion. The control ischemia-reperfusion protocol had 30 or 60 min of ischemia followed by 24 h of reperfusion. Protection was evaluated by measuring the myocardial infarct size as a percentage of the area at risk. The major findings were that regardless of sex, WT mice exhibited robust IPC with significantly smaller myocardial infarction, whereas eNOS−/− mice did not. IPC-induced cardiac protection was absent in eNOS−/− mice of both Jackson and Harvard origin. In general, female WT mice had smaller infarctions compared with male WT mice. Although prolonged ischemia caused significantly larger infarctions in WT mice of both sexes, they were consistently protected by IPC. Importantly, prolonged myocardial ischemia was associated with increased mortality in eNOS−/− mice, and the survival rate was higher in female eNOS−/− mice compared with male eNOS−/− mice. In conclusion, IPC protects WT mice against in vivo myocardial ischemia-reperfusion injury regardless of sex and ischemic duration, but the deletion of eNOS abolishes the cardioprotective effect of classical IPC. PMID:20525875

  6. Relationships between caveolae and eNOS: everything in proximity and the proximity of everything.

    PubMed

    Goligorsky, Michael S; Li, Hong; Brodsky, Sergey; Chen, Jun

    2002-07-01

    Caveolae, flask-shaped invaginations of the plasma membrane occupying up to 30% of cell surface in capillaries, represent a predominant location of endothelial nitric oxide synthase (eNOS) in endothelial cells. The caveolar coat protein caveolin forms high-molecular-weight, Triton-insoluble complexes through oligomerization mediated by interactions between NH2-terminal residues 61-101. eNOS is targeted to caveolae by cotranslational N-myristoylation and posttranslational palmitoylation. Caveolin-1 coimmunoprecipitates with eNOS; interaction with eNOS occurs via the caveolin-1 scaffolding domain and appears to result in the inhibition of NOS activity. The inhibitory conformation of eNOS is reversed by the addition of excess Ca2+/calmodulin and by Akt-induced phosphorylation of eNOS. Here, we shall dissect the system using the classic paradigm of a reflex loop: 1) the action of afferent elements, such as fluid shear stress and its putative caveolar sensor, on caveolae; 2) the ways in which afferent signals may affect the central element, the activation of the eNOS-nitric oxide system; and 3) several resultant well-established and novel physiologically important effector mechanisms, i.e., vasorelaxation, angiogenesis, membrane fluidity, endothelial permeability, deterrance of inflammatory cells, and prevention of platelet aggregation.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

    PubMed Central

    Vecoli, Cecilia; Novelli, Michela; Pippa, Anna; Giacopelli, Daniela; Beffy, Pascale; Masiello, Pellegrino; L’Abbate, Antonio; Neglia, Danilo

    2014-01-01

    Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS−/− and eNOS+/− mice were studied. WT and eNOS+/− mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS−/−. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS−/−) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS−/− and eNOS+/− mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS−/−. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary

  13. Surgical threshold for bicuspid aortic valve aneurysm: a case for individual decision-making.

    PubMed

    Adamo, Luigi; Braverman, Alan C

    2015-09-01

    The bicuspid aortic valve (BAV) affects 1-2% of the population and may be associated with important valvular disease and an increased risk of aortic root and/or ascending aortic aneurysm and dissection. BAV aortic aneurysm and dissection occur earlier in life than when these disorders are associated with a tricuspid aortic valve (TAV). Alterations in the aortic media and differences in aortic elastic properties and wall stress also accompany BAV aortopathy. With appropriate follow-up and timely surgery, population studies have documented a survival rate for patients with BAV no different from age-matched controls. Guidelines have previously recommended prophylactic aortic surgery at a smaller aortic aneurysm size for patients with BAV compared with aneurysms in patients with a TAV. Recent guidelines have presented differing indications regarding the appropriate timing of prophylactic surgery for BAV aneurysms, giving the recommendation for surgery when the aortic root and/or ascending aortic exceeds 5.5 cm (unless certain factors are present), the same size for which TAV-associated aortic aneurysm surgery is recommended. We review the pathophysiology of BAV aortopathy, the clinical history of BAV ascending aortic disease, areas of uncertainty and make a case for a patient-centered, individualised decision regarding the optimal timing of aortic aneurysm surgery in BAV disease.

  14. Mechanism of aortic root dilation and cardiovascular function in tetralogy of Fallot.

    PubMed

    Seki, Mitsuru; Kuwata, Seiko; Kurishima, Clara; Nakagawa, Ryo; Inuzuka, Ryo; Sugimoto, Masaya; Saiki, Hirofumi; Iwamoto, Yoichi; Ishido, Hirotaka; Masutani, Satoshi; Senzaki, Hideaki

    2016-05-01

    The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF. © 2016 Japan Pediatric Society.

  15. Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177.

    PubMed

    Mount, Peter F; Hill, Rebecca E; Fraser, Scott A; Levidiotis, Vicki; Katsis, Frosa; Kemp, Bruce E; Power, David A

    2005-11-01

    A fundamental aspect of acute renal ischemia is energy depletion, manifest as a falling level of ATP that is associated with a simultaneous rise in AMP. The energy sensor AMP-activated protein kinase (AMPK) is activated by a rising AMP-to-ATP ratio, but its role in acute renal ischemia is unknown. AMPK is activated in the ischemic heart and is reported to phosphorylate both endothelial nitric oxide synthase (eNOS) and acetyl-CoA carboxylase. To study activation of AMPK in acute renal ischemia, the renal pedicle of anesthetized Sprague-Dawley rats was cross-clamped for increasing time intervals. AMPK was strongly activated within 1 min and remained so after 30 min. However, despite the robust activation of AMPK, acute renal ischemia did not increase phosphorylation of the AMPK phosphorylation sites eNOS-Ser(1177) or acetyl-CoA carboxylase-Ser(79). Activation of AMPK in bovine aortic endothelial cells by the ATP-depleting agent antimycin A and the antidiabetic drug phenformin also did not increase phosphorylation of eNOS-Ser(1177), confirming that AMPK activation and phosphorylation of eNOS are dissociated in some situations. Immunoprecipitation studies demonstrated that the dissociation between AMPK activation and phosphorylation of eNOS-Ser(1177) was not due to changes in the physical associations between AMPK, eNOS, or heat shock protein 90. In conclusion, acute renal ischemia rapidly activates the energy sensor AMPK, which is known to maintain ATP reserves during energy stress. The substrates it phosphorylates, however, are different from those in other organs such as the heart.

  16. Aortic Blood Flow Reversal Determines Renal Function: Potential Explanation for Renal Dysfunction Caused by Aortic Stiffening in Hypertension.

    PubMed

    Hashimoto, Junichiro; Ito, Sadayoshi

    2015-07-01

    Aortic stiffness determines the glomerular filtration rate (GFR) and predicts the progressive decline of the GFR. However, the underlying pathophysiological mechanism remains obscure. Recent evidence has shown a close link between aortic stiffness and the bidirectional (systolic forward and early diastolic reverse) flow characteristics. We hypothesized that the aortic stiffening-induced renal dysfunction is attributable to altered central flow dynamics. In 222 patients with hypertension, Doppler velocity waveforms were recorded at the proximal descending aorta to calculate the reverse/forward flow ratio. Tonometric waveforms were recorded to measure the carotid-femoral (aortic) and carotid-radial (peripheral) pulse wave velocities, to estimate the aortic pressure from the radial waveforms, and to compute the aortic characteristic impedance. In addition, renal hemodynamics was evaluated by duplex ultrasound. The estimated GFR was inversely correlated with the aortic pulse wave velocity, reverse/forward flow ratio, pulse pressure, and characteristic impedance, whereas it was not correlated with the peripheral pulse wave velocity or mean arterial pressure. The association between aortic pulse wave velocity and estimated GFR was independent of age, diabetes mellitus, hypercholesterolemia, and antihypertensive medication. However, further adjustment for the aortic reverse/forward flow ratio and pulse pressure substantially weakened this association, and instead, the reverse/forward flow ratio emerged as the strongest determinant of estimated GFR (P=0.001). A higher aortic reverse/forward flow ratio was also associated with lower intrarenal forward flow velocities. These results suggest that an increase in aortic flow reversal (ie, retrograde flow from the descending thoracic aorta toward the aortic arch), caused by aortic stiffening and impedance mismatch, reduces antegrade flow into the kidney and thereby deteriorates renal function.

  17. 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

  18. 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

  19. Gender differences in abdominal aortic aneurysms.

    PubMed

    Hannawa, Kevin K; Eliason, Jonathan L; Upchurch, Gilbert R

    2009-01-01

    Abdominal aortic aneurysms (AAAs) comprise the tenth leading cause of death in Caucasian males 65 to 74 years of age and accounted for nearly 16,000 deaths overall in 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 owing to excessive local production of matrix-degrading enzymes and is accompanied by smooth muscle cell loss and thinning of the aortic wall. At present, no medical therapies are 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 is 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.

  20. 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.

  1. 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

  2. Effects of aerobic exercise on the blood pressure, oxidative stress and eNOS gene polymorphism in pre-hypertensive older people.

    PubMed

    Zago, Anderson Saranz; Park, Joon-Young; Fenty-Stewart, Nicola; Silveira, Leonardo Reis; Kokubun, Eduardo; Brown, Michael D

    2010-11-01

    The polymorphisms of endothelial nitric oxide synthase (eNOS) are associated with reduced eNOS activity. Aerobic exercise training (AEX) may influence resting nitric oxide (NO) production, oxidative stress and blood pressure. The purpose of this study was to investigate the effect of AEX on the relationship among blood pressure, eNOS gene polymorphism and oxidative stress in pre-hypertensive older people. 118 pre-hypertensive subjects (59 ± 6 years) had blood samples collected after a 12 h overnight fast for assessing plasma NO metabolites (NOx) assays, thiobarbituric acid reactive substances (T-BARS) and superoxide dismutase activity (ecSOD). eNOS polymorphism (T-786C and G-894T) was done by standard PCR methods. All people were divided according to the genotype results (G1: TT/GG, G2: TT/GT + TT, G3: TC + CC/GG, G4: TC + CC/GT + TT). All parameters were measured before and after 6 months of AEX (70% of VO(2 max)). At baseline, no difference was found in systolic and diastolic blood pressure, ecSOD and T-BARS activity. Plasma NOx levels were significantly different between G1 (19 ± 1 μM) and G4 (14.2 ± 0.6 μM) and between G2 (20.1 ± 1.7 μM) and G4 (14.2 ± 0.6 μM). Therefore, reduced NOx concentration in G4 group occurred only when the polymorphisms were associated, suggesting that these results are more related to genetic factors than NO-scavenging effect. After AEX, the G4 increased NOx values (17.2 ± 1.2 μM) and decreased blood pressure. G1, G3 and G4 decreased T-BARS levels. These results suggest the AEX can modulate the NOx concentration, eNOS activity and the relationship among eNOS gene polymorphism, oxidative stress and blood pressure especially in C (T-786C) and T (G-894T) allele carriers.

  3. Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models.

    PubMed

    Milewicz, Dianna M; Prakash, Siddharth K; Ramirez, Francesco

    2017-01-14

    Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

  4. Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: possible relationship to aortic dissection, atherosclerosis, and hypertension.

    PubMed

    Su, Jialin; Li, Jianfeng; Li, Wenyan; Altura, Bella; Altura, Burton

    2004-01-01

    Cocaine abuse is known to induce many adverse cardiovascular effects, including hypertension, atherosclerosis, and aortic dissection. A major physiological event leading to these pathophysiological actions of cocaine could be apoptosis. This study was designed to investigate if primary cultured rat aortic vascular smooth muscle cells (VSMCs) can undergo apoptosis when treated with cocaine. After treatment with cocaine (10(-6) to 10(-4) M), morphological analysis of aortic VSMCs using confocal fluoresence microscopy showed that the percentage of apoptotic aortic VSMCs increased after cocaine (10(-6) to 10(-4) M) treatment for 12, 24, and 48 h. These results demonstrate that aortic VSMCs can undergo rapid apoptosis in response to cocaine in a concentration-dependent manner. Cocaine-induced apoptosis may thus play a major role in cocaine abuse-induced aortic dissection, atherosclerosis, and hypertension.

  5. Novel morphological features for prediction of distal thoracic aortic enlargement after thoracic endovascular aortic repair of DeBakey IIIb aortic dissection.

    PubMed

    Ge, Yang Yang; Xue, Yan; Guo, Wei; Zhang, Hong Peng; Liu, Xiao Ping; Xiong, Jiang; Jia, Xin; Ma, Xiao Hui; Wang, Li Jun

    2017-09-05

    To assess the novel morphological features for DeBakey IIIb aortic dissection in predicting distal thoracic aortic enlargement after thoracic endovascular aortic repair (TEVAR). Sixty-seven patients who underwent TEVAR for DeBakey IIIb aortic dissection between January 2011 and December 2013 at our center were divided based on preoperative computer tomography angiography (CTA) features into 3 groups: I (n = 27) and III (n = 9), with true and false lumen, respectively, coursing closely along thoracic vertebral bodies; and II, spiral configuration (n = 31). Distal thoracic aortic enlargement was determined using pre- and postoperative CTA images. At median 12.2 (interquartile range, 4.3-26.6) months, 12 patients developed distal thoracic aortic enlargement, with estimated cumulative incidence tending to increase from categories I to III (P for trend < .01). Categories II and III vs. I had more frequently concave location of primary entry tear (P < .01), larger dissection length and height index (L/Hi) (P = .05), and greater number of abdominal small branches involved preoperatively (P = .03), with otherwise similar baseline characteristics; and significantly greater total aortic diameter increase and lower false lumen regression up to 24 months, and lower true lumen expansion up to 12 months. In multivariable regression analysis, categories II and III were independently associated with distal thoracic aortic enlargement (hazard ratio, 19.95 [95% confidence interval, 2.14-186.09]; 41.23 [3.61-470.22], respectively) after adjustment for Society of Vascular Surgery score, preoperative maximum total aortic diameter, L/Hi, and number of abdominal small branches involved preoperatively. The CTA-based morphological features described in this study might improve preoperative risk stratification of DeBakey IIIb aortic dissection, with categories II and III having higher risk of distal thoracic aortic enlargement after TEVAR. Copyright © 2017. Published by Elsevier Inc.

  6. Redox-sensitive up-regulation of eNOS by purple grape juice in endothelial cells: role of PI3-kinase/Akt, p38 MAPK, JNK, FoxO1 and FoxO3a.

    PubMed

    Alhosin, Mahmoud; Anselm, Eric; Rashid, Sherzad; Kim, Jong Hun; Madeira, Socorro Vanesca Frota; Bronner, Christian; Schini-Kerth, Valérie B

    2013-01-01

    The vascular protective effect of grape-derived polyphenols has been attributable, in part, to their direct action on blood vessels by stimulating the endothelial formation of nitric oxide (NO). The aim of the present study was to determine whether Concord grape juice (CGJ), which contains high levels of polyphenols, stimulates the expression of endothelial NO synthase (eNOS) in porcine coronary artery endothelial cells and, if so, to determine the signaling pathway involved. CGJ dose- and time-dependently increased eNOS mRNA and protein levels and this effect is associated with an increased formation of NO in endothelial cells. The stimulatory effect of CGJ on eNOS mRNA is not associated with an increased eNOS mRNA stability and inhibited by antioxidants such as MnTMPyP, PEG-catalase, and catalase, and by wortmannin (an inhibitor of PI3-kinase), SB 203580 (an inhibitor of p38 MAPK), and SP 600125 (an inhibitor of JNK). Moreover, CGJ induced the formation of reactive oxygen species (ROS) in endothelial cells and this effect is inhibited by MnTMPyP, PEG-catalase, and catalase. The CGJ-induced the phosphorylation of p38 MAPK and JNK kinases is abolished by MnTMPyP. CGJ induced phosphorylation of transcription factors FoxO1 and FoxO3a, which regulate negatively eNOS expression, and this effect is prevented by MnTMPyP, PEG-catalase, wortmannin, SB203580 and SP600125. Moreover, chromatin immunoprecipitation assay indicated that the FoxO3a protein is associated with the eNOS promoter in control cells and that CGJ induced its dissociation. Thus, the present study indicates that CGJ up-regulates the expression of eNOS mRNA and protein leading to an increased formation of NO in endothelial cells. The stimulatory effect of CGJ is a redox-sensitive event involving PI3-kinase/Akt, p38 MAPK and JNK pathways, and the inactivation of the FoxO transcription factors, FoxO1 and FoxO3a, thereby preventing their repression of the eNOS gene.

  7. Redox-Sensitive Up-Regulation of eNOS by Purple Grape Juice in Endothelial Cells: Role of PI3-Kinase/Akt, p38 MAPK, JNK, FoxO1 and FoxO3a

    PubMed Central

    Rashid, Sherzad; Kim, Jong Hun; Frota Madeira, Socorro Vanesca; Bronner, Christian; Schini-Kerth, Valérie B.

    2013-01-01

    The vascular protective effect of grape-derived polyphenols has been attributable, in part, to their direct action on blood vessels by stimulating the endothelial formation of nitric oxide (NO). The aim of the present study was to determine whether Concord grape juice (CGJ), which contains high levels of polyphenols, stimulates the expression of endothelial NO synthase (eNOS) in porcine coronary artery endothelial cells and, if so, to determine the signaling pathway involved. CGJ dose- and time-dependently increased eNOS mRNA and protein levels and this effect is associated with an increased formation of NO in endothelial cells. The stimulatory effect of CGJ on eNOS mRNA is not associated with an increased eNOS mRNA stability and inhibited by antioxidants such as MnTMPyP, PEG-catalase, and catalase, and by wortmannin (an inhibitor of PI3-kinase), SB 203580 (an inhibitor of p38 MAPK), and SP 600125 (an inhibitor of JNK). Moreover, CGJ induced the formation of reactive oxygen species (ROS) in endothelial cells and this effect is inhibited by MnTMPyP, PEG-catalase, and catalase. The CGJ-induced the phosphorylation of p38 MAPK and JNK kinases is abolished by MnTMPyP. CGJ induced phosphorylation of transcription factors FoxO1 and FoxO3a, which regulate negatively eNOS expression, and this effect is prevented by MnTMPyP, PEG-catalase, wortmannin, SB203580 and SP600125. Moreover, chromatin immunoprecipitation assay indicated that the FoxO3a protein is associated with the eNOS promoter in control cells and that CGJ induced its dissociation. Thus, the present study indicates that CGJ up-regulates the expression of eNOS mRNA and protein leading to an increased formation of NO in endothelial cells. The stimulatory effect of CGJ is a redox-sensitive event involving PI3-kinase/Akt, p38 MAPK and JNK pathways, and the inactivation of the FoxO transcription factors, FoxO1 and FoxO3a, thereby preventing their repression of the eNOS gene. PMID:23533577

  8. Association between three eNOS polymorphisms and cancer risk: a meta-analysis.

    PubMed

    Wu, Xun; Wang, Zhi-Feng; Xu, Yin; Ren, Rui; Heng, Bao-Li; Su, Ze-Xuan

    2014-01-01

    Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of cancer, but the results are still debatable. Therefore, we performed a systematic review to provide a more complete picture and conducted a meta-analysis to derive a precise estimation. We searched PubMed, EMBASE, EBSCO, Google Scholar and China National Knowledge Infrastructure (CNKI) databases until April 2014 to identify eligible studies. Thirty-one studies with cancer patients and controls were included in the meta-analysis. Overall, the polled analysis revealed that the T-786C polymorphism was significantly associated with increased cancer risk under multiple genetic models (C vs T: OR=1.135, 95%CI=1.048-1.228; CC vs TT: OR=1.278, 95%CI=1.045- 1.562; TC vs TT: OR=1.136, 95%CI=1.023-1.261; CC+TC vs TT: OR=1.159, 95%CI=1.047-1.281; CC vs TC+TT: OR=1.204, 95%CI= 1.003-1.447). G894T was associated with significant risk for females (TT vs GG: OR=1.414, 95%CI=1.056-1.892; TT vs GT+GG: OR=1.356, 95%CI=1.108-1.661) and for breast cancer (T vs G: OR=1.097, 95%CI=1.001-1.203; TT vs GG: OR=1.346, 95%CI=1.012-1.789; TT vs GT+GG: OR=1.269, 95%CI=1.028-1.566). Increased susceptibility was revealed for prostate cancer with 4a/b (ba vs bb: OR=1.338, 95%CI=1.013-1.768; aa+ba vs bb: OR=1.474, 95%CI=1.002-2.170). This meta-analysis indicated that the eNOS T-786C polymorphism is associated with elevated cancer risk; the G894T polymorphism contributes to susceptibility to breast cancer and cancer generally in females; and the 4a/b polymorphism may be associated with prostate cancer risk.

  9. Transcatheter aortic valve implantation with Core Valve: First Indian experience of three high surgical risk patients with severe aortic stenosis

    PubMed Central

    Seth, Ashok; Rastogi, Vishal; Kumar, Vijay; Maqbool, Syed; Mustaqueem, Arif; Sekar, V. Ravi

    2013-01-01

    The prevalence of aortic stenosis is increasing with aging population. However with multiple co-morbidities and prior procedures in this aging population, more and more patients are being declared unfit for the ‘Gold Standard’ treatment i.e. surgical aortic valve replacement (AVR). Among the patients who are unfit or high risk for aortic valve replacement (AVR) by open heart surgery, transcatheter aortic valve implantation (TAVI) has been proven to be a valuable alternative improving survival and quality of life. We report first Indian experience of Core Valve (Medtronic Inc.) implantation in three high surgical risk patients performed on 22nd and 23rd February 2012. PMID:23993000

  10. 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.

  11. (−)-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

  12. 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.

  13. 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.

  14. Aortic Arch and Thoracic Aorta Curvature Remodeling after Thoracic Endovascular Aortic Repair.

    PubMed

    Mestres, Gaspar; Garcia, Marvin E; Yugueros, Xavier; Urrea, Rodrigo; Tripodi, Paolo; Gomez, Fernando; Maeso, Jordi; Riambau, Vincent

    2017-01-01

    The objective of this study was to analyze the original curvature of the aortic arch and thoracic aorta, and how it is modified after the placement of a thoracic endograft. We retrospectively analyzed all patients primarily treated for thoracic aortic aneurysms and blunt traumatic aortic injuries by means of an endograft sealed into the aortic arch (zones, Z1-Z3) in 2 different centers (Vascular Surgery Division, Hospital Clinic, UB; and Vascular and Endovascular Surgery Department, Hospital Vall d'Hebron, UAB; Barcelona, Spain), between 2010 and 2015. The last preoperative and early (1-month) postoperative computed tomography angiography (CTA) was obtained for all cases, and an accurate 3-dimensional (3D) center lumen line was created, from the aortic valve to the renal arteries. Angles in 2-dimensional (2D; XY-plane) and 3D (referred to cranial-caudal Z-axis) were analyzed in: the distal ascending aorta, aortic arch, and thoracic aorta (at 5, 10, 15, and 20 cm from the brachiocephalic trunk [BCT]) and celiac trunk (CT). Changes in preoperative-postoperative CTA were compared independently for both diseases. Thirty-six cases were included (20 aneurysms, 16 blunt traumatic injuries; mean age, 69.5 and 42.5 years). After placement of an aortic endograft (sealed in Z1-Z2 in 30% of aneurysms and 75% of traumatic injuries; mean endograft length: 22.6 cm and 11.3 cm, respectively), a global left anterior displacement of the ascending aorta was observed (2D examination: -13.1° and -7.5°, P = 0.049 and 0.041, respectively). The 3D examination showed an average increase of the aortic angle at 5 and 10 cm from the BCT in the whole sample (+4.0°, +4.9° in reference to the vertical; P = 0.017, 0.001), softening the curvature of the proximal descending thoracic aorta. In addition, in traumatic injuries, a decrease in the aortic arch angle was observed (-3.5°, P = 0.030). Placement of an endograft into the aortic arch and proximal thoracic aorta engenders a

  15. 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

  16. 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

  17. 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

  18. 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

  19. Simple Renal Cysts as Markers of Thoracic Aortic Disease.

    PubMed

    Ziganshin, Bulat A; Theodoropoulos, Panagiotis; Salloum, Mohammad N; Zaza, Khaled J; Tranquilli, Maryann; Mojibian, Hamid R; Dahl, Neera K; Fang, Hai; Rizzo, John A; Elefteriades, John A

    2016-01-08

    Thoracic aortic aneurysm is usually a clinically silent disease; timely detection is largely dependent upon identification of clinical markers of thoracic aortic disease (TAD); (bicuspid aortic valve, intracranial aortic aneurysm, bovine aortic arch, or positive family history). Recently, an association of simple renal cysts (SRC) with abdominal aortic aneurysm and aortic dissection was established. The aim of our study was to evaluate the prevalence of SRC in patients with TAD in order to assess whether the presence of SRC can be used as a predictor of TAD. We evaluated the prevalence of SRC in 842 patients with TAD (64.0% males) treated at our institution from 2004 to 2013 and compared to a control group of patients (n=543; 56.2% males). Patients were divided into 4 groups: ascending aortic aneurysm (456; 54.2%); descending aortic aneurysm (86; 10.2%); type A aortic dissection (118; 14.0%); and type B aortic dissection (182; 21.6%). SRC were identified by abdominal computed tomography or magnetic resonance imaging of these patients. Prevalence of SRC is 37.5%, 57.0%, 44.1%, and 47.3% for patients with ascending aneurysm, descending aneurysm, type A dissection, and type B dissection, respectively. Prevalence of SRC in the control group was 15.3%. Prevalence of SRC was not significantly different between male and female aortic disease patients, despite reported general male predominance (2:1), which was also observed in our control group (1.7:1). This study establishes an increased prevalence of SRC in patients with TAD. SRC can potentially be used as a marker for timely detection of patients at risk of TAD. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  20. 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

  1. Aortic Valve Stenosis

    MedlinePlus

    ... evaluation of aortic stenosis in adults. http://www.uptodate.com/home. Accessed April 29, 2014. Mohty D, ... Valvular heart disease in elderly adults. http://www.uptodate.com/home. Accessed May 2, 2014. Bonow RO, ...

  2. 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 ...

  3. Aortic Valve Stenosis

    MedlinePlus

    ... pulmonary valve and aortic valve. Each valve has flaps (cusps or leaflets) that open and close once ... valve consists of three tightly fitting, triangular-shaped flaps of tissue called cusps. Some children are born ...

  4. Advances in aortic disease management: a year in review.

    PubMed

    Garg, Vinay; Ouzounian, Maral; Peterson, Mark D

    2016-03-01

    The medical and surgical management of aortic disease is continually changing in search for improved outcomes. Our objective is to highlight recent advances in a few select areas pertaining to aortic disease and aortic surgery: the genetics of aortopathy, medical therapy of aortic aneurysms, advances in cardiac imaging, and operative strategies for the aortic arch. As our understanding of the genetic basis for aortopathy continues to improve, routine genetic testing may be of value in assessing patients with genetically triggered forms of aortic disease. With regard to medical advances, treating patients with Marfan syndrome with either losartan or atenolol at an earlier stage in their disease course improves outcomes. In addition, novel imaging indices such as wall shear stress and aortic stiffness assessed by MRI may become useful markers of aortopathy and warrant further study. With regard to the optimal technique for cerebral perfusion in aortic arch surgery, high-quality data are still lacking. Finally, in patients with complex, multilevel aortic disease, the frozen elephant trunk is a viable single-stage option compared with the conventional elephant trunk, although with an increased risk for spinal cord injury. Based on recent advances, continued studies in genetics, cardiac imaging, and surgical trials will further elucidate the etiology of aortopathy and ultimately guide management, both medically and surgically.

  5. 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

  6. [Gene-environment interaction for the HIF1-A 1772C>T polymorphisms and cigarette smoking increase susceptibility to abdominal aortic aneurysm].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Oszkinis, Grzegorz; Staniszewski, Ryszard

    2012-01-01

    Pathological changes in the vascular vessels, such as the presence of atherosclerotic plaques or aneurysmal dilatations, are associated with the local conditions of ischemial/hypoxia. Polymorphisms in the HIF1A gene, encoding an oxygen-regulated HIF-1 subunit (HIF-1a), determine inter-individual variability in vascular response to hypoxia. Stimulation of selected pathways, related to this response (i.e. angiogenesis) is impaired by cigarette smoke exposure. In this work, we examined the associations between 1772C>T polymorphism (rs11549465) located in the coding region of HIF1A gene (Pro582-Ser), smoking and the occurrence of abdominal aortic aneurysm (AAA). Moreover, the relations of these factors with the presence of peripheral arterial disease (PAD) in patients with AAA were studied. The case-control study was designed, in which a group of 1060 Caucasian subjects: 535 AAA patients and 525 controls, was analyzed. Data regarding smoking status were collected using questionnaire. Past and current smokers were analyzed together. In the group of 220 AAA subjects the coexistence of PAD was characterized. HIF-1A genotypes were assessed by PCR-RFLP method. Genetic-environmental interactions were examined by a two-by-four tables. In these analyzes, logistic regression models were used to adjusting for the relevant covariates. The frequency of HIF1A 1772T allele in AAA group (0,067) was similar to that observed in the control group (0,070). In the analyses of genetic-environmental interactions was observed that the co-occurrence of HIF1A 1772CT and TT genotypes and exposure to tobacco smoke has a strong multiplicative effect on the susceptibility to the AAA development. The age and gender adjusted odds ratios (ORs) were: 7,6 for smoking alone (p<0,0001); 0,65 for 1772CT and TT genotypes alone (p=0,3) and 14,4for smoking plus 1772CT and TT genotypes (p<0,0001). The proportion of smokers carrying 1772T allele was higher among patients with advanced form of PAD (femoro

  7. Endovascular aneurysm repair reverses the increased titer and the inflammatory activity of interleukin-1α in the serum of patients with abdominal aortic aneurysm.

    PubMed

    Yates, Clara M; Abdelhamid, Mohamed; Adam, Donald J; Nash, Gerard B; Bradbury, Andrew W; Rainger, G Ed

    2011-08-01

    To examine serum cytokine/chemokine profiles before and 6 months after endovascular repair (EVAR) of abdominal aortic aneurysm (AAA) and to determine whether they correlate with serum inflammatory activity using an in vitro model of leukocyte recruitment. Serum IL-1-α, IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ, IP-10, MCP-1, TNF-α, and TNF-β were measured using a cytometry-based immunoassay. To test patient serum for direct inflammatory activity, human endothelial cells (EC) were stimulated with 30% patient serum for 24 hours. To test patient serum for the ability to prime EC for inflammatory responses, EC were incubated with 30% patient serum for 24 hours, followed by stimulation with low-dose (5 U/mL) TNF for 4 hours. Under both regimens of stimulation, the degree of EC activation was assessed by assaying neutrophil recruitment in a flow-based model. Only IL-1α (67.9 ± 10.4 pg/mL vs 41.9 ± 7.4 pg/mL) and IL-8 (51.5 ± 5.1 vs 32.6 ± 4.7 pg/mL) changed significantly after surgery. Patient serum alone was unable to activate EC. However, serum from both time points could prime EC responses to low-dose TNF. Thus, after priming with preoperative serum, EC stimulated with TNF could recruit 76.7 ± 12.0 neutrophils/mm(2) into the subendothelial cell space. Post-EVAR serum was significantly less effective (44.4 ± 10.2 neutrophils/mm(2)). This reduction in neutrophil recruitment correlated with reduced IL-1α in post-EVAR serum. The addition of a neutralizing antibody against IL-1α to pre-EVAR serum inhibited EC priming and neutrophil recruitment, strongly implying that this cytokine was the priming agent. EVAR reduces serum IL-1α and its inflammatory activity in patient serum. IL-1α is, therefore, implicated in the molecular pathology of AAAs and may have potential as a clinically useful biomarker. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  8. [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.

  9. Significant negative correlations between capillary expressed eNOS and Alzheimer lesion burden.

    PubMed

    Jeynes, Brian; Provias, John

    2009-10-09

    Nitric oxide [NO] is known to have vasoregulatory, neuroprotective and blood-brain barrier (BBB) related transport functions in the human CNS. Altered NO levels are suspected of contributing to neurodegenerative disorders, including Alzheimer's disease (AD). NO is produced as a result of the activity of one or more of three isoforms of nitrogen oxide synthase (NOS). In this study we compared Alzheimer and normative comparison brain samples, from temporal and calcarine cortices, with respect to the interactive correlation between eNOS, iNOS and nNOS isoform positive capillaries and the presence of neurofibrillary tangles (NFTs) and senile plaques (SPs). Cortical samples were taken from the superior temporal and calcarine cortices of 10 confirmed AD and 10 non-demented comparison group (CG) brains. Contiguous coronal sections were stained using immunohistochemistry techniques to stain for tau protein, beta amyloid (A beta) n-termini ([40 and 42]), eNOS, iNOS and nNOS. The densities of NFTs, SPs, and eNOS, iNOS and nNOS positive capillaries were recorded. Non-parametric statistical analyses were applied to the data. Our results demonstrate a significant negative correlation between the presence of eNOS positive capillaries and NFTs and SPs in both cortices in AD brains. Our results support the view that eNOS activity should be targeted for further investigation, and that factors involved in the regulation of NO production may be amenable to therapeutic intervention.

  10. 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

  11. 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

  12. Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone.

    PubMed

    Lee, Chien-Chang; Lee, Meng-Tse Gabriel; Chen, Yueh-Sheng; Lee, Shih-Hao; Chen, Yih-Sharng; Chen, Shyr-Chyr; Chang, Shan-Chwen

    2015-11-01

    Fluoroquinolones have been associated with collagen degradation, raising safety concerns related to more serious collagen disorders with use of these antibiotics, including aortic aneurysm and dissection. To examine the relationship between fluoroquinolone therapy and the risk of developing aortic aneurysm and dissection. We conducted a nested case-control analysis of 1477 case patients and 147 700 matched control cases from Taiwan's National Health Insurance Research Database (NHIRD) from among 1 million individuals longitudinally observed from January 2000 through December 2011. Cases patients were defined as those hospitalized for aortic aneurysm or dissection. One hundred control patients were matched for each case based on age and sex. Current, past, or any prior-year use of fluoroquinolone. Current use was defined as a filled fluoroquinolone prescription within 60 days of the aortic aneurysm or dissection; past use refers to a filled fluoroquinolone prescription between 61 and 365 days prior to the aortic aneurysm; and any prior-year use refers to having a fluoroquinolone prescription filled for 3 or more days any time during the 1-year period before the aortic aneurysm or dissection. Risk of developing aortic aneurysm or dissection. A total of 1477 individuals who experienced aortic aneurysm or dissection were matched to 147 700 controls. After propensity score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio [RR], 2.43; 95% CI, 1.83-3.22), as was past use, although this risk was attenuated (RR, 1.48; 95% CI, 1.18-1.86). Sensitivity analysis focusing on aortic aneurysm and dissection requiring surgery also demonstrated an increased risk associated with current fluoroquinolone use, but the increase was not statistically significant (propensity score-adjusted RR, 2.15; 95% CI, 0.97-4.60). Use of fluoroquinolones was associated with an increased risk of aortic aneurysm and

  13. 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

  14. 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.

  15. Tyrosine phosphorylation of eNOS regulates myocardial survival after an ischaemic insult: role of PYK2.

    PubMed

    Bibli, Sofia-Iris; Zhou, Zongmin; Zukunft, Sven; Fisslthaler, Beate; Andreadou, Ioanna; Szabo, Csaba; Brouckaert, Peter; Fleming, Ingrid; Papapetropoulos, Andreas

    2017-07-01

    Endothelial nitric oxide (NO) synthase (eNOS) is known to play a cardioprotective protective. However, the molecular mechanisms regulating eNOS activity during ischaemia/reperfusion (I/R) injury are incompletely understood. eNOS is a substrate for several kinases that positively or negatively affect its enzymatic activity. Herein, we sought to correlate eNOS phosphorylation status with cardiomyocyte survival and we investigated the contribution of the proline-rich tyrosine kinase 2 (PYK2)/eNOS axis to the regulation of myocardial infarct size in vivo. Exposure of H9c2 cardiomyocytes to H2O2 lead to PYK2 phosphorylation on its activator site (Y402) and eNOS phosphorylation on the inhibitor site Y656 and the activator site S1176. Both H2O2-induced eNOS phosphorylation events were abolished by PYK2 pharmacological inhibition or gene knockdown. Activity assays demonstrated that phosphorylation of the tyrosine inhibitory site exerts a dominant effect over S1176. In cardiomyocytes subjected to oxidative stress or oxygen-glucose deprivation, inhibition of PYK2 limited cell injury; this effect was prevented by inhibition of NO production. In vivo, ischaemia-reperfusion induced an early activation of PYK2, leading to eNOS phosphorylation on Y656, which, in turn, reduced NO output, as judged by the low tissue levels of its downstream effector cGMP. Moreover, pharmacological blockade of PYK2 alleviated eNOS inhibition and prevented cardiac damage following I/R injury in wild-type, but not in eNOS KO mice. The current studies demonstrate that PYK2 is a pivotal regulator of eNOS function in myocardial infarction and identify PYK2 as a novel therapeutic target for cardioprotection.

  16. Aortic involvement in relapsing polychondritis.

    PubMed

    Le Besnerais, Maëlle; Arnaud, Laurent; Boutémy, Jonathan; Bienvenu, Boris; Lévesque, Hervé; Amoura, Zahir; Marie, Isabelle

    2017-05-17

    To assess prevalence of aortic involvement in relapsing polychondritis (RP) patients; to evaluate clinical features and long-term outcome of RP patients exhibiting aortitis, aortic ectasia and/or aneurysm. One hundred and seventy-two RP patients underwent aortic computed tomography (CT)-scan; they were seen in 3 medical centers. Eleven patients (6.4%) had aortic involvement, occurring within a median time of 2 years after RP diagnosis. CT-scan showed isolated aortitis (n=2); the 9 other patients exhibited: aortitis and aortic aneurysm (n=2) or ectasia (n=1), isolated aortic aneurysm (n=4) or ectasia (n=2); aortic localizations were as follows: thoracic (n=6), abdominal (n=2), thoracic and abdominal (n=4) aorta. Patients exhibited: resolution (n=3) improvement (n=3), stabilization (n=4) or deterioration (n=1) of aortic localization. Five patients experienced recurrence of aortic localization; one patient died of aortic abdominal aneurysm rupture. Predictive factors of death related to aortic complications were: aortitis on CT-scan, higher median levels of erythrocyte sedimentation rate. Predictive parameters of aortic relapses were: aortitis on CT-scan and involvement of the abdominal aorta. This study underlines that aortic involvement is severe in RP. Furthermore, we suggest that RP patients exhibiting poor prognostic factors, including panaortitis and higher values of ESR, may require more aggressive therapy. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  17. Frequency of abdominal aortic expansion after thoracic endovascular repair of type B aortic dissection.

    PubMed

    Weber, Tim F; Böckler, Dittmar; Müller-Eschner, Matthias; Bischoff, Moritz; Kronlage, Moritz; von Tengg-Kobligk, Hendrik; Kauczor, Hans-Ulrich; Hyhlik-Dürr, Alexander

    2016-12-01

    To determine abdominal aortic expansion after thoracic endovascular aortic repair (TEVAR) in patients with aortic dissection type B and 36 months minimum follow-up. Retrospective study of 18 TEVAR patients with follow-up >36 months. Abdominal aortic diameters at celiac trunk (location B) and infrarenal aorta (location C) were recorded on the first and last imaging after TEVAR. False lumen thrombosis was determined at level of endograft (A) and at B and C. Aortic expansion was defined as diameter increase of 5 mm or 15%. Correlation analyses were performed to investigate potential determinants of expansion. Median follow-up was 75.2 months. Sixteen of 18 patients (88.9%) demonstrated abdominal expansion. Mean expansion was 9.9 ± 6.1 mm at B and 11.7 ± 6.5 mm at C, without a difference between acute and chronic dissections. Critical diameters of 55 mm were reached in two patients treated for chronic dissection (11.1%). Annual diameter increase was significantly greater at locations with baseline diameters >30 mm (2.1 ± 1.1 mm vs. 1.0 ± 0.6 mm, p = 0.009). Baseline diameters were greater in patients with chronic dissections. Abdominal aortic expansion can be frequently recognized after TEVAR for aortic dissection type B and occurs independently from thoracic false lumen thrombosis. Clinical significant abdominal aortic expansion may occur more frequently in patients treated with TEVAR for chronic dissection. © The Author(s) 2016.

  18. 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.

  19. 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.

  20. Congenital valvular aortic stenosis in young adults: predictors for rate of progression of stenosis and aortic dilatation.

    PubMed

    van der Linde, Denise; Andrinopoulou, Elini-Rosalina; Oechslin, Erwin N; Budts, Werner; van Dijk, Arie P J; Pieper, Petronella G; Wajon, Elly M C J; Post, Marco C; Witsenburg, Maarten; Silversides, Candice K; Oxenius, Angela; Bogers, Ad J J C; Takkenberg, Johanna J M; Roos-Hesselink, Jolien W

    2013-09-30

    Congenital aortic stenosis (AS) is the most common obstructive left-sided cardiac lesion in young adults, however little is known about the progression in adults. Therefore, we aimed to evaluate the progression rate of AS and aortic dilatation in a large multicenter retrospective cohort of asymptomatic young adults with congenital valvular AS. Data were obtained from chart abstraction. Linear mixed-effects models were used to evaluate the progression of AS and aortic dilatation over time. A joint model combining longitudinal echocardiographic and survival data was used for survival analysis. A total of 414 patients (age 29 ± 10 years, 68% male) were included. Median follow-up duration was 4.1 (2.5-5.1) years (1587 patient-years). Peak aortic velocity was 3.4 ± 0.7 m/s at baseline and did not change over time in the total patient population (-0.01 ± 0.03 m/s/year). Increased left ventricular mass was significantly associated with faster AS progression (p<0.001). Aortic dilatation was present in 34% at baseline and 48% at follow-up (p<0.001). The aortic diameter linearly increased over time with a rate of 0.7 ± 0.2mm/year. Rate of aortic dissection was 0.06% per patient-year. Seventy patients required an aortic valve intervention (4.4% per patient-year), with AS progression rate as most powerful predictor (HR 5.11 (95% CI 3.47-7.53)). In the majority of patients with mild-to-moderate congenital AS, AS severity does not progress over time. However patients with left ventricular hypertrophy are at risk for faster progression and should be monitored carefully. Although aortic dissections rarely occur, aortic dilatation is common and steadily progresses over time, warranting serial aortic imaging. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. 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 ...

  2. 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.

  3. Evaluation of aortic stiffness (aortic pulse-wave velocity) before and after elective abdominal aortic aneurysm repair procedures: a pilot study.

    PubMed

    Paraskevas, Kosmas I; Bessias, Nikolaos; Psathas, Chrysovalantis; Akridas, Konstantinos; Dragios, Theodoros; Nikitas, Georgios; Andrikopoulos, Vassilios; Mikhailidis, Dimitri P; Kyriakides, Zenon S

    2009-12-09

    The main clinical criterion for abdominal aortic aneurysm (AAA) repair operations is an AAA diameter >/=5.5 cm. When AAAs increase in size, specific changes occur in the mechanical properties of the aortic wall. Pulse-wave velocity (PWV) has been used as an indicator of vascular stiffness. A low PWV may predict AAA rupture risk and is an early predictor of cardiovascular mortality. We investigated the prognostic value of PWV before and after elective AAA repair procedures. Twenty four patients scheduled for an open AAA repair underwent a preoperative carotid-femoral aortic PWV measurement. A second aortic PWV measurement was carried out 6 months postoperatively. The mean aortic PWV increased from 7.84 +/- 1.85 preoperatively to 10.08 +/- 1.57 m/sec 6 months postoperatively (mean change: 2.25; 95% confidence interval 1.4 to 3.1 m/sec; p<0.0001). The preprocedural PWV measurement did not correlate with AAA diameter (Spearman's rank correlation coefficient rho=0.12; p=0.59). Whether the increase in aortic PWV postoperatively suggests a decreased cardiovascular risk following AAA repair remains to be established. Aortic PWV should also be investigated as an adjunct tool for assessing AAA rupture risk.

  4. [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.

  5. Increased Neuron Specific Enolase Expression by Urothelial Cells Exposed to or Malignantly Transformed by Exposure to Cd+2 or As+3

    PubMed Central

    Soh, Maureen; Dunlevy, Jane R.; Garrett, Scott H.; Allen, Christina; Sens, Donald A.; Zhou, Xu Dong; Sens, Mary Ann; Somji, Seema

    2012-01-01

    Neuron specific enolase (ENO2, γ-enolase) is a biomarker used to help identify neuroendocrine differentiation in tumors. This laboratory has shown that ENO2 might be a biomarker for exposure to cadmium and arsenite. In this study these observations are extended to the urothelial cell, where environmental exposures are strongly linked to urothelial cancer. The UROtsa urothelial cell line and its Cd+2- and As+3-transformed counterparts were used as the model. Acute exposure of the UROtsa cells to both As+3- and Cd+2-caused significant increases in ENO2 expression. Treatment with the histone deacetlyase inhibitor was also shown to significantly increase the expression of ENO2 mRNA. The expression of ENO2 was significantly elevated in the Cd+2- and As+3-transformed UROtsa cells and tumor transplants. In contrast, ENO1, was unaffected by exposure to As+3 or Cd+2. Immunofluorescence showed ENO2 associated with both the nucleus and cytoplasm and cytoplasmic ENO2 co-localized with ENO1. The findings extend the evidence suggesting a link between As+3 and Cd+2 exposure and neuroendocrine differentiation in tumors. The results suggest that ENO2 might be a biomarker of human exposure to Cd+2 and As+3 that operates through histone modification. PMID:22613180

  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. 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.

  8. A2B adenosine receptor contributes to penile erection via PI3K/AKT signaling cascade-mediated eNOS activation

    PubMed Central

    Wen, Jiaming; Grenz, Almut; Zhang, Yujin; Dai, Yingbo; Kellems, Rodney E.; Blackburn, Michael R.; Eltzschig, Holger K.; Xia, Yang

    2011-01-01

    Normal penile erection is under the control of multiple factors and signaling pathways. Although adenosine signaling is implicated in normal and abnormal penile erection, the exact role and the underlying mechanism for adenosine signaling in penile physiology remain elusive. Here we report that shear stress leads to increased adenosine release from endothelial cells. Subsequently, we determined that ecto-5′-nucleotidase (CD73) is a key enzyme required for the production of elevated adenosine from ATP released by shear-stressed endothelial cells. Mechanistically, we demonstrate that shear stress-mediated elevated adenosine functions through the adenosine A2B receptor (A2BR) to activate the PI3K/AKT signaling cascade and subsequent increased endothelial nitric oxide synthase (eNOS) phosphorylation. These in vitro studies led us to discover further that adenosine was induced during sustained penile erection and contributes to PI3K/AKT activation and subsequent eNOS phosphorylation via A2BR signaling in intact animal. Finally, we demonstrate that lowering adenosine in wild-type mice or genetic deletion of A2BR in mutant mice significantly attenuated PI3K/AKT activation, eNOS phosphorylation, and subsequent impaired penile erection featured with the reduction of ratio of maximal intracavernosal pressure to systemic arterial pressure from 0.49 ± 0.03 to 0.41 ± 0.05 and 0.38 ± 0.04, respectively (both P<0.05). Overall, using biochemical, cellular, genetic, and physiological approaches, our findings reveal that adenosine is a novel molecule signaling via A2BR activation, contributing to penile erection via PI3K/AKT-dependent eNOS activation. These studies suggest that this signaling pathway may be a novel therapeutic target for erectile disorders.—Wen, J., Grenz, A., Zhang, Y., Dai, Y., Kellems, R. E., Blackburn, M. R., Eltzschig, H. K., Xia, Y. A2B adenosine receptor contributes to penile erection via PI3K/AKT signaling cascade-mediated eNOS activation. PMID

  9. A correlative study of aortic valve rotation angle and thoracic aortic sizes using ECG gated CT angiography.

    PubMed

    Saremi, Farhood; Cen, Steven; Tayari, Nazila; Alizadeh, Houman; Emami, Amir; Lin, Leah; Fleischman, Fernando

    2017-04-01

    Various degrees of aortic valve rotation may be seen in individuals with no history of congenital cardiovascular malformations, but its association with aortic sizes has not been studied. Gated computed tomographic (CT angiograms in 217 patients were studied (66.7±15; 22-97 years old)). Aortic diameters were determined at 5 anatomic locations. The length of the aorta from sinus to left subclavian artery was measured. The angle of valve rotation was recorded by measuring the angle between a line connecting the midpoint of the non-coronary sinus to the anterior commissure and another line along the interatrial septum. Rotation angles were correlated with aortic measurements. Patients were separated into two groups based on aortic sizes and into three groups based on age. The threshold for aortic dilatation was set at maximum ascending aorta diameter ≥40mm (≥21mm body surface area [BSA] indexed). No significant difference in rotation angles was seen between the three age groups or between genders. Rotation angles were significantly correlated with maximal, average, and BSA adjustment of the aortic root and ascending aortic measurements. The aortic root angles were significantly different between the dilated versus nondilated aortas. There was no significant association between the rotation angles and age, length of ascending aorta, or diameters of descending aorta. Multivariate adaptive regression splines showed 25° of aortic root rotation as the diagnostic cut off for ascending aorta dilation. Above the 25° rotation, every 10° of increasing rotation was associated with a 3.78±0.87mm increase in aortic diameter (p<0.01) and a 1.73±0.25 times increased risk for having a dilated aorta (p<0.01). Rotation angles of the aortic valve may be an independent non-invasive imaging marker for dilatation of the ascending aorta. Patients with increased rotation angle of the aortic valve may have higher risk for development or acceleration of an ascending aortic dilatation

  10. [The different genotypes of MTHFR 1298A>C and PON1 -108C>T polymorphisms confer the increased risk of the abdominal aortic aneurysm in the smoking and nonsmoking persons].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2005-01-01

    In abdominal aortic aneurysm (AAA) both the etiology and the pathogenesis are of the multifactorial character. The genetic component in the determination of this disease is proven by its familial occurrence. Smoking represents the best recognized risk factor of the AAA development. Increased concentrations of homocysteine (Hcy) in plasma are the common finding in these patients. It is assumed that the Hcy thiolactone, the most reactive metabolite of Hcy, may participate in the aortic wall destruction in AAA. The polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C) influence tissue concentrations of the Hcy. Paraoxonase (PON1), the enzyme associated in plasma with the HDL fraction, as lactonase detoxicates the Hcy thiolactone. The promotor polymorphism of PON1 - 108C>T gene may determine the lower activity of this enzyme. In the case-control study of 106 patients with AAA and 97 healthy persons, the effects of selected genetic and nongenetic risk factors on development of AAA were assessed, considering the possibilities of interaction between them. It was found, that the arterial hypertension, cigarette smoking and the lower HDL fraction are independent risk factors of AAA. The arterial hypertension was a risk factor both in the smoking and the nonsmoking males, whereas the lower HDL fraction has been the risk factor only for the smoking men. By the multivariate analysis in the nonsmoking males the MTHFR 1298 AC and CC genotypes increased the risk of AAA development 4,8-fold in relation to the MTHFR 1298 AA nonsmoking males. In reference to the genotypes of the expected high impact on the metabolism of Hcy and of Hcy thiolactone, the genotypes of MTHFR 677TT and PON1 -108CT and TT were more frequent in smoking ones, but the difference was not significant. This observation fits with the assumption that the influence of smoking on the occurrence of AAA prevails over that of genetic variability. When the patients age was considered

  11. Nitrones Reverse Hyperglycemia-Induced Endothelial Dysfunction in Bovine Aortic Endothelial Cells

    PubMed Central

    Headley, Colwyn A.; DiSilvestro, David; Hemann, Craig; Bryant, Kelsey E.; Chen, Chun-Aun; Das, Amlan; Ziouzenkova, Ouliana; Durand, Grégory; Villamena, Frederick A.

    2016-01-01

    Hyperglycemia has been implicated in the development of endothelial dysfunction through heightened ROS production. Since nitrones reverse eNOS dysfunction, increase antioxidant enzyme activity, and suppress pro-apoptotic signaling pathway and mitochondrial dysfunction from ROS-induced toxicity, the objective of this study was to determine whether nitrone spin traps DMPO, PBN and PBN-LA were effective at duplicating these effects and improving glucose uptake in an in vitro model of hyperglycemia-induced dysfunction using bovine aortic endothelial cells (BAEC). BAEC were cultured in DMEM medium with low (5.5 mM glucose, LG) or high glucose (50 mM, HG) for 14 days to model in vivo hyperglycemia as experienced in humans with metabolic disease. Improvements in cell viability, intracellular oxidative stress, NO and tetrahydrobiopterin levels, mitochondrial membrane potential, glucose transport, and activity of antioxidant enzymes were measured from single treatment of BAEC cells with nitrones for 24 h after hyperglycemia. Chronic hyperglycemia significantly increased intracellular ROS by 50%, decreased cell viability by 25%, reduced NO bioavailability by 50%, and decreased BH4 levels by 15% thereby decreasing NO production. Intracellular glucose transport and SOD activity were also decreased by 50% and 25% respectively. Nitrone (PBN and DMPO, 50 μM) treatment of BAEC cells grown in hyperglycemic conditions resulted in in the normalization of outcome measures except for SOD and catalase activities. Our findings demonstrate that the nitrones reverse the deleterious effects of hyperglycemia in BAEC cells. We believe that in vivo testing of these nitrone compounds in models of cardiometabolic disease is warranted. PMID:26774452

  12. Subcoronary versus supracoronary aortic stenosis. an experimental evaluation

    PubMed Central

    2011-01-01

    Background Valvular aortic stenosis is the most common cause of left ventricular hypertrophy due to gradually increasing pressure work. As the stenosis develop the left ventricular hypertrophy may lead to congestive heart failure, increased risk of perioperative complications and also increased risk of sudden death. A functional porcine model imitating the pathophysiological nature of valvular aortic stenosis is very much sought after in order to study the geometrical and pathophysiological changes of the left ventricle, timing of surgery and also pharmacological therapy in this patient group. Earlier we developed a porcine model for aortic stenosis based on supracoronary aortic banding, this model may not completely imitate the pathophysiological changes that occurs when valvular aortic stenosis is present including the coronary blood flow. It would therefore be desirable to optimize this model according to the localization of the stenosis. Methods In 20 kg pigs subcoronary (n = 8), supracoronary aortic banding (n = 8) or sham operation (n = 4) was preformed via a left lateral thoracotomy. The primary endpoint was left ventricular wall thickness; secondary endpoints were heart/body weight ratio and the systolic/diastolic blood flow ratio in the left anterior descending coronary. Statistical evaluation by oneway anova and unpaired t-test. Results Sub- and supracoronary banding induce an equal degree of left ventricular hypertrophy compared with the control group. The coronary blood flow ratio was slightly but not significantly higher in the supracoronary group (ratio = 0.45) compared with the two other groups (subcoronary ratio = 0.36, control ratio = 0.34). Conclusions A human pathophysiologically compatible porcine model for valvular aortic stenosis was developed by performing subcoronary aortic banding. Sub- and supracoronary aortic banding induce an equal degree of left ventricular hypertrophy. This model may be valid for experimental investigations of aortic

  13. 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.

  14. Aortic hammer syndrome.

    PubMed

    Komen, Niels; Vercauteren, Sven; de Roover, Dominique

    2011-08-01

    To present a case of penetrating aortic ulcer with extraordinary etiology. A 57-year-old man was admitted with acute retrosternal and interscapular pain. He was a demolition worker and often used a pneumatic drill to which he pressed his chest as he drilled. Clinical examination showed previously undiagnosed hypertension. Computed tomographic angiography disclosed a penetrating aortic ulcer in the descending thoracic aorta without any sign of atherosclerosis. Initial treatment consisted of blood pressure control. However, due to progression of the lesion, endovascular treatment was performed to implant a covered endoprosthesis. We hypothesize that the etiology of the ulcer was the shear forces developed by incorrect, repetitive use of the pneumatic hammer in combination with the untreated hypertension. This is analogous to the hypothenar hammer syndrome, and we propose naming this the "aortic hammer syndrome."

  15. 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

  16. [Abdominal aortic aneurysm and renovascular disease].

    PubMed

    Riambau, Vicente; Guerrero, Francisco; Montañá, Xavier; Gilabert, Rosa

    2007-06-01

    Recent technological advances in the diagnosis and therapy of abdominal aortic aneurysm and renovascular disease are continuing to bring about changes in the way patients suffering from these conditions are treated. The prevalence of both these conditions is increasing. This is due to greater life-expectancy in patients with arteriosclerosis, a pathogenetic factor underlying both conditions. The application of diagnostic imaging techniques to non-vascular conditions has led to the early diagnosis of abdominal aortic aneurysm. Clinical suspicion of reno-vascular disease can be confirmed easily using high-resolution diagnostic imaging modalities such as CT angiography and magnetic resonance angiography. Endovascular intervention is successfully replacing conventional surgical repair techniques, with the result that it may be possible to improve outcome in both conditions using effective and minimally invasive approaches. Future technological developments will enable these endovascular techniques to be applied in the large majority of patients with abdominal aortic aneurysm or renovascular disease.

  17. Abdominal aortic aneurysms: an autoimmune disease?

    PubMed

    Jagadesham, Vamshi P; Scott, D Julian A; Carding, Simon R

    2008-12-01

    Abdominal aortic aneurysms (AAAs) are a multifactorial degenerative vascular disorder. One of the defining features of the pathophysiology of aneurysmal disease is inflammation. Recent developments in vascular and molecular cell biology have increased our knowledge on the role of the adaptive and innate immune systems in the initiation and propagation of the inflammatory response in aortic tissue. AAAs share many features of autoimmune disease, including genetic predisposition, organ specificity and chronic inflammation. Here, this evidence is used to propose that the chronic inflammation observed in AAAs is a consequence of a dysregulated autoimmune response against autologous components of the aortic wall that persists inappropriately. Identification of the molecular and cellular targets involved in AAA formation will allow the development of therapeutic agents for the treatment of AAA.

  18. Etiology of bicuspid aortic valve disease: Focus on hemodynamics.

    PubMed

    Atkins, Samantha K; Sucosky, Philippe

    2014-12-26

    The bicuspid aortic valve (BAV) is the most common form of inheritable cardiac defect. Although this abnormality may still achieve normal valvular function, it is often associated with secondary valvular and aortic complications such as calcific aortic valve disease and aortic dilation. The clinical significance and economic burden of BAV disease justify the need for improved clinical guidelines and more robust therapeutic modalities, which address the root-cause of those pathologies. Unfortunately, the etiology of BAV valvulopathy and aortopathy is still a debated issue. While the BAV anatomy and its secondary complications have been linked historically to a common genetic root, recent advances in medical imaging have demonstrated the existence of altered hemodynamics near BAV leaflets prone to calcification and BAV aortic regions vulnerable to dilation. The abnormal mechanical stresses imposed by the BAV on its leaflets and on the aortic wall could be transduced into cell-mediated processes, leading ultimately to valvular calcification and aortic medial degeneration. Despite increasing evidence for this hemodynamic etiology, the demonstration of the involvement of mechanical abnormalities in the pathogenesis of BAV disease requires the investigation of causality between the blood flow environment imposed on the leaflets and the aortic wall and the local biology, which has been lacking to date. This editorial discusses the different hypothetical etiologies of BAV disease with a particular focus on the most recent advances in cardiovascular imaging, flow characterization techniques and tissue culture methodologies that have provided new evidence in support of the hemodynamic theory.

  19. Acute aortic syndromes: definition, prognosis and treatment options.

    PubMed

    Carpenter, S W; Kodolitsch, Y V; Debus, E S; Wipper, S; Tsilimparis, N; Larena-Avellaneda, A; Diener, H; Kölbel, T

    2014-04-01

    Acute aortic syndromes (AAS) are life-threatening vascular conditions of the thoracic aorta presenting with acute pain as the leading symptom in most cases. The incidence is approximately 3-5/100,000 in western countries with increase during the past decades. Clinical suspicion for AAS requires immediate confirmation with advanced imaging modalities. Initial management of AAS addresses avoidance of progression by immediate medical therapy to reduce aortic shear stress. Proximal symptomatic lesions with involvement of the ascending aorta are surgically treated in the acute setting, whereas acute uncomplicated distal dissection should be treated by medical therapy in the acute period, followed by surveillance and repeated imaging studies. Acute complicated distal dissection requires urgent invasive treatment and thoracic endovascular aortic repair has become the treatment modality of choice because of favorable outcomes compared to open surgical repair. Intramural hematoma, penetrating aortic ulcers, and traumatic aortic injuries of the descending aorta harbor specific challenges compared to aortic dissection and treatment strategies are not as uniformly defined as in aortic dissection. Moreover these lesions have a different prognosis. Once the acute period of aortic syndrome has been survived, a lifelong medical treatment and close surveillance with repeated imaging studies is essential to detect impending complications which might need invasive treatment within the short-, mid- or long-term.

  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. Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene.

    PubMed

    Salvi, Erika; Kuznetsova, Tatiana; Thijs, Lutgarde; Lupoli, Sara; Stolarz-Skrzypek, Katarzyna; D'Avila, Francesca; Tikhonoff, Valerie; De Astis, Silvia; Barcella, Matteo; Seidlerová, Jitka; Benaglio, Paola; Malyutina, Sofia; Frau, Francesca; Velayutham, Dinesh; Benfante, Roberta; Zagato, Laura; Title, Alexandra; Braga, Daniele; Marek, Diana; Kawecka-Jaszcz, Kalina; Casiglia, Edoardo; Filipovsky, Jan; Nikitin, Yuri; Rivolta, Carlo; Manunta, Paolo; Beckmann, Jacques S; Barlassina, Cristina; Cusi, Daniele; Staessen, Jan A

    2013-11-01

    A case-control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase (eNOS) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% (P<0.01) lower. In the population, systolic/diastolic blood pressure increased over 7.6 years (median) by 9.7/6.8 mm Hg in 28 TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers (P≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6-11.1; P=0.028) and 4.8 mm Hg diastolic (CI, 1.5-8.2; P=0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes (P≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24-3.37; P=0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension.

  2. Serine 1179 Phosphorylation of Endothelial Nitric Oxide Synthase Increases Superoxide Generation and Alters Cofactor Regulation.

    PubMed

    Peng, Hu; Zhuang, Yugang; Harbeck, Mark C; He, Donghong; Xie, Lishi; Chen, Weiguo

    2015-01-01

    Endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis. In addition to producing NO, eNOS can also generate superoxide (O2-.) in the absence of the cofactor tetrahydrobiopterin (BH4). Previous studies have shown that bovine eNOS serine 1179 (Serine 1177/human) phosphorylation critically modulates NO synthesis. However, the effect of serine 1179 phosphorylation on eNOS superoxide generation is unknown. Here, we used the phosphomimetic form of eNOS (S1179D) to determine the effect of S1179 phosphorylation on superoxide generating activity, and its sensitivity to regulation by BH4, Ca2+, and calmodulin (CAM). S1179D eNOS exhibited significantly increased superoxide generating activity and NADPH consumption compared to wild-type eNOS (WT eNOS). The superoxide generating activities of S1179D eNOS and WT eNOS did not differ significantly in their sensitivity to regulation by either Ca2+ or CaM. The sensitivity of the superoxide generating activity of S1179D eNOS to inhibition by BH4 was significantly reduced compared to WT eNOS. In eNOS-overexpressing 293 cells, BH4 depletion with 10mM DAHP for 48 hours followed by 50ng/ml VEGF for 30 min to phosphorylate eNOS S1179 increased ROS accumulation compared to DAHP-only treated cells. Meanwhile, MTT assay indicated that overexpression of eNOS in HEK293 cells decreased cellular viability compared to control cells at BH4 depletion condition (P<0.01). VEGF-mediated Serine 1179 phosphorylation further decreased the cellular viability in eNOS-overexpressing 293 cells (P<0.01). Our data demonstrate that eNOS serine 1179 phosphorylation, in addition to enhancing NO production, also profoundly affects superoxide generation: S1179 phosphorylation increases superoxide production while decreasing sensitivity to the inhibitory effect of BH4 on this activity.

  3. 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

  4. Critical Transitions in Early Embryonic Aortic Arch Patterning and Hemodynamics

    PubMed Central

    Kowalski, William J.; Dur, Onur; Wang, Yajuan; Patrick, Michael J.; Tinney, Joseph P.; Keller, Bradley B.; Pekkan, Kerem

    2013-01-01

    Transformation from the bilaterally symmetric embryonic aortic arches to the mature great vessels is a complex morphogenetic process, requiring both vasculogenic and angiogenic mechanisms. Early aortic arch development occurs simultaneously with rapid changes in pulsatile blood flow, ventricular function, and downstream impedance in both invertebrate and vertebrate species. These dynamic biomechanical environmental landscapes provide critical epigenetic cues for vascular growth and remodeling. In our previous work, we examined hemodynamic loading and aortic arch growth in the chick embryo at Hamburger-Hamilton stages 18 and 24. We provided the first quantitative correlation between wall shear stress (WSS) and aortic arch diameter in the developing embryo, and observed that these two stages contained different aortic arch patterns with no inter-embryo variation. In the present study, we investigate these biomechanical events in the intermediate stage 21 to determine insights into this critical transition. We performed fluorescent dye microinjections to identify aortic arch patterns and measured diameters using both injection recordings and high-resolution optical coherence tomography. Flow and WSS were quantified with 3D computational fluid dynamics (CFD). Dye injections revealed that the transition in aortic arch pattern is not a uniform process and multiple configurations were documented at stage 21. CFD analysis showed that WSS is substantially elevated compared to both the previous (stage 18) and subsequent (stage 24) developmental time-points. These results demonstrate that acute increases in WSS are followed by a period of vascular remodeling to restore normative hemodynamic loading. Fluctuations in blood flow are one possible mechanism that impacts the timing of events such as aortic arch regression and generation, leading to the variable configurations at stage 21. Aortic arch variations noted during normal rapid vascular remodeling at stage 21 identify a

  5. Acquired aortic atresia: Catheter therapy using covered stents.

    PubMed

    Momenah, Tarek S; Khan, Muhammad A; Qureshi, Shakeel; Hijazi, Ziyad M

    2015-11-15

    To maintain aortic continuity, aortic arch interruption is usually treated surgically. We present our experience of aortic arch reconstruction using percutaneous implantation of covered stents and mid-term follow-up. To describe the feasibility, safety, and effectiveness using percutaneous placement of covered stents for functional aortic atresia and mid-term follow-up. Nine patients (7 males), mean age of 30.8 ±16.2 years (range 13-58 years) and mean body weight of 65.7± 14.9 kg (range 52-95 kg), were investigated for systemic hypertension and found to have functional aortic interruption. All were treated with percutaneous perforation, combined with balloon dilation and implantation of covered stents. After stent implantation, control angiograms were performed. All the patients had functional aortic interruption and continuity was established by perforating the atretic segment with trans-septal Brockenbrough needle or the stiff end of a guide wire. A covered Cheatham-Platinum CP stent was used to establish the luminal continuity of the aortic arch. Angiograms after stent deployment showed good forward flow through the stent and hemodynamic assessment revealed minimal gradients across the stent. The mean invasive descending aortic systolic blood pressure before stenting was 86.6 ± 14.3 mm Hg, which increased to 116.5 ± 16.3 mm Hg, after stenting (P = 0.004). The mean invasive descending aortic diastolic blood pressure before stenting was 63.6 ± 8.1 mm Hg, which increased to 79.7 ± 13.3 mm Hg after stenting (P = 0.002). Percutaneous treatment of functional aortic atresia with covered stents is feasible, safe, and effective alternative to surgery with excellent short- and mid-term results. © 2015 Wiley Periodicals, Inc.

  6. Injuries to the Aorta, Aortic Annulus, and Left Ventricle During Transcatheter Aortic Valve Replacement: Management and Outcomes.

    PubMed

    Langer, Nathaniel B; Hamid, Nadira B; Nazif, Tamim M; Khalique, Omar K; Vahl, Torsten P; White, Jonathon; Terre, Juan; Hastings, Ramin; Leung, Diana; Hahn, Rebecca T; Leon, Martin; Kodali, Susheel; George, Isaac

    2017-01-01

    The experience with transcatheter aortic valve replacement is increasing worldwide; however, the incidence of potentially catastrophic cardiac or aortic complications has not decreased. In most cases, significant injuries to the aorta, aortic valve annulus, and left ventricle require open surgical repair. However, the transcatheter aortic valve replacement patient presents a unique challenge as many patients are at high or prohibitive surgical risk and, therefore, an open surgical procedure may not be feasible or appropriate. Consequently, prevention of these potentially catastrophic injuries is vital, and practitioners need to understand when open surgical repair is required and when alternative management strategies can be used. The goal of this article is to provide an overview of current management and prevention strategies for major complications involving the aorta, aortic valve annulus, and left ventricle.

  7. Piper sarmentosum increases nitric oxide production in oxidative stress: a study on human umbilical vein endothelial cells.

    PubMed

    Ugusman, Azizah; Zakaria, Zaiton; Hui, Chua Kien; Nordin, Nor Anita Megat Mohd

    2010-07-01

    Nitric oxide produced by endothelial nitric oxide synthase (eNOS) possesses multiple anti-atherosclerotic properties. Hence, enhanced expression of eNOS and increased Nitric oxide levels may protect against the development of atherosclerosis. Piper sarmentosum is a tropical plant with antioxidant and anti-inflammatory activities. This study aimed to investigate the effects of Piper sarmentosum on the eNOS and Nitric oxide pathway in cultured human umbilical vein endothelial cells (HUVECs). HUVECS WERE DIVIDED INTO FOUR GROUPS: control, treatment with 180 microM hydrogen peroxide (H(2)O(2)), treatment with 150 microg/mL aqueous extract of Piper sarmentosum, and concomitant treatment with aqueous extract of PS and H(2)O(2) for 24 hours. Subsequently, HUVECs were harvested and eNOS mRNA expression was determined using qPCR. The eNOS protein level was measured using ELISA, and the eNOS activity and Nitric oxide level were determined by the Griess reaction. Human umbilical vein endothelial cells treated with aqueous extract of Piper sarmentosum showed a marked induction of Nitric oxide. Treatment with PS also resulted in increased eNOS mRNA expression, eNOS protein level and eNOS activity in HUVECs. Aqueous extract of Piper sarmentosum may improve endothelial function by promoting NO production in HUVECs.

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis

    PubMed Central

    Smith, J. Gustav; Luk, Kevin; Schulz, Christina-Alexandra; Engert, James C.; Do, Ron; Hindy, George; Rukh, Gull; Dufresne, Line; Almgren, Peter; Owens, David S.; Harris, Tamara B.; Peloso, Gina M.; Kerr, Kathleen F.; Wong, Quenna; Smith, Albert V.; Budoff, Matthew J.; Rotter, Jerome I.; Cupples, L. Adrienne; Rich, Stephen; Kathiresan, Sekar; Orho-Melander, Marju; Gudnason, Vilmundur; O’Donnell, Christopher J.; Post, Wendy S.; Thanassoulis, George

    2014-01-01

    aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in