scholarly journals Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

2011 ◽  
Vol 301 (5) ◽  
pp. H2093-H2101 ◽  
Author(s):  
Baptiste Kurtz ◽  
Helene B. Thibault ◽  
Michael J. Raher ◽  
John R. Popovich ◽  
Sharon Cawley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mitochondrial Respiration ◽  
Pressure Overload ◽  
Lv Remodeling ◽  
Stress Levels ◽  
Nitric Oxide Synthase 3 ◽  
And Function ◽  
Oxide Synthase

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload

2007 ◽  
Vol 293 (1) ◽  
pp. H620-H627 ◽  
Author(s):  
Emmanuel S. Buys ◽  
Michael J. Raher ◽  
Sarah L. Blake ◽  
Tomas G. Neilan ◽  
Amanda R. Graveline ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Lv Remodeling ◽  
And Function ◽  
Oxide Synthase ◽  
Deficient Mice

Although nitric oxide synthase (NOS)3 is implicated as an important modulator of left ventricular (LV) remodeling, its role in the cardiac response to chronic pressure overload is controversial. We examined whether selective restoration of NOS3 to the hearts of NOS3-deficient mice would modulate the LV remodeling response to transverse aortic constriction (TAC). LV structure and function were compared at baseline and after TAC in NOS3-deficient (NOS3−/−) mice and NOS3−/− mice carrying a transgene directing NOS3 expression specifically in cardiomyocytes (NOS3−/−TG mice). At baseline, echocardiographic assessment of LV dimensions and function, invasive hemodynamic measurements, LV mass, and myocyte width did not differ between the two genotypes. Four weeks after TAC, echocardiographic and hemodynamic indexes of LV systolic function indicated that contractile performance was better preserved in NOS3−/−TG mice than in NOS3−/− mice. Echocardiographic LV wall thickness and cardiomyocyte width were greater in NOS3−/− mice than in NOS3−/−TG mice. TAC-induced cardiac fibrosis did not differ between these genotypes. TAC increased cardiac superoxide generation in NOS3−/−TG but not NOS3−/− mice. The ratio of NOS3 dimers to monomers did not differ before and after TAC in NOS3−/−TG mice. Restoration of NOS3 to the heart of NOS3-deficient mice attenuates LV hypertrophy and dysfunction after TAC, suggesting that NOS3 protects against the adverse LV remodeling induced by prolonged pressure overload.

Abstract 15999: The Divergent Effects of Exercise Training After Myocardial Infarction or Pressure Overload Depend Critically on Endothelial Nitric Oxide Synthase

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yanti Octavia ◽  
Elza v Deel ◽  
Monique d Waard ◽  
Martine d Boer ◽  
An Moens ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Exercise Training ◽  
Endothelial Nitric Oxide Synthase ◽  
Pressure Overload ◽  
Beneficial Effects ◽  
Enhanced Chemiluminescence ◽  
Enos Uncoupling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

AIMS: Beneficial effects of aerobic exercise training are widely recognized. However, previously we discovered that the positive effects of exercise depend on the underlying cause of cardiac failure. Here we tested the hypothesis that endothelial nitric oxide synthase (eNOS) dependent regulation of the balance between nitric oxide and superoxide (O2•-) is critically involved in determining the effects of exercise. METHODS: Mice were exposed to 8 weeks of voluntary wheel running exercise training (EX) or sedentary housing (SED) immediately following myocardial infarction (MI), pressure overload from a transverse aortic constriction (TAC), or sham (SH) surgery. Subsequently, left ventricular (LV) ejection fraction (EF) was measured by echocardiography and Picrosirius Red staining was performed to measure collagen content. Additionally, total and NOS-dependent LV O2•- were measured using lucigenin-enhanced chemiluminescence without or with NOS inhibitor, L-NAME. eNOS uncoupling was evaluated by determining eNOS monomer dimer protein ratio and peroxynitrite (ONOO-) levels were measured through luminol-enhanced chemiluminescence. RESULTS: Cardiac dysfunction and fibrosis were ameliorated by exercise in MI but not in TAC mice (Table 1). MI and TAC both increased LV O2•- levels. Strikingly, EX diminished O2•- generation in MI, but exacerbated O2•- generation in TAC (Table 1). Furthermore, the EX-induced increase in O2•- levels in TAC were largely NOS-dependent. Accordingly, MI and TAC-induced eNOS uncoupling was normalized by EX in MI but aggravated in TAC mice (Table 1). Similarly, increased ONOO- levels following MI and TAC were diminished by EX in MI, but exacerbated by EX in TAC (Table 1). CONCLUSIONS: EX reduces eNOS-mediated cardiac oxidative stress in MI. In contrast, beneficial effects of EX are lacking in cardiac pressure-overload following TAC, due to EX-induced aggravation of ONOO- formation, eNOS uncoupling and concomitant oxidative stress.

scholarly journals A short duration of high-fat diet induces insulin resistance and predisposes to adverse left ventricular remodeling after pressure overload

2008 ◽  
Vol 295 (6) ◽  
pp. H2495-H2502 ◽  
Author(s):  
Michael J. Raher ◽  
Helene B. Thibault ◽  
Emmanuel S. Buys ◽  
Darshini Kuruppu ◽  
Nobuyuki Shimizu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Myocardial Perfusion ◽  
Short Duration ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Systemic Hypertension ◽  
High Fat ◽  
Lv Remodeling ◽  
And Function ◽  
The Impact

Insulin resistance is an increasingly prevalent condition in humans that frequently clusters with disorders characterized by left ventricular (LV) pressure overload, such as systemic hypertension. To investigate the impact of insulin resistance on LV remodeling and functional response to pressure overload, C57BL6 male mice were fed a high-fat (HFD) or a standard diet (SD) for 9 days and then underwent transverse aortic constriction (TAC). LV size and function were assessed in SD- and HFD-fed mice using serial echocardiography before and 7, 21, and 28 days after TAC. Serial echocardiography was also performed on nonoperated SD- and HFD-fed mice over a period of 6 wk. LV perfusion was assessed before and 7 and 28 days after TAC. Nine days of HFD induced systemic and myocardial insulin resistance (assessed by myocardial 18F-fluorodeoxyglucose uptake), and myocardial perfusion response to acetylcholine was impaired. High-fat feeding for 28 days did not change LV size and function in nonbanded mice; however, TAC induced greater hypertrophy, more marked LV systolic and diastolic dysfunction, and decreased survival in HFD-fed compared with SD-fed mice. Compared with SD-fed mice, myocardial perfusion reserve was decreased 7 days after TAC, and capillary density was decreased 28 days after TAC in HFD-fed mice. A short duration of HFD induces insulin resistance in mice. These metabolic changes are accompanied by increased LV remodeling and dysfunction after TAC, highlighting the impact of insulin resistance in the development of pressure-overload-induced heart failure.

Nitric oxide synthase and changes in oxidative stress levels in embryonic kidney observed in a rabbit model of intrauterine growth restriction

2016 ◽  
Vol 36 (7) ◽  
pp. 628-635 ◽  
Author(s):  
Horacio Figueroa ◽  
Jorge Cifuentes ◽  
Mauricio Lozano ◽  
Cristobal Alvarado ◽  
Claudia Cabezas ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Intrauterine Growth Restriction ◽  
Rabbit Model ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Stress Levels ◽  
Oxide Synthase

scholarly journals Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension

2016 ◽  
Vol 310 (1) ◽  
pp. L40-L49 ◽  
Author(s):  
Adeleye J. Afolayan ◽  
Annie Eis ◽  
Maxwell Alexander ◽  
Teresa Michalkiewicz ◽  
Ru-Jeng Teng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Nitric Oxide Synthase ◽  
Mitochondrial Biogenesis ◽  
Endothelial Nitric Oxide Synthase ◽  
Copy Number ◽  
And Function ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2, partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen.

Role of TLR-4/IL-6/TNF-α, COX-II and eNOS/iNOS pathways in the impact of carvedilol against hepatic ischemia reperfusion injury

2021 ◽  
pp. 096032712199944
Author(s):  
Mohamed IA Hassan ◽  
Fares EM Ali ◽  
Abdel-Gawad S Shalkami
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Liver Enzymes ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Aim: Hepatic ischemia/reperfusion (I/R) injury is a syndrome involved in allograft dysfunction. This work aimed to elucidate carvedilol (CAR) role in hepatic I/R injury. Methods: Male rats were allocated to Sham group, CAR group, I/R group and CAR plus I/R group. Rats subjected to hepatic ischemia for 30 minutes then reperfused for 60 minutes. Oxidative stress markers, inflammatory cytokines and nitric oxide synthases were measured in hepatic tissues. Results: Hepatocyte injury following I/R was confirmed by a marked increase in liver enzymes. Also, hepatic I/R increased the contents of malondialdehyde however decreased glutathione contents and activities of antioxidant enzymes. Furthermore, hepatic I/R caused elevation of toll-like receptor-4 (TLR-4) expression and inflammatory mediators levels such as tumor necrosis factor-α, interleukin-6 and cyclooxygenase-II. Hepatic I/R caused down-regulation of endothelial nitric oxide synthase and upregulation of inducible nitric oxide synthase expressions. CAR treatment before hepatic I/R resulted in the restoration of liver enzymes. Administration of CAR caused a significant correction of oxidative stress and inflammation markers as well as modulates the expression of endothelial and inducible nitric oxide synthase. Conclusions: CAR protects liver from I/R injury through reduction of the oxidative stress and inflammation, and modulates endothelial and inducible nitric oxide synthase expressions.

Inducible nitric oxide synthase augments injury elicited by oxidative stress in rat cardiac myocytes

1998 ◽  
Vol 274 (1) ◽  
pp. C245-C252 ◽  
Author(s):  
Junsuke Igarashi ◽  
Masashi Nishida ◽  
Shiro Hoshida ◽  
Nobushige Yamashita ◽  
Hiroaki Kosaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Myocardial Injury ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
No Donor ◽  
Oxide Synthase ◽  
Gpx Activity

The effects of nitric oxide (NO) produced by cardiac inducible NO synthase (iNOS) on myocardial injury after oxidative stress were examined. Interleukin-1β induced cultured rat neonatal cardiac myocytes to express iNOS. After induction of iNOS,l-arginine enhanced NO production in a concentration-dependent manner. Glutathione peroxidase (GPX) activity in myocytes was attenuated by elevated iNOS activity and by an NO donor, S-nitroso- N-acetyl-penicillamine (SNAP). Although NO production by iNOS did not induce myocardial injury, NO augmented release of lactate dehydrogenase from myocyte cultures after addition of H2O2(0.1 mM, 1 h). Inhibition of iNOS with Nω-nitro-l-arginine methyl ester ameliorated the effects of NO-enhancing treatments on myocardial injury and GPX activity. SNAP augmented the myocardial injury induced by H2O2. Inhibition of GPX activity with antisense oligodeoxyribonucleotide for GPX mRNA increased myocardial injury by H2O2. Results suggest that the induction of cardiac iNOS promotes myocardial injury due to oxidative stress via inactivation of the intrinsic antioxidant enzyme, GPX.

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