Inducible Nitric Oxide Synthase Deficiency Protects the Heart From Systolic Overload–Induced Ventricular Hypertrophy and Congestive Heart Failure

Abstract

Abstract-Inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes of patients and experimental animals with congestive heart failure (CHF). Here we show that iNOS expression plays a role in pressure overload-induced myocardial chamber dilation and hypertrophy. In wild-type mice, chronic transverse aortic constriction (TAC) resulted in myocardial iNOS expression, cardiac hypertrophy, ventricular dilation and dysfunction, and fibrosis, whereas iNOS-deficient mice displayed much less hypertrophy, dilation, fibrosis, and dysfunction. Consistent with these findings, TAC resulted in marked increases of myocardial atrial natriuretic peptide 4-hydroxy-2-nonenal (a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) in wild-type mice but not in iNOS-deficient mice. In response to TAC, myocardial endothelial NO synthase and iNOS was expressed as both monomer and dimer in wild-type mice, and this was associated with increased reactive oxygen species production, suggesting that iNOS monomer was a source for the increased oxidative stress. Moreover, systolic overload-induced Akt, mammalian target of rapamycin, and ribosomal protein S6 activation was significantly attenuated in iNOS-deficient mice. Furthermore, selective iNOS inhibition with 1400W (6 mg/kg per hour) significantly attenuated TAC induced myocardial hypertrophy and pulmonary congestion. These data implicate iNOS in the maladaptative response to systolic overload and suggest that selective iNOS inhibition or attenuation of iNOS monomer content might be effective for treatment of systolic overload-induced cardiac dysfunction. (Circ Res. 2007;100:1089-1098.)Key Words: superoxide anion Ⅲ peroxynitrite Ⅲ iNOS monomer Ⅲ mTOR S everal investigators have demonstrated that inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes and endocardial endothelium of patients and animals with ventricular hypertrophy or congestive heart failure (CHF) regardless of cause. 1-4 Thus, iNOS was coexpressed with tumor necrosis factor-␣ in cardiac myocytes from patients with dilated cardiomyopathy 2 and increased in several animal models of ventricular hypertrophy or CHF. 5 Although unregulated NO production by iNOS has been proposed to exert negative effects on cardiomyocyte function, the effect of iNOS expression on ventricular hypertrophy and CHF in the in vivo heart is controversial. Thus, Heger et al 6 reported that overexpression of iNOS in cardiac myocytes increased myocardial NOS activity and NO production but had no effect on cardiac morphology or function. In contrast, Mungrue et al 7 reported that cardiac-specific overexpression of iNOS resulted in inflammatory cell infiltrate, left ventricular (LV) hypertrophy, dilation, fibrosis, and contractile dysfunction. The level of iNOS expression in these transgenic mice would depend on the promoter activity, and the iNOSrelated phenotypes might vary depending on the level of myocardial iNOS expression. Furthermore, the effects of stress-induced iNOS expression in...

Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction

“…The lack of change in myocardial nitrotyrosine content in the EC-SOD −/− mice under unstressed conditions may be accounted for by insufficient sensitivity of the assays for detecting small changes in these measurements. The increase of cardiac fibrosis in the EC-SOD −/− mice is analogous to previous reports that EC-SOD exerts anti-fibrotic activity in the lung [5,12] The increases of nitrotyrosine in the mice subjected to MI in the present study are consistent with previous reports demonstrating increased oxidative stress in the failing heart [1,13,19,20]. Thus, in animals with aortic constriction or MI, the development of heart failure was associated with increases of myocardial nitrotyrosine [13,20] and myocardial superoxide production [13,20,21].…”

“…The increase of cardiac fibrosis in the EC-SOD −/− mice is analogous to previous reports that EC-SOD exerts anti-fibrotic activity in the lung [5,12] The increases of nitrotyrosine in the mice subjected to MI in the present study are consistent with previous reports demonstrating increased oxidative stress in the failing heart [1,13,19,20]. Thus, in animals with aortic constriction or MI, the development of heart failure was associated with increases of myocardial nitrotyrosine [13,20] and myocardial superoxide production [13,20,21]. Several sources for increased superoxide production have been identified in the failing heart, including the mitochondrial respiratory chain [22], uncoupled nitric oxide synthase [13,20], NADPH oxidase [23] and xanthine oxidase [24].…”

“…Echocardiographic images were obtained with a Visualsonics high resolution Veve 660 system as previously described [13]. LV cross sectional area at end diastole (LVCSA d ) and at end systole (LVCSA s ), LV long axis diameter at end diastole (LVD d ) or at end systole (LVD s ), and LV short axis wall thickness were measured.…”

Chronic hypoxia increases peroxynitrite, MMP9 expression, and collagen accumulation in fetal guinea pig hearts

“…Although O 2 − levels were not measured in the current study, the evidence that both LNIL and NAC inhibit lipid peroxidation is consistent with oxidative stress, associated with generation of NO and O 2 − , respectively. We propose that the increase in lipid peroxidation in HPX fetal hearts is likely mediated through increased peroxynitrite generation (36,37).…”

Nitric Oxide Synthases and Heart Failure ― Lessons from Genetically Manipulated Mice

“…However, cardiomyo- [50] showed improved survival, lessened LV remodeling and dysfunction, and decreased myocardial apoptosis. Furthermore, iNOS-KO mice with heart failure induced by cardio-specific overexpression of tumor necrosis factor-α exhibited improved β-adrenergic inotropic responsiveness.…”