Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Abstract

. Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289: H2616-H2623, 2005. First published July 29, 2005 doi:10.1152/ajpheart.00546.2005.-Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS Ϫ/Ϫ ), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N -nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS Ϫ/Ϫ mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MIϩvehicle, and MIϩL-NAME (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS Ϫ/Ϫ compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS Ϫ/Ϫ mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

“…The importance of the CNP/NPRB axis is furthermore illustrated by a series of studies about nitric oxide synthase, supporting the concept that cGMP, a second messenger not stimulated by interaction of CNP with NPRC, is a key player in the local regulation of cardiac remodelling and function after myocardial infarction [36][37][38][39].…”

Inhibition of inducible nitric oxide synthase (iNOS) by simvastatin attenuates cardiac hypertrophy in rats

“…It was proved that ISO administration increased iNOS producing greater amounts of NO [27,30]. iNOS is expressed at low levels in cytosol of normal cardiomyocytes but could be induced in response to several stimuli such as tissue injury, inflammation, cytokines, and growth factors as well as cardiovascular disease [10,31,49,61]. Overexpression of iNOS causes cardiomyopathy, heart block, and sudden death [36].…”

“…Several investigators have demonstrated that iNOS expression in cardiomyocytes is increased by numerous stimuli including inflammatory mediators, cytokines, tissue ischaemia, hypertension, and LVH [19,31,38,44]. Overexpression of iNOS in cardiomyocytes increased myocardial nitric oxide (NO) production and resulted in inflammatory cell infiltrate, LVH, cardiac fibrosis and contractile dysfunction.…”

Pharmacological Prevention and Reversion of Erectile Dysfunction After Radical Prostatectomy, by Modulation of Nitric Oxide/cGMP Pathways

“…Continuous long-term administration of nitric oxide donors and ■ phosphodiesterase 5 inhibitors has shown preventive and corrective effects in a rat model of PD: studies in patients with PD are now needed 45 days later 11,[37][38][39][40][41] at the injection site. Other less frequently employed but nonetheless useful animal models are based on either the successive injections of an adenoviral construct expressing a constitutively active tGF-β1 protein, leading to penile curvature during the erect state and, at times, calcification within the plaque, 42 or on a single fibrin injection that mimics the extravasation of fibrinogen, initiating acute inflammation followed by the rapid development of the PD-like plaque.…”

“…14,15,17 Both tGF-β1 and myostatin, another profibrotic factor within the tGF-β family, are involved in this process, 41 and it is quite likely that the key downstream signaling occurs via the smad pathway, which is the mechanism common to most factors in this family. 43 a tight skin (tsk) mouse model has been described that develops a spontaneous PD-like plaque with penile bending and areas of chondroid metaplasia with heterotypic ossification.…”