Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart

Abstract

Nitric oxide (NO) produced in the heart by nitric oxide synthase (NOS) is a highly reactive signaling molecule and an important modulator of myocardial function. NOS catalyzes the conversion of L: -arginine to L: -citrulline and NO but under particular circumstances reactive oxygen species (ROS) can be formed instead of NO (uncoupling). In the heart, three NOS isoforms are present: neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3) are constitutively present enzymes in distinct subcellular locations within cardiomyocytes, whereas inducible NOS (iNOS, NOS2) is absent in the healthy heart, but its expression is induced by pro-inflammatory mediators. In the tissue, NO has two main effects: (i) NO stimulates the activity of guanylate cyclase, leading to cGMP generation and activation of protein kinase G, and (ii) NO nitrosylates tyrosine and thiol-groups of cysteine in proteins. Upon nitrosylation, proteins may change their properties. Changes in (i) NOS expression and activity, (ii) subcellular compartmentation of NOS activity, and (iii) the occurrence of uncoupling may lead to multiple NO-induced effects, some of which being particularly evident during myocardial overload as occurs during aortic constriction and myocardial infarction. Many of these NO-induced effects are considered to be cardioprotective but particularly if NOS becomes uncoupled, formation of ROS in combination with a low NO bioavailability predisposes for cardiac damage.

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

“…Overexpression of iNOS is known to cause cardiac fibrosis, apoptosis of cardiomyocytes and cardiac hypertrophy, whilst iNOS deficiency prevents congestive heart failure [50]. In this study we found that cardiac iNOS gene and protein expression was increased in obese females hearts compared with controls.…”

Angiotensin-(1-7) Prevents Cardiomyocyte Pathological Remodeling Through a Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate–Dependent Pathway

“…Other than eNOS, neuronal NO synthase (nNOS) also leads to NO production in the heart and has been shown to participate in cardiac protection. 19,20 Figure 2D shows pronounced changes in nNOS in cardiomyocytes from TG rats when compared with cells from SD rats treated or not with Ang II. Moreover, nNOS expression was also higher in cardiomyocytes from Ang II-infused TG rats.…”

“…NO signals in cells directly or indirectly through a cGMP-dependent signaling pathway. 20 Involvement of cGMP on Ang-(1-7) cardioprotective effects was investigated in cells treated with a guanylyl cyclase inhibitor, 1H-1,2,4oxadiazolo4,2-aquinoxalin-1-one (ODQ; 50 mol/L). As shown in Figure 4, ODQ blunted Ang-(1-7) antihypertrophic effects.…”

Serum nitrotyrosine concentration in dogs with myxomatous mitral valve disease

“…Many studies in humans and animals have reported that iNOS expression, which induce NO production, is increased in various cardiac diseases, such as myocardial infarction, DCM, ischemic heart disease, and valvular heart disease [3,10,11]. Umar et al [21] reported that cardiac remodeling, resulting in ventricular hypertrophy, dilatation, and sudden cardiac death can be initiated by iNOS overexpression. Another report indicated that the left ventricular ejection fraction and nitrotyrosine concentration had a statistically significant negative linear relationship in cytokine-induced myocardial dysfunction of dogs [18].…”