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

Abstract

Nitric oxide (NO) possesses multiple biological actions that contribute to the maintenance of cardiovascular homeostasis [1][2][3][4][5][6]. NO is formed from its precursor L-arginine by a family of NO synthases (NOSs) with stoichiometric production of L-citrulline. The NOS system consists of three different NOS isoforms, encoded by three distinct NOS genes, including neuronal (nNOS; also known as NOS-1), inducible (iNOS; also known as NOS-2) and endothelial NOS (eNOS; also known as NOS-3). It was initially indicated that nNOS and eNOS are constitutively expressed mainly in the nervous system 903-0215, JapanAbstract : Nitric oxide (NO) is synthesized by three distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human heart. The roles of NOSs in the pathogenesis of heart failure have been described in pharmacological studies with NOS inhibitors. Recently, genetically engineered animals have been used. We have generated mice in which all 3 NOS isoforms are completely disrupted (triple n/i/ eNOS / mice). Morphological, echocardiographic, and hemodynamic analysis were performed in wild-type, singly nNOS / , iNOS / , eNOS / , and triple n/i/eNOS / mice. Importantly, significant left ventricular (LV) hypertrophy and diastolic dysfunction was noted only in n/i/eNOS / mice, and those pathology was similar to diastolic heart failure in humans. Finally, treatment with an angiotensin II type 1 (AT1) receptor blocker, significantly prevented those abnormalities. These results provide the evidence that AT1 receptor pathway plays a center role in the pathogenesis of cardiac disorders in the n/i/eNOS / mice. Our studies with triple n/i/eNOS / mice provide pivotal insights into an understanding of the pathophysiology of NOSs in human heart failure.

Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation

“…In this respect, the lack of this vasodilating action in NOS1-/- mice has been suggested to affect muscle performance [ 71 ]. Results obtained in NOS1-/- mice with different cardiac injuries indicated a protective role of nNOS, although an opposite effect cannot be excluded [ 90 , 91 ]. The deficit in exercise performance of NOS1-/- muscles may be the consequence, at least in part, of a decreased oxygen delivery following blood flow impairment.…”

Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators

“…Since constitutive nitric oxide (NO) synthases (NOS) are among the crucial factors responsible for the maintenance of myocardial Ca 2+ homeostasis, myocardial relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli, the aberrant regulation and dysfunction of these important proteins in hypertension, hemodynamic overload, and atrial fibrillation are known to lead to the production of superoxide instead of NO (Carnicer et al, 2013 ; Shibata et al, 2013 ). Deregulation of NOS1 and NOS3 phosphorylation and glutathionylation are potent contributors to vascular disease, myocardial ischemia, reperfusion injury, MI, cardiac hypertrophy, and failure (Carnicer et al, 2013 ).…”

The Protective Effect of Antioxidants Consumption on Diabetes and Vascular Complications

“…In fact, NOS-opathies include three isoforms: neuronal (nNOS; NOS1), inducible (iNOS; NOS2), and the most well studied endothelial (eNOS; NOS3). Deletion of all three in mice results in spontaneous coronary artery diseases, myocardial infarction, and sudden cardiac death, [223,224] and results confirmed a protective role of eNOS and nNOS, whereas iNOS was found to exert an unfavorable role. Khanna et al recently reviewed the implication of isoforms in diabetic cardiomyopathy and highlighted the important role of epigenetic modifications in the regulation of gene expression [225].…”