Neuronal nitric oxide synthase in hypertension – an update

Abstract

Hypertension is a prevalent condition worldwide and is the key risk factor for fatal cardiovascular complications, such as stroke, sudden cardiac death and heart failure. Reduced bioavailability of nitric oxide (NO) in the endothelium is an important precursor for impaired vasodilation and hypertension. In the heart, NO deficiency deteriorates the adverse consequences of pressure-overload and causes cardiac hypertrophy, fibrosis and myocardial infarction which lead to fatal heart failure and sudden cardiac death. Recent consensus is that both endothelial and neuronal nitric oxide synthases (eNOS or NOS3 and nNOS or NOS1) are the constitutive sources of NO in the myocardium. Between the two, nNOS is the predominant isoform of NOS that controls intracellular Ca2+ homeostasis, myocyte contraction, relaxation and signaling pathways including nitroso-redox balance. Notably, our recent research indicates that cardiac eNOS protein is reduced but nNOS protein expression and activity are increased in hypertension. Furthermore, nNOS is induced by the interplay between angiotensin II (Ang II) type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R), mediated by NADPH oxidase and reactive oxygen species (ROS)-dependent eNOS activity in cardiac myocytes. nNOS, in turn, protects the heart from pathogenesis via positive lusitropy in hypertension. Soluble guanylate cyclase (sGC)-cGMP/PKG-dependent phosphorylation of myofilament proteins are novel targets of nNOS in hypertensive myocardium. In this short review, we will endeavor to overview new findings of the up-stream and downstream regulation of cardiac nNOS in hypertension, shed light on the underlying mechanisms which may be of therapeutic value in hypertensive cardiomyopathy.

Erythropoietin alleviates post-resuscitation myocardial dysfunction in rats potentially through increasing the expression of angiotensin II receptor type 2 in myocardial tissues

“…In RAS, Ang I is converted into Ang II by angiotensin-converting enzyme (ACE). When Ang II binds to AT1R in the myocardium, the Ang II-AT1R axis acts as a detrimental effector, causing myocardial cell damage and development of heart failure in the following manner: Development of myocardial hypertrophy and increased production of reactive oxygen free radicals leads to cell mitochondrial damage and myocardial cell apoptosis ( 21 , 24 ); promotion of the expression of proinflammatory transcription factors, nuclear factor-κB and interleukin-6 in cells, which subsequently promotes inflammatory reactions; through the action of NADPH oxidase, ultimately increasing the production of reactive oxygen free radicals, which causes damage to cell mitochondria, myocardial hypertrophy, and myocardial fibrosis and dysfunction ( 25 ); and through the phosphatidylinositol 3-kinase/Akt pathway, wherein Akt phosphorylation is reduced and cardiac hypertrophy and cardiomyocyte autophagy are promoted, leading to heart failure ( 26 ). Strohmenger et al ( 27 ) demonstrated that administration of the Ang II antagonist telmisartan during the port-resuscitation phase in pigs improved myocardial contractility.…”

Catechins Blunt the Effects of oxLDL and its Primary Metabolite Phosphatidylcholine Hydroperoxide on Endothelial Dysfunction Through Inhibition of Oxidative Stress and Restoration of eNOS in Rats

“…Increased ROS bioavailability along with decreased NO production and increased NO consumption have been proposed to contribute to the events underlying endothelial injury. Reduced bioavailability of NO in the endothelium is an important precursor for impaired vasodilation and hypertension [20, 21]. The renal arterial infusion of oxLDL greatly enhanced ischemia/reperfusion-induced ROS and inhibited nitric oxide bioactivity [18].…”

Yogurt and Cardiometabolic Diseases: A Critical Review of Potential Mechanisms

“…Another potential mechanism is that calcium may indirectly promote endothelial NO synthase activity and NO-mediated vasodilation, increasing insulin secretion or action. Indeed, endothelial NO synthase expression and activation is defective in hypertensive individuals, and this is believed to contribute to elevated blood pressure (208).…”