Nitric oxide synthases: regulation and function

Abstract

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

“…Adenoviral eNOS transduction into SMCs is a model we and others have used to study the effect of localized delivery of NO to SMC [11,12,14,21], which is relevant to developing a gene therapy approach to halting deleterious intimal hyperplasia in injured arterial vessels [7] [6]. Following the validation of genes up and down-regulated, we identified a cluster of HSP70 genes that were up-regulated by eNOS overexpression in human SMCs.…”

“…There are three main nitric oxide synthase (NOS) isoforms, nNOS (neuronal), iNOS (inducible) and eNOS (endothelial) and all catalyze the production of NO from L-arginine and oxygen. In the endothelium eNOS is the enzyme most active in generating NO, and whose deficiency is linked to vascular maladies [5,6]. It is established that reduced eNOS activity causes an increase in smooth muscle cell proliferation after vascular injury, leading to an increase in the intimal layer of the vascular wall, and further narrowing of the vessel lumen.…”

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

“…Furthermore, a recent study in patients showed reduced renal NOx excretion in response to the VEGF receptor antagonistic RTKI pazopanib 17. Endogenous NO is formed by conversion of l ‐arginine to citrulline and NO by 3 NO synthases (NOS1‐3) 18. In addition, NO can be formed in mammals independent of NOS activity by sequential reduction of nitrate via nitrite to NO, and oral nitrate supplementation has been shown to reduce arterial pressure as well as renal damage 19, 20, 21, 22, 23…”

In vitro effect of nanosilver on gene expression of superoxide dismutases and nitric oxide synthases in chicken sertoli cells

“…Thus, indicating that nanosilver is not toxic in low concentration, although it affects gene expression in its all concentrations. Certainly, the activation of an enzyme was influenced by several factors in the cell in that the amount of its gene expression would be the only factor (Yamakura and Kawasaki, 2010;Forstermann and Sessa, 2012). In addition, the final function of an enzyme could not be resulted only from variations in its gene expression.…”