Endothelial NOS

eNOS is a dimer containing two identical monomers of 140 kD constituted by a reductase domain, which displays binding sites for nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD), and an oxidase domain, which displays binding sites for heme group, zinc, the cofactor tetrahydrobiopterin (BH4), and the substrate L-arginine.

[18] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.

[27] Furthermore, part of antioxidants properties of NO is attributable to up-regulation of heme-oxygenase-I and ferritin expression, which reduce superoxide anion concentrations in blood vessels.

[28] eNOS expression and activity are carefully controlled by multiple interconnected mechanisms of regulation present at the transcriptional, posttranscriptional, and posttranslational levels.

[30] Posttranslational modifications of eNOS include fatty acid acylation, protein-protein interactions, substrate, and co-factor availability, and degree of phosphorylation.

[34] The C allele for the g.-786T>C polymorphism, which results in reduced eNOS expression and NO production,[35] was associated with increased risk for hypertension,[36] preeclampsia,[37] diabetic nephropathy,[38] and retinopathy,[39] migraine,[40] and erectile dysfunction.

[41] The presence of ‘Asp’ allele for the Glu298Asp polymorphism reduces eNOS activity,[42] and was associated with higher susceptibility to hypertension,[43][44] preeclampsia,[45] diabetes mellitus,[46] migraine,[40] and erectile dysfunction.

[61][62] Together, these studies suggest that statins, ACEi and PDE-5 inhibitors may restore an impaired NO production in subjects carrying the variant allele/genotype for g.-786T>C NOS3 polymorphism, thus attenuating the cardiovascular risk.

In addition to analysis of genetic polymorphisms individually, haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 were shown to affect the responses to sildenafil in patients with erectile dysfunction.