The Ever-Expanding Influence of the Endothelial Nitric Oxide Synthase

Nitric oxide (NO) generated by the endothelial NO synthase (eNOS) plays an essential role in the maintenance of vascular homeostasis and the prevention of vascular inflammation. There are a myriad of mechanisms that regulate the activity of the enzyme that may prove to represent interesting therapeutic opportunities. In this regard, the kinases that phosphorylate the enzyme and regulate its activity in situations linked to vascular disease seem to be particularly promising. Although the actions of NO were initially linked mainly to the activation of the guanylyl cyclase and the generation of cyclic GMP in vascular smooth muscle cells and platelets, it is now clear that NO elicits the majority of its actions via its ability to modify redox-activated cysteine residues in a process referred to as S-nitrosylation. The more wide spread use of mass spectrometry to detect S-nitrosylated proteins has helped to identify just how large the NO sphere of influence is and just how many cellular processes are affected. It may be an old target, but the sheer impact of eNOS on vascular health really justifies a revaluation of therapeutic options to maintain and protect its activity in situations associated with a high risk of developing cardiovascular disease.