Pharmacological Prevention of eNOS Uncoupling

Huige      Li; Ulrich      Forstermann

Abstract

Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the endothelial NO synthase (eNOS). This endothelium-derived NO is a protective molecule with antihypertensive, antithrombotic and anti-atherosclerotic properties. Cardiovascular risk factors such as hypertension, hypercholesterolemia, cigarette smoking and diabetes mellitus induce oxidative stress mostly by stimulation of the NADPH oxidase. Overproduction of reactive oxygen species leads to oxidation of tetrahydrobiopterin (BH₄), the essential cofactor of eNOS. In BH₄ deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide- producing enzyme. Consequently, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to cardiovascular pathology. Therefore, pharmacological approaches that prevent eNOS uncoupling are of therapeutic interest. Among the drugs currently in clinical use, the renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, AT1 receptor blockers, the selective aldosterone antagonist eplerenone, statins, nebivolol and pentaerithrityl tetranitrate have been shown to have the potential to prevent or reverse eNOS uncoupling under experimental conditions. Resveratrol, BH4, sepiapterin, folic acid and AVE3085 have also been shown to recouple eNOS and improve endothelial function. The long-term benefit of these compounds, however, is still controversial.

Keywords: Nitric oxide, endothelial NO synthase, eNOS uncoupling, NADPH oxidase; oxidative stress.