Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease

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Abstract

Highlights

▸ Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is an anti-atherosclerotic molecule. ▸ Hypercholesterolemia leads to oxidative stress, uncoupling of eNOS and reduced eNOS activity. ▸ The resulting reduction in NO bioavailability promotes atherogenesis. ▸ Some compounds can prevent eNOS uncoupling and enhance eNOS activity at the same time. ▸ Such pharmacological approaches are of therapeutic interest.

Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is an antihypertensive, antithrombotic and anti-atherosclerotic molecule. Hypercholesterolemia leads to a reduction in vascular NO bioavailability. This is attributed to a dysfunction of the eNOS enzyme and a reduced eNOS activity. NADPH oxidase-mediated oxidative stress 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. As a consequence of eNOS uncoupling, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to atherogenesis. Therefore, pharmacological approaches that prevent eNOS uncoupling and enhance eNOS activity are of therapeutic interest. Angiotensin-converting enzyme inhibitors, AT1 receptor blockers, statins, nebivolol and resveratrol have been shown to reverse eNOS uncoupling and to stimulate eNOS activity concurrently. Molecular mechanisms of the aforementioned drugs/compounds on eNOS functionality is summarized and discussed in this review.

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