Journal
CURRENT OPINION IN PHARMACOLOGY
Volume 13, Issue 2, Pages 161-167Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.coph.2013.01.006
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Funding
- Collaborative Research Center [SFB 553]
- DFG (Deutsche Forschungsgemeinschaft), Bonn, Germany [LI-1042/1-1]
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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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