Biomedical Fast Takes

In cardiovascular disease, resveratrol reverses eNOS uncoupling to …

Enhance NO Power

A central cause of the decreased bioactivity of nitric oxide (NO) in cardiovascular diseases is the uncoupling of endothelial NO synthase (eNOS). This may be caused by the oxidative stress-mediated deficiency of the NOS cofactor tetrahydrobiopterin (BH4). For this reason, the reversal of eNOS uncoupling might represent a novel therapeutic approach.

‡ Folate has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH4 oxidation and improving eNOS coupling.2

In a new study, the treatment of apolipoprotein E (ApoE)§ knockout mice with resveratrol resulted in the up-regulation of endogenous antioxidants including superoxide dismutase isoforms, glutathione peroxidase, and catalase in the hearts of ApoE-KO mice. At the same time, the cardiac expression of the rate-limiting enzyme in BH4 biosynthesis, was enhanced by resveratrol. This enhancement was accompanied by an elevation in BH4 levels.

§ ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. It was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. In the last few years, it has been studied for its role in Alzheimer’s disease, immunoregulation, and cognition.

Superoxide production from ApoE-KO mice hearts was reduced by a NOS inhibitor, indicating eNOS uncoupling in this pathological model. Resveratrol treatment resulted in a reversal of eNOS uncoupling. Treatment of human endothelial cells with resveratrol led to an up-regulation of superoxide dismutase isoforms, glutathione peroxidase, and catalase.

Resveratrol decreased
superoxide production and
enhanced the inactivation of
reactive oxygen species.

In summary, in this study resveratrol decreased superoxide production and enhanced the inactivation of reactive oxygen species. The resulting reduction in BH4 oxidation, together with the enhanced biosynthesis of BH4, was probably responsible for the reversal of eNOS uncoupling. This novel mechanism (reversal of eNOS uncoupling) may be a principal factor contributing to the protective effects of resveratrol for cardiovascular disease.


  1. Xia N, Daiber A, Habermeier A, Closs EI, Thum T, Spanier G, Lu Q, Oelze M, Torzewski M, Lackner KJ, Münzel T, Förstermann U, Li H. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther 2010 Oct;335(1):149-54.

  2. Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leeson P, Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 2006 Sep 12;114(11):1193-201.

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