Upregulation and Activation of eNOS by Resveratrol * Response
Wallerath et al 1 reported that the stilbene derivative transresveratrol, an ingredient of red wine, stimulates acute nitric oxide (NO) release from vascular endothelial cells and induces upregulation of endothelial nitric oxide synthase (eNOS) gene expression after 24 to 72 hours incubation. Resveratrol-enhanced eNOS expression and activity were considered to contribute to the vasoprotective activity of red wine. However, this conclusion may be premature, because contradicting findings and
... ng findings and possible adverse consequences of eNOS overexpression have to be considered. (1) Conducting tone measurements on endothelium-preserved arteries, we and others detected no resveratrol-induced vasodilatations. 2,3 Consistently, real-time measurements of resveratrolmediated NO release from porcine coronary arteries revealed only nonsignificant elevations of 15Ϯ6% over basal NO levels. 3 In contrast, Wallerath et al 1 determined acute NO effects of resveratrol in a cell culture system of EA.hy 926 and calculated eNOS activity indirectly by assessment of cGMP increase in reporter cells which may not reflect the situation in preserved native endothelium. (2) Wallerath et al 1 suggested resveratrol is a major antioxidant constituent of red wine. However, many studies showed that other phenols (eg, gallic acid, flavonoids, and tannins) are present in red wines in far higher concentrations and exhibit greater antioxidant activity than resveratrol. Moreover, the free trans-resveratrol content of the wines tested by Wallerath et al 1 was higher (29.8 and 73.6 mol/l, respectively) than in most red wines (with concentrations Ͻ10 mol/l). Additionally, we found superoxide scavenging capacity and inhibition of superoxidegenerating enzymes by resveratrol to be several orders of magnitude lower compared with other wine phenols (Taubert et al, unpublished data, 2002), making resveratrol intake with red wine unlikely to delay superoxide-induced NO degradation. (3) Recent evidence indicates that resveratrol is nearly completely metabolized to the 4Ј-O-glucuronide before entering systemic circulation, 4 so that in vivo vascular effects may be limited to this conjugate, whereas biological effects in the present study were only assessed employing unconjugated resveratrol. (4) It has not been unequivocally proven that eNOS upregulation exerts only beneficial vascular effects. Conversely, longterm overexpression of eNOS has been recently found to accelerate atherogenesis in apoE-deficient mice. 5 In conclusion, we believe that summarized evidence to date is not sufficient to propose a vasoprotective activity of resveratrol in vivo. Hence, it appears speculative to postulate resveratrol to be implicated in the cardioprotection of red wine.