Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2

Abstract

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. Resveratrol was shown to confer vasoprotection in animal models of type 2 diabetes and aging. However, the mechanisms by which resveratrol exerts its anti-oxidative vasculoprotective effects are not completely understood. We found that in cultured coronary arterial endothelial cells resveratrol increased transcriptional activity of Nrf2 and up-regulates the expression of the Nrf2 target genes NQO1, GCLC and HMOX1. Resveratrol treatment also significantly attenuated high glucose (30 mM) -induced mitochondrial and cellular oxidative stress (assessed by flow cytometry using MitoSox and DHE staining). The aforementioned effects of resveratrol were significantly attenuated by siRNA downregulation of Nrf2 or overexpression of Keap-1, which inactivates Nrf2. To test the effects of resveratrol in vivo, we used mice fed a high fat diet (HFD). In HFD-fed Nrf2+/+ mice resveratrol treatment attenuated vascular oxidative stress, improved acetylcholine-induced vasodilation and inhibited vascular apoptosis. These effects of resveratrol were diminished in HFD-fed Nrf2−/− mice. Thus, resveratrol both in vitro and in vivo confers vasoprotective effects, which are mediated by activation of Nrf2. (Funding: ADA, AFAR, NIH).