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Resveratrol attenuates TNF--induced activation of coronary arterial endothelial cells: role of NF-B inhibition

Department of Physiology, New York Medical College, Valhalla, New York

Submitted 30 March 2006 ; accepted in final form 8 May 2006

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its cardioprotective effects are not completely understood. Because TNF--induced endothelial activation and vascular inflammation play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits TNF--induced signal transduction in human coronary arterial endothelial cells (HCAECs). We found that TNF- significantly increased adhesiveness of the monocytic THP-1 cells to HCAECs, an effect that could be inhibited by pretreatment with resveratrol and the NF-B inhibitor pyrrolidine dithiocarbamate. Previously, we found that TNF- activates NAD(P)H oxidases, and our recent data showed that TNF--induced endothelial activation was prevented by the NAD(P)H oxidase inhibitor apocynin or catalase plus SOD. Resveratrol also inhibited H₂O₂-induced monocyte adhesiveness. Using a reporter gene assay, we found that, in HCAECs, TNF- significantly increased NF-B activity, which could be inhibited by resveratrol (>50% inhibition at 10^–6 mol/l) and pyrrolidine dithiocarbamate. Resveratrol also inhibited TNF--induced, NF-B-driven luciferase expression in rat aortas electroporated with the reporter gene construct. In TNF--treated HCAECs, resveratrol (in the submicromolar range) significantly attenuated expression of NF-B-dependent inflammatory markers inducible nitric oxide synthase, IL-6, bone morphogenetic protein-2, ICAM-1, and VCAM. Thus resveratrol at nutritionally relevant concentrations inhibits TNF--induced NF-B activation and inflammatory gene expression and attenuates monocyte adhesiveness to HCAECs. We propose that these anti-inflammatory actions of resveratrol are responsible, at least in part, for its cardioprotective effects.

stilbene; atheroprotection; phytoestrogen; vascular aging; inflammation

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