Modulatory effect of resveratrol, a natural phytoalexin, on endothelial adhesion molecules and intracellular signal transduction

Resveratrol (3,4',5-trihydroxystilbene), a stress-induced molecule present in Vitis Vinifera organs, is a natural ingredient in wine, therefore present in the Mediterranean diet. Recent studies associated red wine consumption,with decreased mortality from cardiovascular disease in wine-drinking countries. As resveratrol has been documented in the medical literature as an active ingredient in traditional Oriental medicine together with other related stilbenes, a role far this compound was hypothesized for its antiaggregating, hypolipemic and anti-inflammatory activities. Objections to this hypothesis were: a) the low amount of resveratrol in wines, and b) lack of data on resveratrol's kinetics and metabolism. We demonstrated that i) both trans- and cis-forms of resveratrol isomers and their glycosides should be considered for biological activity and that ii) resveratrol is absorbed after oral wine ingestion, enters the bloodstream and reaches peak plasma concentration of 1 mu M after 1 h. Most studies confirmed resveratrol's activities at concentrations above 1 mu M, casting doubts on its efficacy when present at lower concentrations attained with diet. Considering resveratrol's protein kinase inhibitor activity it can be shown that resveratrol down-regulates expression of adhesion molecules ICAM-1 and VCAM-1 at 100 nM. Thus, low doses of resveratrol nor only decrease two adhesion molecules usually expressed in atherogenesis and metastatic and inflammatory processes, but may also interfere with cell DNA. Parallelisms of intracellular signal transduction in plant and eukaryotic cells, different activity on mitogen-activated protein kinases and oxidative pathways, and modulation of transcription factors NFkB and AP1 could help to explain the action of resveratrol.