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Background:Resveratrol is a phytoalexin present in red wine. It has been shown to protect LDL from peroxidative degradation. Objective: In consideration of the low plasma concentration of orally adsorbed resveratrol (which is insufficient for antioxidant protection of LDL), we studied another effect of the compound. Design: Because resveratrol is a tyrosine kinase inhibitor like other members of the tyrphostin family, we hypothesized that it has the ability to modify intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule l (VCAM-1) expression by stimulated endothelial cells. We studied the ability of resveratrol to inhibit such adhesion molecule expression and to block the adhesion of monocytes and granulocytes to endothelial cells. Results: We showed that resveratrol, at concentrations as low as 1 mol/L and 100 nmol/L, significantly inhibited ICAM-1 and VCAM-1 expression by tumor necrosis factor ␣ (TNF-␣)-stimulated human umbilical vein endothelial cells and lipopolysaccharide-stimulated human saphenous vein endothelial cells (HSVEC), respectively. In addition, we showed that resveratrol induced a significant inhibition in the adhesion of U937 monocytoid cells to lipopolysaccharide-stimulated HSVEC. Such inhibition was comparable with that obtained when anti-VCAM-1 monoclonal antibody was used instead of resveratrol. Resveratrol also significantly inhibited the adhesion of neutrophils to TNF-␣-stimulated NIH/3T3 ICAM-1-transfected cells, whereas neutrophils activated by formyl-methionyl-leucyl-phenylalanine did not significantly modify adhesion to NIH/3T3 ICAM-1-transfected cells. Conclusions: Our results indicate activity of resveratrol on endothelial cells and a new interpretation of an effect independent of its antioxidant function.

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Aims/hypothesis. Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mechanisms are poorly understood. We tested the hypothesis that insulin increases monocyte-endothelial interactions, which are implicated in atherosclerosis. Methods. We treated human umbilical vein endothelial cells with insulin (10 −10 to 10 −7 mol/l) for 0 to 24 h. To dissect potentially implicated signal transduction pathways, we treated endothelial cells with known pharmacological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3′-kinase (PI3′-kinase) inhibitor wortmannin (3×10 −8 to 10 −6 mol/l), involved in insulin-induced endothelial nitric oxide synthase stimulation, and the p38 mitogen-activated protein (p38MAP) kinase inhibitor SB-203580 (10 −7 to 2×10 −6 mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays.Results. At pathophysiological concentrations (10 −9 to 10 −7 mol/l), insulin concentration-dependently induced vascular cell adhesion molecule (VCAM)-1 (average increase: 1.8-fold) peaking at 16 h. By contrast, the expression of intercellular adhesion molecule-1 and E-selectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the absence of cytotoxicity, wortmannin significantly potentiated the effect of insulin alone on VCAM-1 surface expression and monocytoid cell adhesion, whereas SB-203580 (10 −6 mol/l) completely abolished such effects. Conclusions/interpretation. These observations indicate that insulin promotes VCAM-1 expression in endothelial cells through a p38MAP-kinase pathway, amplified by the PI3′-kinase blockage. This could contribute to explaining the increased atherosclerosis occurring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3′-kinase pathway. [Diabetologia (2004) Macro-and microvascular complications are the major causes of morbidity and mortality in Type 1 and Type 2 diabetes [1]. The pathogenesis of accelerated atherosclerosis in diabetes is not known, but several mechanisms have been implicated. Clinical and epidemiological studies have shown associations between hyperinsulinaemia, accompanying states of insulin resistance, and cardiovascular disease. These are partly independent of related risk factors like hypertriglyceridaemia, low HDL concentrations and hypertension [1]. Compensatory hyperinsulinaemia resulting from insulin resistance increases the production of plasminogen activator inhibitor-1 and various growth