Resveratrol, a Polyphenolic Compound Found in Wine, Inhibits Tissue Factor Expression in Vascular Cells

Abstract

Abstract-A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease mortality. The phytochemical resveratrol found in wine, derived from grapes, has been thought to be responsible for cardiovascular benefits associated with wine consumption because it was shown to have antioxidant and antiplatelet activities. In the present investigation, we examined the effect of resveratrol on induction of tissue factor (TF) expression in vascular cells that were exposed to pathophysiological stimuli. The data presented herein show that resveratrol, in a dose-dependent manner, inhibited the expression of TF in endothelial cells stimulated with a variety of agonists, including interleukin-1␤ (IL-1␤), tumor necrosis factor-␣ (TNF␣) and lipopolysaccharide (LPS). A similar inhibition of TF induction was also seen in LPS stimulated monocytes that were pretreated with resveratrol before their stimulation with LPS. In addition, resveratrol was shown to inhibit the LPS-induced expression of TNF␣ mRNA in endothelial cells and of TNF␣ and IL-1␤ mRNA in monocytes. Nuclear run-on analysis in endothelial cells showed that resveratrol inhibited TF expression at the level of transcription.

Suppression of human monocyte tissue factor induction by red wine phenolics and synthetic derivatives of resveratrol

“…Induction of TF and measurement of TF procoagulant activity were performed essentially as described earlier [13,14]. Briefly, 1 ml of PBMC was aliquoted into round bottom polypropylene tubes.…”

“…The cell pellets were suspended in 250 µl of buffer A containing 15 mM n-octyl-B-Dglucopyranoside, freeze-thawed twice, and sonicated for 30 s. Aliquots of cell lysates were incubated in a 96-well microplate with a reagent mixture containing factor VIIa (10 nM), factor X (175 nM) and CaCl 2 (5 mM, all concentrations are final concentrations, total volume, 50 µl) for 15 min. Factor Xa generated in the reaction mixture was measured in a chromogenic assay as described earlier [13]. Serial dilutions of relipidated human TF were used (substituted in place of cell lysates) to construct a standard curve.…”

“…To test whether resveratrol and quercetin (two phenolic compounds that were shown to inhibit TF expression [13,14]) exhibit synergism, PBMC were pretreated with varying concentrations of resveratrol, quercetin alone or in combination of the two, followed by a 6 h incubation with 10 ng/ml LPS to induce tissue factor expression. As evident from Fig.…”

“…Cardiovascular benefits associated with moderate wine consumption have been thought to stem, at least partly, from antioxidant [7][8][9] and anti-platelet activities [10][11][12] of wine phenolics, particularly resveratrol. Recent studies published by us [13,14] and others [15] showed that resveratrol and quercetin suppressed tissue factor induction in vascular cells. Resveratrol and other wine phenolics were also shown to inhibit synthesis of proatherogenic eicosanoids [12], reduce inflammation [16][17][18] and suppress skin carcinogenesis [19,20].…”

“…In addition, TF-FVIIa and other activated coagulation proteases activate protease-activated receptors (PARs), which trigger a plethora of signaling events leading to functional alterations that are relevant to pathogenesis of atherosclerosis and coronary heart diseases (CHD) [36][37][38][39]. Therefore, we hypothesized earlier that the red wine phenolics provide protection against atherosclerosis and CHD by suppressing the aberrant expression of TF, and showed that the wine phenolics, resveratrol and quercetin, suppressed TF induction on endothelial cells and mononuclear cells [13,14]. However, a 10 to 100 µM concentration of resveratrol or quercetin was required to suppress TF induction.…”