Concerted effort by studies in our and other laboratories on the cardioprotective effects of resveratrol, and red wine with and without alcohol, have shown the following. First, resveratrol inhibits low-density lipoprotein (LDL) oxidation. Oxidation of LDL is considered a key primary event in the initiation of atherosclerosis. Because resveratrol has antioxidant properties, we tested whether it affected LDL oxidation. LDL isolated from normolipidemic adult males was oxidatively modified using Cu2+, with and without the addition of resveratrol. LDL oxidation was monitored by reactivity to thiobarbituric acid, agarose gel electrophoresis, and uptake into macrophages. Resveratrol significantly inhibited LDL oxidation.4–6 Secondly, resveratrol is shown to inhibit platelet aggregation—platelets are actively involved in the process of hemostasis, by which injury in the vascular endothelium is rapidly repaired in order not to compromise the fluidity of the blood. In normal endothelium injury, platelets adhere to the subendothelial matrix of a damaged vessel, spread over the surface and recruit additional platelets to form a thrombus. Improper regulation or over reactivity of this repair system can lead to pathological thrombosis. Studies show that platelet aggregation by a number of agonists is suppressed by resveratrol, both in vitro and in vivo.7–9 Administration of resveratrol (4 mg/kg/day) to rabbits fed a high cholesterol diet caused a 35% reduction in the average ADP-induced platelet aggregation rate (PAR), which was indistinguishable from animals fed a normal diet.7,10 Third, resveratrol suppresses proliferation of smooth muscle cells and pulmonary aortic endothelial cells. Migration and proliferation of smooth muscle cells in the intima of susceptible vessels is a requisite for atherogenesis. We found that exposure to resveratrol reduces proliferation of smooth muscle cells accompanied by G1S block.11–13 Similarly, resveratrol also inhibits proliferation of cultured bovine pulmonary aortic endothelial cells (BPAEC) concomitant with induction of nitric oxide synthase in a dose-dependent manner.14–16 Fourth, in rabbits intragastrically fed resveratrol (4 mg/kg/day) for a duration of five weeks beginning one week prior to induced endothelial injury by denudation in the iliac artery, hyperplasia in the damaged endothelial vessel wall was inhibited, as evidenced by reduction of intimal proliferation index [scored as the ratio of intimal to (intimal + medial) area] from 0.41 ± 0.13 in control animals to 0.28 ± 0.07 in resveratrol-fed animals (P < 0.01). In addition, the relative content of smooth muscle cells, characterized by their “hills and valley” shape and positive reactivity for α-actin, in the intima of resveratrol-fed animals was also proportionately suppressed.17,18 Fifth, the mean area of atherosclerotic plaques was reduced from 56.4 ± 13.5 in rabbits fed a hypercholesterolemic diet to 33.6 ± 19.6 (arbitrary units) in animals fed resveratrol.19 Lastly, resveratrol pronouncedly inhibits proliferation of cultured human aortic smooth muscle cells,20,21 concomitant with dose-dependent increase in the expression of tumor suppressor gene p53, heat shock protein HSP27, quinone reductase 1 and 2, and altered subcellular distribution of nitric oxide synthase and apoptosis inducing factor.20
Taken together, these results provide support for the conclusion that resveratrol acts as a cardioprotective agent by a plethora of activities impinging on events key to the prevention of atherosclerosis and CHD, thereby reinforcing the notion that age-adjusted CHD deaths may be independently modulated by diet-based strategies including use of grape polyphenol resveratrol.