Resveratrol in Metabolic Syndrome: Effect on Platelet Hyper-reactivity and HDL Lipid Peroxidation

Patients with metabolic syndrome are at increased risk of thrombotic complications, including myocardial infarction and cardiovascular death. A meta-analysis of the studies assessing cardiovascular risk in metabolic syndrome found a pooled relative risk for incident cardiovascular events and death of 1.78. This propensity for thrombotic vascular events is in the context of an increasing prevalence of metabolic syndrome, which in the 2003-2006 NHANES Survey was found in 34% of the US population over the age of 20. Two important contributors to the development of myocardial infarction and stroke are lipid rich atheromatous plaques and concomitant platelet aggregation in response to the fissuring of these plaques. A growing body of evidence implicates oxidative modification of lipoprotein lipids and apolipoproteins in the genesis of plaques. Platelet hyperactivity and the variable response to antiplatelet therapy are features of the metabolic syndrome. Oxidative modifications of LDL enhance activation of platelets, which themselves are oxidatively stressed. Myeloperoxidase (MPO) initiates lipid peroxidation leading to dysfunctional HDL production. Therefore, the hypotheses for the proposed investigations will address the effects of resveratrol on platelet hyperactivity and HDL protein modifications in patients with metabolic syndrome. Resveratrol, as predicted from its structure, is an electron rich molecule that can reduce free radicals. It has distinctive actions, however, that differ from compounds that are conventionally referred to as "anti-oxidants". It has particular potency as an inhibitor of radical formation by a number of peroxidases that likely participate in the pathophysiology of metabolic syndrome. These include MPO, the peroxidase site of prostaglandin H synthase-1 (PGHS-1; cyclooxygenase-1(COX-1)) and cytochrome c. We will test the hypothesis that: 1. resveratrol reduces platelet activation in patients with metabolic syndrome. and 2. that resveratrol reduces the oxidative modification of HDL proteins in patients with metabolic syndrome.