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Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the “French paradox”

The mortality rate from coronary artery disease (CAD) in France is ~50% compared to other European countries and the United States (“French paradox”). Epidemiological studies indicate an inverse relationship between moderate wine consumption and CAD mortality. Here, we demonstrate that preincubation of vascular smooth muscle cells (VSMCs) with red wine, but not white wine, inhibits ligand binding and the subsequent tyrosine phosphorylation of the platelet‐derived growth factor β receptor (βPDGFR), which plays a critical role in the pathogenesis of atherosclerosis. As a consequence, red wine abrogates the ligand‐induced recruitment of βPDGFR‐associated signaling molecules (RasGAP, SHP‐2, PI3K, PLCγ), PDGF‐dependent downstream events such as Erk activation and induction of immediate early genes, and VSMC proliferation and migration. Wine analysis revealed flavonoids of the catechin family as major constituents of red wine, and these were identified as potent inhibitors of βPDGFR signaling. Importantly, the concentrations of red wine/catechins shown to inhibit the PDGFR in vitro correlate with the serum levels after red wine consumption in humans. We conclude that nonalcoholic constituents of red wine, which accumulate during the “mash fermentation,” inhibit ßPDGFR activation and PDGF‐dependent cellular responses in VSMCs. Therefore, catechinmediated inhibition of βPDGFR signaling offers a molecular explanation for the “French paradox.”