Differential effects of red and white wines on inhibition of the platelet-derived growth factor receptor: impact of the mash fermentation

Moderate wine consumption is associated with a significant reduction of cardiovascular mortality. The molecular basis of this phenomenon remains unknown. Platelet-derived growth factor (PDGF) is an important contributor to atherogenesis. We investigated the effects of selected red and white wines on PDGF receptor (PDGFR) signalling in rat and human vascular smooth muscle cells (VSMCs). All red wines concentration dependently inhibited the ligand-induced tyrosine phosphorylation of the PDGFR, downstream signalling events such as mitogen activated protein (MAP) kinase activation (Erk 1/2) and induction of immediate early genes (Egr-1, c-fos), and PDGF-induced cellular responses, whereas all white wines had no effect. At concentrations achieved after wine consumption in humans, all red wines completely abolished PDGF-dependent VSMC proliferation and migration. Red wines also inhibited PDGFR phosphorylation in vascular tissue, and in human coronary smooth muscle cells. Quantitative analyses of all tested wines and of samples collected at various time points (Days 0-16) of the 'mash fermentation', which is only performed for red wine, revealed that flavonoids of the catechin family, which potently inhibit PDGFR signalling, are extracted from grape seeds and skins during this process and therefore accumulate specifically in red wine. The accumulation of flavonoids correlated with the inhibitory potency of red wines on PDGFR signalling. Furthermore, this procedure could be imitated by incubation of wines with shredded grape seeds, and flavonoid-enriched white wine inhibited the PDGFR as potently as red wines. Only red wines abrogate a critical pathogenic mechanism during atherogenesis, PDGFR signalling, in VSMCs. This effect is mediated by non-alcoholic constituents, which accumulate during the mash fermentation. Our findings offer a molecular explanation for the vasoprotective effects particularly of red wine. Therefore, future epidemiological studies should consider differential protective effects of red and white wine in vivo.