Cell membrane mediated (−)-epicatechin effects on upstream endothelial cell signaling: Evidence for a surface receptor

The consumption of cacao-derived products, particularly in the form of dark chocolate is known to provide beneficial cardiovascular effects in normal individuals and in those with vascular dysfunction (reduced nitric oxide [NO] bioavailability and/or synthesis). Upstream mechanisms by which flavonoids exert these effects are poorly understood and may involve the participation of cell membrane receptors. We previously demonstrated that the flavanol (−)-epicatechin (EPI) stimulates NO production via Ca+2-independent eNOS activation/phosphorylation. We wished to investigate the plausible participation of a cell surface receptor using a novel cell-membrane impermeable EPI–Dextran conjugate (EPI–Dx). Under Ca2+-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10 min with EPI or EPI–Dx at equimolar concentrations (100 nM). Results demonstrate that both EPI and EPI–Dx induced the phosphorylation/activation of PI3K, PDK-1, AKT and eNOS. Interestingly, EPI–Dx effects were significantly higher in magnitude than those of EPI alone. The capacity of EPI–Dx to stimulate cell responses supports the existence of an EPI cell membrane receptor mediating eNOS activation.

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