title: Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling: evidence for a surface receptor.
abstract: 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 Ca(2+)-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10min with EPI or EPI-Dx at equimolar concentrations (100nM). 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.
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, United States; Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Miron, México, DF CP11340, Mexico.
authors.forename: Aldo
authors.initials: A
authors.lastname: Moreno-Ulloa
authors.affiliation: Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California, Tijuana, Baja California, Mexico.
authors.forename: Diego
authors.initials: D
authors.lastname: Romero-Perez
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
authors.affiliation: Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Miron, México, DF CP11340, Mexico.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, United States; Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Miron, México, DF CP11340, Mexico. Electronic address: israel.ramirez14@hotmail.com.
authors.forename: Israel
authors.initials: I
authors.lastname: Ramirez-Sanchez
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003911:Dextrans / Q000737:chemistry; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D003911:Dextrans; D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D002392:Catechin
keywords: Endothelial cells; Epicatechin; PI3K/AKT; eNOS