title: The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER).
abstract: We have provided evidence that the stimulatory effects of (-)-epicatechin ((-)-EPI) on endothelial cell nitric oxide (NO) production may involve the participation of a cell-surface receptor. Thus far, such entity(ies) has not been fully elucidated. The G protein-coupled estrogen receptor (GPER) is a cell-surface receptor that has been linked to protective effects on the cardiovascular system and activation of intracellular signaling pathways (including NO production) similar to those reported with (-)-EPI. In bovine coronary artery endothelial cells (BCAEC) by the use of confocal imaging, we evidence the presence of GPER at the cell-surface and on F-actin filaments. Using in silico studies we document the favorable binding mode between (-)-EPI and GPER. Such binding is comparable to that of the GPER agonist, G1. By the use of selective blockers, we demonstrate that the activation of ERK 1/2 and CaMKII by (-)-EPI is dependent on the GPER/c-SRC/EGFR axis mimicking those effects noted with G1. We also evidence by the use of siRNA the role that GPER has on mediating ERK1/2 activation by (-)-EPI. GPER appears to be coupled to a non Gαi/o or Gαs, protein subtype. To extrapolate our findings to an ex vivo model, we employed phenylephrine pre-contracted aortic rings evidencing that (-)-EPI can mediate vasodilation through GPER activation. In conclusion, we provide evidence that suggests the GPER as a potential mediator of (-)-EPI effects and highlights the important role that GPER may have on cardiovascular system protection.
authors: University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, USA; Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Aldo
authors: A
authors: Moreno-Ulloa
authors: Laboratorio de modelado Molecular y Diseño de Fármacos, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: David
authors: D
authors: Mendez-Luna
authors: Universidad Autónoma de Baja California, Facultad de Odontología, Mexicali, BC, Mexico.
authors: Ernesto
authors: E
authors: Beltran-Partida
authors: Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Carmen
authors: C
authors: Castillo
authors: Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Gustavo
authors: G
authors: Guevara
authors: University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, USA; Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Israel
authors: I
authors: Ramirez-Sanchez
authors: Laboratorio de modelado Molecular y Diseño de Fármacos, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico; Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: José
authors: J
authors: Correa-Basurto
authors: Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Guillermo
authors: G
authors: Ceballos
authors: University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, USA. Electronic address: fvillarr@ucsd.edu.
authors: Francisco
authors: F
authors: Villarreal
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000199:Actins; D004967:Estrogens; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D010656:Phenylephrine; D009569:Nitric Oxide; D002392:Catechin; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: (−)-Epicatechin; Cacao; Docking; EGFR; ERK 1/2; GPER