The effects of (−)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER)

[Display omitted] 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 re...

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Bibliographic Details
Published in:Pharmacological research 2015-10, Vol.100, p.309-320
Main Authors: Moreno-Ulloa, Aldo, Mendez-Luna, David, Beltran-Partida, Ernesto, Castillo, Carmen, Guevara, Gustavo, Ramirez-Sanchez, Israel, Correa-Basurto, José, Ceballos, Guillermo, Villarreal, Francisco
Format: Article
Language:English
Subjects:
(−)-Epicatechin
Actins - metabolism
Animals
Arteries - drug effects
Arteries - metabolism
Cacao
Catechin - pharmacology
Cattle
Cells, Cultured
Docking
EGFR
Endothelial Cells - drug effects
Endothelial Cells - metabolism
ERK 1/2
Estrogens - metabolism
Extracellular Signal-Regulated MAP Kinases - metabolism
GPER
Male
Nitric Oxide - metabolism
Phenylephrine - pharmacology
Rats
Rats, Wistar
Receptors, Cell Surface - metabolism
Receptors, Estrogen - metabolism
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - drug effects
Vasodilation - drug effects
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Summary:[Display omitted] 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.
ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2015.08.014