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Significance Statement
Flavonoids are known for their healthy effects and limited toxicity. The flavanol (-)-epicatechin increases endothelial cell nitric oxide (NO) but the mechanism of this cardiovascular effect is not fully understood. The authors in this paper demonstrated using a variety of techniques (cellular, ex-vivo and siRNA methods) the participation of GPER as a mediator of (-)-epicatechin effect. These studies highlight the importance of GPER as a potential drug target for treatment of cardiovascular diseases
Journal Reference
Pharmacol Res. 2015;100:309-20.
Moreno-Ulloa A1, Mendez-Luna D2, Beltran-Partida E3, Castillo C4, Guevara G4, Ramirez-Sanchez I1, Correa-Basurto J5, Ceballos G4, Villarreal F6.
[expand title=”Show Affiliations”]- 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.
- Laboratorio de modelado Molecular y Diseño de Fármacos, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
- Universidad Autónoma de Baja California, Facultad de Odontología, Mexicali, BC, Mexico.
- Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
- 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.
- University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, USA. Electronic address: [email protected].
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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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