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

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.

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  1. 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.
  2. Laboratorio de modelado Molecular y Diseño de Fármacos, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
  3. Universidad Autónoma de Baja California, Facultad de Odontología, Mexicali, BC, Mexico.
  4. Laboratorio de Investigación Integral Cardiometabólica, Sección de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
  5. 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.
  6. University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, USA. Electronic address: [email protected].
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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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effects (-)-epicatechin on endothelial cells involve G protein-coupled estrogen receptor (GPER)