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

Aldo Moreno-Ulloa, David Mendez-Luna, Ernesto Beltran-Partida, Carmen Castillo, Gustavo Guevara, Israel Ramirez-Sanchez, José Correa-Basurto, Guillermo Ceballos, Francisco Villarreal

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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.

Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalPharmacological Research
Volume100
DOIs
StatePublished - 9 Oct 2015

Keywords

  • (-)-Epicatechin
  • Cacao
  • Docking
  • EGFR
  • ERK 1/2
  • ERK 1/2
  • GPER

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