TY - JOUR
T1 - The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER)
AU - Moreno-Ulloa, Aldo
AU - Mendez-Luna, David
AU - Beltran-Partida, Ernesto
AU - Castillo, Carmen
AU - Guevara, Gustavo
AU - Ramirez-Sanchez, Israel
AU - Correa-Basurto, José
AU - Ceballos, Guillermo
AU - Villarreal, Francisco
N1 - Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/10/9
Y1 - 2015/10/9
N2 - 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.
AB - 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.
KW - (-)-Epicatechin
KW - Cacao
KW - Docking
KW - EGFR
KW - ERK 1/2
KW - ERK 1/2
KW - GPER
UR - http://www.scopus.com/inward/record.url?scp=84941128004&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2015.08.014
DO - 10.1016/j.phrs.2015.08.014
M3 - Artículo
C2 - 26303816
SN - 1043-6618
VL - 100
SP - 309
EP - 320
JO - Pharmacological Research
JF - Pharmacological Research
ER -