G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3β Pathway after Ischemia/Reperfusion

Abstract

Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively. Analysis of the three ER knockouts (Esr1-/-, Esr2-/- and Gper1-/-) showed that only the Gper1-/- hearts lost their ability to be protected by 40 nM estrogen as measured by heart function, infarct size and mitochondrial Ca2+ overload, an index of mitochondrial permeability transition pore (mPTP) activity. Analysis of Akt, ERK1/2 and GSK-3β salvage kinases uncovered Akt and ERK1/2 transient activation by estrogen whose phosphorylation increased during the first 5 min of non-ischemic perfusion. All these increase in phosphorylation effects were abrogated in Gper1-/-. Inhibition of MEK1/2/ERK1/2 (1 μM U0126) and PI-3K/Akt (10 μM LY294002) signaling showed that the MEK1/2/ERK1/2 pathway via GSK-3β exclusively was responsible for cardioprotection as an addition of U0126 prevented estrogen-induced GSK-3β increased phosphorylation, resistance to mitochondrial Ca2+-overload, functional recovery and protection against infarction. Further, inhibiting PKC translocation (1 μM chelerythrin-chloride) abolished estrogen-induced cardioprotection. These data indicate that estrogen-Gper1 acute coupling plays a key role in cardioprotection against ischemia/reperfusion injury in male mouse via a cascade involving PKC translocation, ERK1/2/GSK-3β phosphorylation leading to the inhibition of the mPTP opening.

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

“…For instance, Pugach et al reported that ERβ was not expressed in either neonatal or adult male or female mouse or rat ventricular myocytes. This observation is inconsistent with earlier reports . In addition, there are controversies surrounding the cellular localization of GPR30.…”

Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors

“…It could stimulate the MEK1/2-ERK1/2 pathway, which in turn induces GSK3-β phosphorylation preventing opening of mPTP, or it could act straight to GSK3-β to prevent mPTP opening. These evidences uphold once again the role that the RAF/ MEK/ERK signaling pathway has in cardioprotection, this is supported by several articles in Literature (Grohé, Kahlert, Löbbert, & Vetter, 1998;Hausenloy & Yellon, 2009;Kabir et al, 2015;Node et al, 1997) Studies revealed how, in cardiomyocytes, the RAF/MEK/ERK pathway carries out in pressure-overloaded myocardium an important role for the development of hypertrophy and ribosomal biogenesis. It regulates hypertrophic gene induction, even though it could be not sufficient for cellular morphological changes necessary for cardiomyocyte hypertrophy.…”

G protein-coupled estrogen receptor regulates heart rate by modulating thyroid hormone levels in zebrafish embryos

“…To identify the receptor required for estradiol's protective effects, Kabir and colleagues subjected hearts from male mutant mice lacking either GPER, ERα or ERβ to ischemia-reperfusion injury in the presence of estradiol or vehicle. Estradiol treatment protected wildtype and ERα and ERβ mutant mice from injury, but had no effect on GPER mutant mice (35), demonstrating that estradiol exerts its protective effects via GPER, independently of ERα or ERβ. The extent to which ER and GPER signaling pathways interact likely depends on cell type, developmental stage, sex and/or pathology.…”