Format

Send to

Choose Destination
Br J Pharmacol. 2017 Dec;174(23):4329-4344. doi: 10.1111/bph.14033. Epub 2017 Oct 22.

Activation of G protein-coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy.

Author information

1
Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
2
Department of Pathophysiology, Xinxiang Medical University, Xinxiang, China.
3
Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
4
Center of Natural and Human Sciences, Federal University of ABC, Sao Paulo, Brazil.

Abstract

BACKGROUND AND PURPOSE:

Recent evidence indicates that GPER (G protein-coupled oestrogen receptor 1) mediates acute pre-ischaemic oestrogen-induced protection of the myocardium from ischaemia/reperfusion injury via a signalling cascade that includes PKC translocation, ERK1/2/ GSK-3β phosphorylation and inhibition of the mitochondrial permeability transition pore (mPTP) opening. Here, we investigated the impact and mechanism involved in post-ischaemic GPER activation in ischaemia/reperfusion injury. We determined whether GPER activation at the onset of reperfusion confers cardioprotective effects by protecting against mitochondrial impairment and mitophagy.

EXPERIMENTAL APPROACH:

In vivo rat hearts were subjected to ischaemia followed by reperfusion with oestrogen (17β-oestradiol, E2), E2 + G15, a GPER antagonist, or vehicle. Myocardial infarct size, the threshold for the opening of mPTP, mitophagy, mitochondrial membrane potential, ROS production, proteins ubiquitinated including cyclophilin D, and phosphorylation levels of ERK and GSK-3β were measured.

RESULTS:

We found that post-ischaemic E2 administration to both male and female ovariectomized-rats reduced myocardial infarct size. Post-ischaemic E2 administration preserved mitochondrial structural integrity and this was associated with a decrease in ROS production and increased mitochondrial membrane potential, as well as an increase in the mitochondrial Ca2+ load required to induce mPTP opening via activation of the MEK/ERK/GSK-3β axis. Moreover, E2 reduced mitophagy via the PINK1/Parkin pathway involving LC3I, LC3II and p62 proteins. All these post-ischaemic effects of E2 were abolished by G15 suggesting a GPER-dependent mechanism.

CONCLUSION:

These results indicate that post-ischaemic GPER activation induces cardioprotective effects against ischaemia/reperfusion injury in males and females by protecting mitochondrial structural integrity and function and reducing mitophagy.

PMID:
28906548
PMCID:
PMC5715577
DOI:
10.1111/bph.14033
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center