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

Yansheng Feng, Ngonidzashe B. Madungwe, Carolina Victoria da Cruz Junho, Jean C Bopassa

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4329-4344
Number of pages16
JournalBritish Journal of Pharmacology
Volume174
Issue number23
DOIs
StatePublished - Dec 1 2017

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Mitochondrial Degradation
Estrogen Receptor alpha
G-Protein-Coupled Receptors
Reperfusion Injury
Reperfusion
Myocardium
Glycogen Synthase Kinase 3
Mitochondrial Membrane Potential
Estrogens
Myocardial Infarction
Phosphorylation
Ubiquitinated Proteins
Mitogen-Activated Protein Kinase Kinases
Estradiol
Ischemia

ASJC Scopus subject areas

  • Pharmacology

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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. / Feng, Yansheng; Madungwe, Ngonidzashe B.; da Cruz Junho, Carolina Victoria; Bopassa, Jean C.

In: British Journal of Pharmacology, Vol. 174, No. 23, 01.12.2017, p. 4329-4344.

Research output: Contribution to journalArticle

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