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

作者：Feng, Yansheng; Madungwe, Ngonidzashe B.; da Cruz Junho, Carolina Victoria; Bopassa, Jean C.^*

来源：British Journal of Pharmacology, 2017, 174(23): 4329-4344.

DOI：10.1111/bph.14033

• PERMEABILITY TRANSITION PORE
• CONCISE GUIDE
• BLOOD-FLOW
• CELL-DEATH
• IN-VIVO
• AUTOPHAGY
• GPR30
• PHARMACOLOGY
• ISCHEMIA
• HEART

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-3 beta 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 (17 beta-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-3 beta 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-3 beta 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.

• 出版日期2017-12
• 单位新乡医学院