TY - JOUR
T1 - 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
AU - Feng, Yansheng
AU - Madungwe, Ngonidzashe B.
AU - da Cruz Junho, Carolina Victoria
AU - Bopassa, Jean C.
N1 - Publisher Copyright:
© 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
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U2 - 10.1111/bph.14033
DO - 10.1111/bph.14033
M3 - Article
C2 - 28906548
AN - SCOPUS:85034080011
SN - 0007-1188
VL - 174
SP - 4329
EP - 4344
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 23
ER -