Mitochondrial benzodiazepine receptors mediate cardioprotection of estrogen against ischemic ventricular fibrillation.
The cardioprotective effects of estrogen remain controversial in clinical practice. Previous reports have shown that cardioprotective mechanisms converge on the mitochondria, but the role of mitochondria in estrogen's actions on cardiac arrhythmias is unclear. Here, we report that stimulation or inhibition of mitochondrial benzodiazepine receptors (mBzR) affected ventricular fibrillation (VF) almost in an "all-or-none" manner in an in vitro rat heart model of ischemic VF. Low concentrations of estrogen did not provide antiarrhythmic effects; however, the combination of mBzR activator and estrogen reduced VF incidence in hearts from either gender. Such synergistic actions also enabled cardiomyocytes to resist metabolic stress-induced intracellular [Ca(2+)](i) overload. Ligand binding experiments revealed that estrogen itself did not affect mBzR activity under basal conditions but promoted its up-regulation under myocardial ischemia. Our results suggest that mBzR may be an important molecule for ischemic arrhythmia and may act as a molecular switch for estrogen's antiarrhythmic effects. This finding provides a clue for elucidating the conflicting results regarding estrogen's cardiac effects in clinical studies and also suggests potential new strategies for hormone treatment in the female population.
Li
Jun
J
Department of Cardiology, Tongji Hospital, Tongji University, Shanghai, China.
Xiao
Junjie
J
Liu
Ying
Y
Zhang
Gaofeng
G
Zhang
Hong
H
Liang
Dandan
D
Liu
Yi
Y
Zhang
Yangyang
Y
Hu
Yaer
Y
Yu
Zhuo
Z
Yan
Biao
B
Jiang
Bing
B
Peng
Luying
L
Zhou
Zhao-Nian
ZN
Chen
Yi-Han
YH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
D002316:Cardiotonic Agents; D002352:Carrier Proteins; D004967:Estrogens; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D004958:Estradiol; D002118:Calcium