Mitochondrial benzodiazepine receptors mediate cardioprotection of estrogen against ischemic ventricular fibrillation
Mitochondrial benzodiazepine receptors mediate cardioprotection of estrogen against ischemic ventricular fibrillation
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DOI：
10.1016/j.phrs.2009.03.003
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发表时间：
2009-07-01
影响因子：
9.3
通讯作者：
Chen, Yi-Han
中科院分区：
文献类型：
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作者：
Li, Jun;Xiao, Junjie;Chen, Yi-Han
雌激素的心脏保护作用在临床实践中仍然存在争议。先前的报道表明，心脏保护机制集中在线粒体上，但线粒体在雌激素对心律失常的作用中所起的作用尚不清楚。在这里，我们报告了在体外大鼠缺血性心室颤动模型中，线粒体苯二氮卓受体（mBzR）的刺激或抑制几乎以“全有或无”的方式影响心室颤动（VF）。低浓度雌激素没有抗心律失常的作用；然而，mBzR激活剂和雌激素的联合使用降低了男女心脏VF的发生率。这种协同作用也使心肌细胞能够抵抗代谢应激诱导的细胞内[Ca2+](i)过载。配体结合实验表明，雌激素本身在基础条件下不影响mBzR活性，但在心肌缺血时促进其上调。我们的研究结果表明mBzR可能是缺血性心律失常的重要分子，并可能作为雌激素抗心律失常作用的分子开关。这一发现为阐明临床研究中雌激素对心脏作用的相互矛盾的结果提供了线索，也为女性人群的激素治疗提供了潜在的新策略。2009爱思唯尔有限公司版权所有。
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 [Ca2+](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. (C) 2009 Elsevier Ltd. All rights reserved.