Parodi-Rullán Rebecca M, Soto-Prado Jadira, Vega-Lugo Jesús, Chapa-Dubocq Xavier, Díaz-Cordero Sara I, Javadov Sabzali
Cell Physiol Biochem. 2018;50(1):288-303. doi: 10.1159/000494006. Epub 2018 Oct 3.
BACKGROUND/AIMS: The mitochondrial permeability transition pore opening plays a critical role in the pathogenesis of myocardial infarction. Inhibition of cyclophilin-D (CyP-D), a key regulator of the mitochondrial permeability transition pore, has been shown to exert cardioprotective effects against ischemia-reperfusion injury on various animal models, mostly in males. However, failure of recent clinical trials requires a detailed elucidation of the cardioprotective efficacy of CyP-D inhibition. The aim of this study was to examine whether cardioprotective effects of sanglifehrin A, a potent inhibitor of CyP-D, on post-infarcted hearts depends on reperfusion.
Acute or chronic myocardial infarction was induced by coronary artery ligation with/without subsequent reperfusion for 2 and 28 days in female Sprague-Dawley rats. Cardiac function was estimated by echocardiography. Oxygen consumption rates, ROS production, permeability transition pore opening, protein carbonylation and respiratory supercomplexes were analyzed in isolated cardiac mitochondria.
Sanglifehrin A significantly improved cardiac function of reperfused hearts at 2 days but failed to protect after 28 days. No protection was observed in non-reperfused post-infarcted hearts. The respiratory control index of mitochondria was significantly reduced in reperfused infarcted hearts at 2-days with no effect at 28-days post-infarction on reperfused and non-reperfused hearts. Likewise, only a minor increase in reactive oxygen species production was observed at 2-days in non-reperfused post-infarcted hearts.
This study demonstrates that CyP-D inhibition exerts cardioprotective effects in reperfused but not in non-reperfused infarcted hearts of female rats, and the effects are observed only during acute post-infarction injury.
背景/目的：线粒体通透性转换孔开放在心肌梗死发病机制中起关键作用。亲环素-D（CyP-D）是线粒体通透性转换孔的关键调节因子，抑制它已被证明在多种动物模型（大多为雄性）中对缺血再灌注损伤具有心脏保护作用。然而，近期临床试验的失败需要详细阐明抑制CyP-D的心脏保护疗效。本研究旨在探讨CyP-D强效抑制剂桑佛莱素A对梗死心脏的心脏保护作用是否依赖于再灌注。
通过结扎雌性Sprague-Dawley大鼠冠状动脉并在有/无随后再灌注的情况下分别持续2天和28天诱导急性或慢性心肌梗死。通过超声心动图评估心脏功能。在分离的心脏线粒体中分析氧消耗率、活性氧生成、通透性转换孔开放、蛋白质羰基化和呼吸超复合体。
桑佛莱素A在2天时显著改善了再灌注心脏的心脏功能，但在28天时未能起到保护作用。在未再灌注的梗死心脏中未观察到保护作用。再灌注梗死心脏在2天时线粒体的呼吸控制指数显著降低，而在梗死后28天，再灌注和未再灌注心脏均未受影响。同样，在未再灌注的梗死心脏中，仅在2天时观察到活性氧生成有轻微增加。
本研究表明，抑制CyP-D对雌性大鼠再灌注梗死心脏具有心脏保护作用，而对未再灌注梗死心脏则无此作用，且这种作用仅在急性梗死后损伤期间观察到。
