Letter to the editor: "cyclosporin A in left ventricular remodeling after myocardial infarction".
Letter to the editor: "cyclosporin A in left ventricular remodeling after myocardial infarction".
复制标题
致编辑的信：“环孢素 A 在心肌梗死后左心室重构中的作用”。
DOI：
10.1152/ajpheart.00961.2013
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Javadov,Sabzali
中科院分区：
文献类型：
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作者：
Javadov,Sabzali
致编辑：我们怀着极大的兴趣阅读了Kholmukhamedov等人发表在《美国生理学杂志——心脏与循环生理学》上的文章。作者证明，免疫抑制剂环孢素A （CsA）可减少心肌梗死（MI）后远端（无危险）心肌区域的细胞凋亡，但不能改善心功能或防止坏死。尽管作者将CsA缺乏保护作用归因于心肌梗死后重构中的线粒体通透性过渡孔（mptp），但我们认为另一种解释可能会澄清这一结果。事实上，线粒体和mPTP开放在心肌梗死引起的心脏重塑、肥厚和心力衰竭中起着复杂的作用。首先，应该指出mPTP在坏死中起关键作用，而不是凋亡。与野生型（对照）细胞相比，亲环蛋白d敲除细胞对凋亡因子的抗性相似，但对坏死因子的抗性更高(5)。尽管mPTP以高电导打开诱导基质肿胀和线粒体外膜破裂，导致细胞色素c从线粒体内膜释放和ATP消耗，但细胞可能通过坏死而不是凋亡而死亡。mPTP开放需要Ca2+、ATP耗竭（高Pi）、高活性氧水平和中性细胞内pH，就像心脏再灌注时发生的那样。然而，由于永久性（无再灌注）冠状动脉结扎（CAL），这些改变在慢性心肌梗死后重塑期间不会严重发展。实际上，我们之前的研究表明，与缺血再灌注相比，永久性CAL治疗12或18周的大鼠心脏mPTP开放较少(1)。因此，我们认为在心肌梗死后，远端心肌中观察到的细胞凋亡可能是由Bax寡聚、Bax/电压依赖性阴离子通道相互作用或其他未知途径引起的mptp不依赖的线粒体外膜通透性所致。其次，由于啮齿动物心脏侧支血流低和/或延迟（CAL后48小时）CsA给药，药物递送到梗死（坏死）区域可能被掩盖。在之前的研究中，CsA在心肌缺血前和/或再灌注后静脉注射（单次或多次注射）可发挥心脏保护作用[见(2)]。也许这解释了为什么作者没有观察到对照组和csa治疗的心肌梗死后组在坏死区域大小或心功能方面的差异。我们想提出CsA减少细胞凋亡的另一种机制。CsA是一种非特异性mPTP抑制剂，与细胞质中的亲环蛋白a结合，抑制钙依赖性蛋白磷酸酶钙调磷酸酶(6)。
TO THE EDITOR: We read with great interest the article by Kholmukhamedov et al.(4) published in the American Journal of Physiology-Heart and Circulatory Physiology. The authors demonstrated that the immunosuppressant cyclosporin A (CsA) decreased apoptosis in remote (not at risk) regions of the myocardium after myocardial infarction (MI) but did not improve cardiac function or prevent necrosis. Though the authors attributed the absence of the protective effects of CsA to mitochondrial permeability transition pores (mPTPs) in post-MI remodeling, we believe that an alternative explanation may clarify the results.Indeed, mitochondria and mPTP opening play a complex role in cardiac remodeling, hypertrophy, and heart failure resulted from MI. First, it should be pointed out that mPTPs play a critical role in necrosis, not apoptosis. Cyclophilin-D knockout cells demonstrated similar resistance to apoptotic factors but higher resistance to necrotic factors (5) compared with wild-type (control) cells. Although mPTP opening at high conductance induces matrix swelling and rupture of the outer mitochondrial membrane, leading to the release of cytochrome c from the inner mitochondrial membrane and depletion of ATP, cells likely die via necrosis, rather than apoptosis. mPTP opening requires Ca2+, ATP depletion (high Pi), high reactive oxygen species levels, and a neutral intracellular pH, as would occur in the heart during reperfusion. However, these alterations do not severely develop during chronic post-MI remodeling, as results from permanent (no reperfusion) coronary artery ligation (CAL). Actually, our previous studies demonstrated less mPTP opening in rat hearts subjected to permanent CAL for 12 or 18 wk when compared with those subjected to ischemia-reperfusion (1). Therefore, we think that the apoptosis observed in the post-MI, remote myocardium may result from mPTP-independent outer mitochondrial membrane permeabilization caused by Bax oligomerization, Bax/voltagedependent anion channel interaction, or other unknown pathways. Second, drug delivery to the infarction (necrotic) area may have been obscured by low collateral flow in rodent hearts and/or delayed (48 h after CAL) CsA administration. In previous studies, CsA exerted cardioprotective effects when administered intravenously (bolus or multiple injections) before MI (ischemia) and/or upon reperfusion [reviewed in (2)]. Perhaps this explains why the authors did not observe a difference between control and CsA-treated post-MI groups with regard to the size of the necrotic area or cardiac function. We would like to propose an alternative mechanism by which CsA could reduce apoptosis. CsA, a nonspecific mPTP inhibitor, binds to cyclophilin A in the cytoplasm and inhibits the calcium-dependent protein phosphatase, calcineurin (6).