Ischemia-reperfusion induces myocardial infarction through mitochondrial Ca²⁺ overload.
Ischemia-reperfusion induces myocardial infarction through mitochondrial Ca²⁺ overload.
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DOI：
10.1016/j.yjmcc.2012.05.012
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发表时间：
2012-08
影响因子：
5
通讯作者：
Kaori Shintani-Ishida;M. Inui;Kenichi Yoshida
中科院分区：
文献类型：
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作者：
Kaori Shintani-Ishida;M. Inui;Kenichi Yoshida
线粒体和肌浆网（SR）对于心肌稳态和心功能的控制都是必不可少的。Ca 2+从胞质溶胶摄取到SR中由Ca 2+依赖性ATP酶SERCA 2a介导，其被受磷蛋白（PLN）可逆地抑制。我们先前表明，去除PLN抑制SERCA2a与（抗）PLN抗体减少胞质Ca 2+超载，从而减弱收缩带和胞衬蛋白水解的蔓延，在心脏缺血后再灌注。我们现在已经研究了抗PLN注射到心脏对大鼠缺血再灌注后心肌梗死（MI）发展的影响。而抗PLN注射衰减胞浆Ca 2+超载，它不影响MI大小6小时后再灌注开始，实际上增加它在30分钟。该抗体还增加了从线粒体到胞质溶胶中的凋亡诱导因子（AIF）的释放，表明线粒体渗透性转换孔（mPTP）的开放增强。在再灌注时给予mPTP阻断剂或线粒体Ca 2+单向转运体阻断剂显著抑制AIF的释放和MI的发展。这些结果表明，通过注射抗PLN增强SR Ca2+负荷促进了Ca2+单向转运体依赖性线粒体Ca2+摄取，从而诱导了早期再灌注期间mPTP开放和MI发展。因此，增强SR的Ca2+负荷，以独立于胞浆Ca2+超载的方式使MI恶化。鉴于胞质钙超载诱导收缩带，我们的研究结果是不一致的收缩带和MI之间的因果关系。
Both mitochondria and the sarcoplasmic reticulum (SR) are essential for myocardial homeostasis and control of cardiac function. Uptake of Ca2+from the cytosol into SR is mediated by the Ca2+-dependent ATPase SERCA2a, which is reversibly inhibited by phospholamban (PLN). We previously showed that removal of PLN inhibition of SERCA2a with an antibody to (anti-) PLN reduces cytosolic Ca2+overload, thereby attenuating the spread of contraction bands and fodrin proteolysis, during reperfusion after cardiac ischemia. We have now examined the effects of anti-PLN injection into the heart on the development of myocardial infarction (MI) after ischemia–reperfusion in rats. Whereas anti-PLN injection attenuated cytosolic Ca2+overload, it did not affect MI size 6h after the onset of reperfusion and actually increased it at 30min. The antibody also increased the release of apoptosis-inducing factor (AIF) from mitochondria into the cytosol, indicative of enhanced opening of the mitochondrial permeability transition pore (mPTP). Administration of an mPTP blocker at the time of reperfusion or of a blocker of the mitochondrial Ca2+uniporter significantly suppressed the release of AIF and the development of MI. These results indicate that the enhancement of SR Ca2+loading by anti-PLN injection facilitated Ca2+uniporter‐dependent mitochondrial Ca2+uptake and thereby induced mPTP opening and MI development during early reperfusion. The enhancement of SR Ca2+loading thus aggravates MI in a manner independent of cytosolic Ca2+overload. Given that cytosolic Ca2+overload induces contraction bands, our findings are inconsistent with a causal relation between contraction bands and MI.