Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction
Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction
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DOI：
10.1152/ajpheart.00663.2007
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发表时间：
2007-10-01
影响因子：
4.8
通讯作者：
Zweier, Jay L.
中科院分区：
文献类型：
--
作者：
Talukder, M. A. Hassan;Kalyanasundaram, Anuradha;Zweier, Jay L.
心肌缺血-再灌注（I/R）损伤与收缩功能障碍、心律失常和心肌细胞死亡有关。肌浆网Ca ~（2+）-ATP酶（SERCA）活性降低导致的细胞内Ca ~（2+）超载是这种损伤的重要机制。虽然SERCA功能的上调被充分证明可以改善缺血后的心脏功能，但是在药理学抑制SERCA改善缺血后功能方面存在相互矛盾的报道。SERCA 2a是调节细胞内Ca 2+稳态的主要心脏亚型;然而，SERCA 1a已被证明取代SERCA 2a，具有更快的Ca 2+转运动力学。因此，为了进一步解决这个问题，并评估是否SERCA 1a表达可以改善缺血后的心脏功能和心肌挽救，在体外和体内心肌I/R研究进行了SERCA 1a转基因（SERCA 1a（+/+））和非转基因（NTG）小鼠。Langendorff灌注的心脏进行30分钟的全脑缺血，然后再灌注。与NTG小鼠相比，SERCA 1a（+/+）小鼠的基线缺血前冠状动脉流量和左心室发展压力显著更大。不依赖于再灌注诱导的氧化应激，与NTG心脏相比，SERCA 1a（+/+）心脏表现出极大改善的缺血后（45分钟）收缩恢复，持续性心律失常较少。形态测量显示心肌结构保存较好，梗死较少，电子显微镜显示SERCA 1a（+/+）心脏的肌原纤维和线粒体超微结构保存较好。重要的是，SERCA 1a（+/+）心脏的缺血内Ca 2+水平显着较低。在体内局部I/R期间也观察到SERCA 1a的心脏保护作用，再灌注24小时后心肌梗死面积减少。因此，SERCA 1a（+/+）心脏明显保护免受I/R损伤，表明SERCA 1a亚型的表达减少缺血后Ca 2+过载，从而提供有效的心肌保护。
Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca2+ overload with reduced activity of sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca2+ homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca2+ transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a(+/+)) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a(+/+) mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a(+/+) hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a(+/+) hearts. Importantly, intraischemic Ca2+ levels were significantly lower in SERCA1a(+/+) hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a(+/+) hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca2+ overload and thus provides potent myocardial protection.