Laboratory of Experimental Cardiology, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
Cardiovasc Res. 2012 Oct 1;96(1):23-31. doi: 10.1093/cvr/cvs232. Epub 2012 Jul 10.
Loss of calcium (Ca(2+)) homeostasis contributes through different mechanisms to cell death occurring during the first minutes of reperfusion. One of them is an unregulated activation of a variety of Ca(2+)-dependent enzymes, including the non-lysosomal cysteine proteases known as calpains. This review analyses the involvement of the calpain family in reperfusion-induced cardiomyocyte death. Calpains remain inactive before reperfusion due to the acidic pHi and increased ionic strength in the ischaemic myocardium. However, inappropriate calpain activation occurs during myocardial reperfusion, and subsequent proteolysis of a wide variety of proteins contributes to the development of contractile dysfunction and necrotic cell death by different mechanisms, including increased membrane fragility, further impairment of Na(+) and Ca(2+) handling, and mitochondrial dysfunction. Recent studies demonstrating that calpain inhibition contributes to the cardioprotective effects of preconditioning and postconditioning, and the beneficial effects obtained with new and more selective calpain inhibitors added at the onset of reperfusion, point to the potential cardioprotective value of therapeutic strategies designed to prevent calpain activation.
钙（Ca(2+)）稳态的丧失通过不同的机制导致再灌注最初几分钟内发生细胞死亡。其中之一是各种依赖 Ca(2+)的酶的不受调节的激活，包括称为钙蛋白酶的非溶酶体半胱氨酸蛋白酶。本综述分析了钙蛋白酶家族在再灌注诱导的心肌细胞死亡中的作用。由于缺血心肌中的酸性 pHi 和增加的离子强度，钙蛋白酶在再灌注前保持不活跃。然而，在心肌再灌注过程中会发生不适当的钙蛋白酶激活，随后广泛的各种蛋白质的蛋白水解作用通过不同的机制导致收缩功能障碍和坏死性细胞死亡的发展，包括膜脆性增加、进一步损害 Na(+)和 Ca(2+)处理以及线粒体功能障碍。最近的研究表明，钙蛋白酶抑制作用有助于预处理和后处理的心脏保护作用，以及在再灌注开始时添加新型和更具选择性的钙蛋白酶抑制剂所获得的有益效果，这表明旨在预防钙蛋白酶激活的治疗策略具有潜在的心脏保护价值。
