Calpain Protects the Heart from Hemodynamic Stress
Calpain Protects the Heart from Hemodynamic Stress
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DOI：
10.1074/jbc.m111.248088
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Taneike, Manabu;Mizote, Isamu;Otsu, Kinya
钙蛋白酶是一类钙离子依赖性细胞内半胱氨酸蛋白酶家族，包括广泛表达的μ-钙蛋白酶和m-钙蛋白酶。两者都是异源二聚体，由不同的大催化亚基（μ-钙蛋白酶的钙蛋白酶1和m-钙蛋白酶的钙蛋白酶2）和共同的调节亚基（钙蛋白酶4）组成。钙蛋白酶在器官（包括心脏）中的生理作用尚不清楚，但已表明钙蛋白酶在患病心脏中被Ca 2+超负荷激活，导致心功能障碍。在这项研究中，产生了心脏特异性钙蛋白酶4缺陷小鼠，以阐明钙蛋白酶在心脏中响应血流动力学应激的作用。心脏特异性钙蛋白酶4缺失导致钙蛋白酶1和2蛋白水平降低，在基线条件下未显示心脏表型，但在压力超负荷后1周引起左心室扩张、收缩功能障碍和心力衰竭伴间质纤维化。压力超负荷钙蛋白酶4缺乏心脏采取了膜不渗透染料，伊文思蓝，表明质膜破坏。使用双光子激光扫描显微镜的膜修复试验显示，钙蛋白酶4缺陷的心肌细胞未能重新密封已被激光照射破坏的质膜。因此，数据表明钙蛋白酶可以保护心脏免受血流动力学压力（例如压力超负荷）的影响。
Calpains make up a family of Ca2+-dependent intracellular cysteine proteases that include ubiquitously expressed mu- and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for mu-calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca2+ overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.