Disruption of Rac1 signaling reduces ischemia-reperfusion injury in the diabetic heart by inhibiting calpain
Disruption of Rac1 signaling reduces ischemia-reperfusion injury in the diabetic heart by inhibiting calpain
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DOI：
10.1016/j.freeradbiomed.2010.09.018
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发表时间：
2010-12-01
影响因子：
7.4
通讯作者：
Peng, Tianqing
中科院分区：
文献类型：
--
作者：
Shan, Limei;Li, Jianmin;Peng, Tianqing
糖尿病可加重心肌缺血/再灌注（I/R）损伤，但其机制尚不完全清楚。本研究探讨了Rad信号和钙蛋白酶在糖尿病心脏I/R损伤加重中的作用。或钙蛋白酶抑制蛋白过度表达的小鼠，用链脲佐菌素使其患糖尿病。I/R后，糖尿病心脏的Rad活性比非糖尿病心脏显著增强，糖尿病心脏显示出比非糖尿病心脏更严重的I/R损伤，表现为更多的乳酸脱氢酶释放和细胞凋亡以及心功能下降。与野生型小鼠相比，糖尿病Rac 1 ko小鼠模型的梗死面积小得多。Rac 1信号的抑制阻止了NADPH氧化酶的活化、活性氧的产生和蛋白质羰基的积累，导致钙蛋白酶活化的抑制。糖尿病心脏I/R损伤及I/R后心功能改善。总之，Rac 1激活增加糖尿病心脏I/R损伤，Rad信号传导的作用至少部分通过钙蛋白酶激活介导（C）2010 Elsevier Inc版权所有
Diabetes increases myocardial ischemia/reperfusion (I/R) injury However the underlying mechanisms remain Incompletely understood This study investigated the role of Rad signaling and calpain in exacerbated I/R injury in diabetic hearts Mice with cardiac specific deletion of Rac1 (Rad ko) and transgenic mice with cardiac specific superoxide dismutase 2 (SOD2) or calpastatin overexpression were rendered diabetic with streptozotocin Isolated perfused hearts were subjected to global I/R. After I/R Rad activity was significantly enhanced in diabetic compared with nondiabetic hearts Diabetic hearts displayed more severe I/R injury than nondiabetic hearts as evidenced by more lactate dehydrogenase release and apoptosis and decreased cardiac function These adverse impacts of diabetes were abrogated in Rac1-ko hearts or by perfusion with the Rac1 inhibitor NSC23766 In an in vivo I/R mouse model infarct size was much smaller in diabetic Rac1 ko compared with wild type mice Inhibition of Rac1 signaling prevented NADPH oxidase activation reactive oxygen species production and protein carbonyl accumulation leading to inhibition of calpain activation Furthermore SOD2 or calpastatin overexpression significantly reduced I/R injury in diabetic hearts and improved cardiac function after I/R. In summary Rac1 activation increases I/R injury in diabetic hearts and the role of Rad signaling is mediated at least in part through calpain activation (C) 2010 Elsevier Inc All rights reserved