Calcineurin Aβ gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction
Calcineurin Aβ gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction
复制标题
DOI：
10.1161/01.res.0000107197.99679.77
复制
发表时间：
2004-01-09
影响因子：
20.1
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Bueno, OF;Lips, DJ;Molkentin, JD
心血管疾病是世界工业化国家死亡和发病的主要原因，其中冠心病（CHD）占这些死亡人数的66%。急性心肌梗死是一种典型的与长期冠心病相关的后遗症，通过细胞凋亡和坏死死亡导致心室心肌的大规模损失。在本研究中，我们研究了钙调素活化蛋白磷酸酶钙调磷酸酶（PP2B）在心脏急性缺血再灌注损伤后心脏凋亡的调控作用。钙调磷酸酶- β基因靶向小鼠在缺血再灌注损伤后，与品系匹配的野生型对照小鼠相比，存活心肌损失更大，DNA阶梯和TUNEL增强，功能性能损失更大。进行RNA表达谱分析以揭示与这种心脏保护丧失相关的潜在机制。有趣的是，钙调磷酸酶β(-/-)心脏的特征是基因表达普遍下调，约占所有被调查基因的6%。与这一观察结果一致，活化T细胞核因子(NFAT)-荧光素酶报告基因转基因小鼠在基线和缺血再灌注损伤后的心脏中钙调磷酸酶（-/-）表达降低。最后，激活的NFAT突变体的表达保护心肌细胞免受凋亡刺激，而NFAT的直接抑制则增加了细胞死亡。这些结果代表了第一个基因功能丧失数据，显示了钙调磷酸酶- nfat信号在心脏中的促生存作用。
Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin Abeta gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin Abeta(-/-) hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin Abeta(-/-) hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.