AMPK可能经减轻心肌细胞内质网应激而发挥抗凋亡作用

项目名称： AMPK可能经减轻心肌细胞内质网应激而发挥抗凋亡作用

项目编号： No.31300979

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 张琳

作者单位： 中国人民解放军第四军医大学

项目金额： 26万元

中文摘要： 腺苷酸活化蛋白激酶(AMPK)可抑制细胞凋亡，在心脏缺血-再灌注损伤中发挥重要的保护作用，但其抑制凋亡的机制尚未探明。我们发现模拟失重4周大鼠心肌AMPK表达降低，可影响内质网应激而调节心肌细胞凋亡。本研究拟采用模拟失重4周大鼠，在心脏缺血-再灌注条件下，证明激活AMPK明显降低心肌缺血边界区心肌细胞凋亡率，从而缩小心肌梗死面积，发挥心保护作用。同时阐明AMPK可能通过以下新机制而抑制凋亡：AMPK经抑制蛋白质合成而减轻内质网应激程度；从而阻断因内质网过度应激导致的下游信号转导通路(CHOP-Ero1-IP3R通路)激活，防止内质网钙离子向线粒体的转运；防止因线粒体钙离子超载导致内源性线粒体凋亡通路的激活，从而降低心肌细胞凋亡率。该结果在航天员返回地面时防止立位耐力不良引起心肌损伤中，具有一定的理论参考价值；亦可为临床上防治心肌缺血-再灌注损伤提供新思路。

中文关键词： 模拟失重；心肌细胞；缺血-再灌注；腺苷酸活化蛋白激酶；内质网应激

英文摘要： The AMP-activated protein kinase (AMPK) inhibits apoptosis of cardiomyocytes, and plays an importantly protective role in cardiac ischemia-reperfusion injury. However, the mechanisms underlying the inhibition to apoptosis are still unclear. We have found that the expression of AMPK reduced in hearts of simulated weightlessness rats, and that AMPK could regulate apoptosis of cardiomyocytes through affecting the endoplasmic reticulum stress. Therefore, The aims of this study are (1) to prove that activated AMPK could reduce apoptosis rate in ischemia marginal zone and decreased the infarct size of heart in 4-week simulated weightlessness rats; and (2) to illuminate the mechanisms inhibited apoptosis by AMPK would involve that AMPK reduces the endoplasmic reticulum stress through the inhibition of protein synthesis which alleviates higher endoplasmic reticulum stress. The downstream pathway (CHOP-Ero1-IP3R pathway) induced by the endoplasmic reticulum over-stress would not be activated, and the calcium transport from endoplasmic reticulum to mitochondrion may be reduced. Without the calcium overload in mitochondrion, the endogenous mitochondrial apoptosis pathway may not be activated, and the apoptosis rate would be reduced during ischemia-reperfusion. This study will provide the theoretical basis for preventing as

英文关键词： simulated weightlessness；cardiomyocytes；ischemia-reperfusion；AMP-activated protein kinase (AMPK)；endoplasmic reticulum stress