HSP90依赖的Akt线粒体转位参与IGF-1对低温保存心脏的保护作用  

Heat-shock protein 90-dependent translocation of Akt to mitochondria mediates insulin-like growth factor 1-induced protection of rat hearts under hypothermic preservation

作　　者：余国伟[1] 陈洁[2] 陈莹莹[2] 郑鸣之[3] 沈岳良[2] 

机构地区：[1]浙江大学医学院附属第一医院心胸外科,浙江杭州310058 [2]浙江大学医学院病理与病理生理学系,浙江杭州310058 [3]浙江医学高等专科学校药理教研室,浙江杭州310053

出　　处：《中国病理生理杂志》2012年第10期1773-1778,共6页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81070201);浙江省自然科学基金资助项目(No.Y2100092);浙江省教育厅科研项目(No.Y201019167)

摘　　要：目的:观察胰岛素样生长因子1(IGF-1)是否可对抗低温保存诱导的心肌损伤,并探讨其可能的机制。方法:观察SD大鼠心脏低温保存9 h后,再灌注期左心室发展压(LVDP)和细胞凋亡指数的变化。Westernblotting法检测蛋白激酶B(Akt)蛋白表达。结果:(1)Celsior保存液中加入10 nmol/L IGF-1可促进低温保存9 h后心脏收缩功能的恢复、减少心肌细胞凋亡的发生、抑制线粒体渗透性转换孔开放。(2)IGF-1可上调心脏Akt蛋白磷酸化水平。磷脂酰肌醇3-激酶(PI3K)特异性抑制剂LY294002不仅可降低IGF-1诱导的Akt磷酸化水平,且可逆转IGF-1促进低温保存心脏心功能的恢复和抗凋亡作用。(3)抑制热休克蛋白90(HSP90)可降低IGF-1诱导的Akt磷酸化和线粒体转位,阻断IGF-1的心肌保护作用。结论:IGF-1可明显减少低温保存心脏心肌细胞凋亡的发生,促进再灌注期心功能的恢复,其机制可能与HSP90依赖性Akt的激活和线粒体转位有关。AIM ： To investigate the effect of insulin - like growth factor I （ IGF - 1 ） on hypothermic preservation of rat hearts. METHODS： Isolated rat hearts were preserved in Celsior solution with or without IGF - 1 （10 nmol/L） for 9 h, followed by 60 min of reperfusion. Cell apoptosis was assessed by TUNEL method. The left ventricular developed pressure （LVDP） was recorded. Total Akt protein and phosphorylation of Akt protein were detected by Western blotting. RESULTS： Compared with Celsior solution preservation group, IGF - 1 significantly enhanced the LVDP recovery rate, decreased the apoptotic index, and inhibited the opening of mitochondrial permeability transition pore. IGF - 1 increased the phosphorylation of Akt in 9 h of hypothemically preserved rat heart, which was inhibited by PI3K inhibitor LY294002. LY294002 also abolished the cardioprotection of IGF - 1. 17 - Allylamino - 17 - demethoxy - geldanamycin, a heat - shock protein 90 （HSP90） inhibitor, inhibited the IGF - 1 - induced increase in phosphorylation level of Akt and transola- tion to mitochondria, the improvement of cardiac functions, and the decrease in apoptosis. CONCLUSION： IGF - 1 improves the cardiac functions and decreases apoptosis in the hearts under hypothermic preservation. The mechanism might involve in HSP90 -dependent translocation in Akt to mitochondria.

关 键 词：心脏保存 胰岛素样生长因子1 AKT 热休克蛋白质90 线粒体 

分 类 号：R331[医药卫生—人体生理学]