Autophagy induced by ischemic preconditioning is essential for cardioprotection.
Autophagy induced by ischemic preconditioning is essential for cardioprotection.
复制标题
DOI：
10.1007/s12265-010-9189-3
复制
发表时间：
2010-08
影响因子：
3.4
通讯作者：
Gottlieb, Roberta A.
中科院分区：
文献类型：
--
作者：
Huang, Chengqun;Yitzhaki, Smadar;Perry, Cynthia N.;Liu, Wayne;Giricz, Zoltan;Mentzer, Robert M., Jr.;Gottlieb, Roberta A.
基于越来越多的证据将自噬与预处理联系起来，我们验证了自噬是缺血预处理（IPC）所赋予的心脏保护所必需的假设。我们采用5分钟局部缺血与5分钟再灌注交替的3个周期诱导IPC，并通过冷冻切片的荧光自噬体成像来评估mccherry - lc3转基因小鼠自噬的诱导情况。我们发现，在预处理心脏的危险区，自噬体的数量迅速而显著地增加。在langendorff灌注的心脏中，经过3 × 5分钟缺血的IPC方案，我们还观察到自噬在10分钟内增加，通过p62和尸胺染料结合的Western blotting评估。为了确定自噬在IPC心脏保护中的作用，我们用自噬蛋白Atg5的显性负突变Tat-ATG5K130R抑制自噬。重组Tat-ATG5K130R灌注大鼠心脏后，IPC对心脏的保护作用减弱。为了扩大自噬在心脏保护中的潜在意义，我们还评估了三种结构不相关的心脏保护剂——utp、二氮氧化物和雷诺嗪——在HL-1细胞中诱导自噬的能力。我们发现这三种药物都能诱导自噬；自噬抑制消除了它们的保护作用。综上所述，这些发现确立了自噬在缺血和药物预处理中的末端效应。
Based on growing evidence linking autophagy to preconditioning, we tested the hypothesis that autophagy is necessary for cardioprotection conferred by ischemic preconditioning (IPC). We induced IPC with three cycles of 5 min regional ischemia alternating with 5 min reperfusion and assessed the induction of autophagy in mCherry-LC3 transgenic mice by imaging of fluorescent autophagosomes in cryosections. We found a rapid and significant increase in the number of autophagosomes in the risk zone of the preconditioned hearts. In Langendorff-perfused hearts subjected to an IPC protocol of 3 × 5 min ischemia, we also observed an increase in autophagy within 10 min, as assessed by Western blotting for p62 and cadaverine dye binding. To establish the role of autophagy in IPC cardioprotection, we inhibited autophagy with Tat-ATG5K130R, a dominant negative mutation of the autophagy protein Atg5. Cardioprotection by IPC was reduced in rat hearts perfused with recombinant Tat-ATG5K130R. To extend the potential significance of autophagy in cardioprotection, we also assessed three structurally unrelated cardioprotective agents—UTP, diazoxide, and ranolazine—for their ability to induce autophagy in HL-1 cells. We found that all three agents induced autophagy; inhibition of autophagy abolished their protective effect. Taken together, these findings establish autophagy as an end-effector in ischemic and pharmacologic preconditioning.
登录
查看更多内容
影响因子：
10.8
作者：
Ha, Tuanzhu;Hua, Fang;Li, Chuanfu
通讯作者：
Li, Chuanfu
影响因子：
13.3
作者：
Gurusamy, Narasimman;Lekli, Istyan;Das, Dipak K.
通讯作者：
Das, Dipak K.
影响因子：
37.8
作者：
Gustafsson, ÅB;Sayen, MR;Gottlieb, RA
通讯作者：
Gottlieb, RA
影响因子：
13.3
作者：
Dengiel, Joern;Kristensen, Anders Riis;Andersen, Jens S.
通讯作者：
Andersen, Jens S.
影响因子：
4.8
作者：
Chen, M;Won, DJ;Gottlieb, RA
通讯作者：
Gottlieb, RA