Endoplasmic reticulum stress-dependent activation of ATF3 mediates the late phase of ischemic preconditioning.
Endoplasmic reticulum stress-dependent activation of ATF3 mediates the late phase of ischemic preconditioning.
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DOI：
10.1016/j.yjmcc.2014.08.011
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发表时间：
2014-11
影响因子：
5
通讯作者：
Bhatnagar, Aruni
中科院分区：
文献类型：
--
作者：
Brooks, Alan C.;Guo, Yiru;Singh, Mahavir;McCracken, James;Xuan, Yu-Ting;Srivastava, Sanjay;Bolli, Roberto;Bhatnagar, Aruni
缺血预处理（Ischemic preconditioning，PC）是对短暂性心肌缺血的一种适应性反应，可保护心脏免受随后的缺血/再灌注（ischemia/reperfusion，I/R）损伤。然而，其心脏保护作用的机制仍不清楚。成年雄性C57/BL 6小鼠，预处理6个周期的4分钟冠状动脉闭塞和再灌注，心肌细胞显示核转位的ATF 3，和ATF 6和PERK磷酸化后30分钟。ER蛋白、ATF 3和ATF 4的丰度在PC后24小时增加;然而，在表达XBP-1-Venus融合蛋白的WT或ER应激激活指示剂（ERAI）小鼠中没有IRE-1激活的证据。PC诱导的ATF 3核转位在心脏限制性过表达诱导型ATF 6的转基因小鼠中减弱。缺血PC增加诱导型一氧化氮合酶，环氧合酶-2，血红素加氧酶-1和醛糖还原酶的丰度，WT和ATF 3-null心脏之间的水平相似;然而，增加IL-6和ICAM-1被夸大在ATF 3-null心脏。ATF 3基因的缺失并没有增加非预处理心脏的梗死面积，但消除了PC的心脏保护作用。预处理的ATF 3-null心脏中较大的梗死面积与心肌中较大的中性粒细胞浸润相关，但未观察到炎性单核细胞总数或相对丰度的ATF 3依赖性变化。缺血PC激活未折叠蛋白反应（UPR），ER应激激活ATF 3是晚期PC心脏保护作用的关键。
Ischemic preconditioning (PC) is an adaptive response to transient myocardial ischemia that protects the heart from subsequent ischemia/reperfusion (I/R) injury. However, the mechanisms underlying its cardioprotective effects remain unclear. Myocardium of adult male C57/BL6 mice, preconditioned by 6 cycles of 4 minutes coronary occlusion and reperfusion, showed nuclear translocation of ATF3, and ATF6 and PERK phosphorylation 30 min after PC. The abundance of ER proteins, ATF3 and ATF4 was increased 24 h after PC; however, there was no evidence of IRE-1 activation in WT or ER-stress activated indicator (ERAI) mice expressing XBP-1-Venus fusion protein. PC-induced nuclear translocation of ATF3 was attenuated in transgenic mice with cardiac-restricted overexpression of inducible ATF6. Ischemic PC increased the abundance of inducible nitric oxide synthase, cyclooxygenase-2, heme oxygenase-1 and aldose reductase to levels similar between WT and ATF3-null hearts; however, the increase in IL-6 and ICAM-1 was exaggerated in ATF3-null hearts. Genetic deletion of ATF3 did not increase infarct size in non-preconditioned hearts but abolished the cardioprotective effects of PC. Larger infarct size in preconditioned ATF3-null hearts was associated with greater neutrophil infiltration in the myocardium, but no ATF3-dependent changes in the total or relative abundance of inflammatory monocytes were observed. Ischemic PC activates the unfolded protein response (UPR) and the activation of ATF3 by ER stress is essential for the cardioprotective effects of late PC.
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影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M
影响因子：
37.8
作者：
MURRY, CE;JENNINGS, RB;REIMER, KA
通讯作者：
REIMER, KA
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.97.18.10197
发表时间：
2000-08-29
影响因子：
11.1
作者：
Shinmura, K;Tang, XL;Bolli, R
通讯作者：
Bolli, R
哺乳动物转录因子 ATF6 以跨膜蛋白的形式合成，并在内质网应激时通过蛋白水解激活
影响因子：
3.3
作者：
Haze, K;Yoshida, H;Mori, K
通讯作者：
Mori, K