AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex.
AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex.
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AMP 激活的蛋白激酶通过调节 Keap1-PGAM5 复合物防止坏死性凋亡
DOI：
10.1016/j.ijcard.2018.01.036
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发表时间：
2018-05-15
影响因子：
3.5
通讯作者：
Xu ZX
中科院分区：
文献类型：
--
作者：
Wang YS;Yu P;Wang Y;Zhang J;Hang W;Yin ZX;Liu G;Chen J;Werle KD;Quan CS;Gao H;Zeng Q;Cui R;Liang J;Ding Q;Li YL;Xu ZX
amp活化蛋白激酶（AMPK）在生长调节和代谢重编程中起着至关重要的作用。在不同的细胞和动物模型中，AMPK激活保护细胞免受凋亡的伤害。然而，其在坏死性上睑下垂中的作用仍不清楚。在本研究中，我们证明AMPK在诱导坏死性死亡时被激活，并保护小鼠胚胎成纤维细胞（mef）和心肌细胞免受n -甲基-n ' -硝基-n -亚硝基胍（MNNG）和活性氧（ROS）诱导的坏死性死亡。用化学物质A-769662、2-脱氧葡萄糖（2-DG）和二甲双胍或组成型活性AMPK激活AMPK可显著降低MNNG诱导的坏死和细胞毒性。相反，AMPK抑制剂化合物C、显性阴性AMPK （DN）以及AMPK shRNAs增加了MNNG诱导的坏死和细胞毒性。我们进一步发现AMPK与含有PGAM5和Keap1的蛋白复合物物理相关，从而促进Keap1介导的PGAM5泛素化在坏死坏死诱导下。AMPK激动剂二甲双胍通过下调langendorff灌注大鼠心脏中PGAM5的表达，改善心肌缺血再灌注（IR）损伤，减轻坏死性坏死。激活AMPK通过促进keap1介导的PGAM5降解来防止坏死性坏死。二甲双胍可能通过激活AMPK和减少坏死下垂来保护心肌缺血再灌注损伤。
The AMP-activated protein kinase (AMPK) plays critical roles in growth regulation and metabolism reprogramming. AMPK activation protects cells against apoptosis from injury in different cell and animal models. However, its function in necroptosis remains largely unclear. In the current study, we demonstrated that AMPK was activated upon necroptosis induction and protected mouse embryonic fibroblasts (MEFs) and cardiomyocytes from N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and reactive oxygen species (ROS) induced necroptosis. Activation of AMPK with chemicals A-769662, 2-deoxyglucose (2-DG), and metformin or constitutively active (CA) AMPK markedly decreased necroptosis and cytotoxicity induced by MNNG. In contrast, AMPK inhibitor compound C, dominant negative (DN) AMPK, as well as AMPK shRNAs increased necroptosis and cytotoxicity induced by MNNG. We further showed that AMPK physically associated with a protein complex containing PGAM5 and Keap1 whereby facilitating Keap1-mediated PGAM5 ubiquitination upon necroptosis induction. The AMPK agonist metformin ameliorated myocardial ischemia and reperfusion (IR) injury and reduced necroptosis through down-regulating the expression of PGAM5 in the Langendorff-perfused rat hearts. Activation of AMPK protects against necroptosis via promoting Keap1-mediated PGAM5 degradation. Metformin may act as a valuable agent for the protection of myocardial ischemia and reperfusion injury by activating AMPK and reducing necroptosis.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
9.5
作者：
Oerlemans, Martinus I. F. J.;Liu, Jia;Sluijter, Joost P. G.
通讯作者：
Sluijter, Joost P. G.
影响因子：
19.6
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
DOI：
10.4049/jimmunol.1501662
发表时间：
2016-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Moriwaki K;Farias Luz N;Balaji S;De Rosa MJ;O'Donnell CL;Gough PJ;Bertin J;Welsh RM;Chan FK
通讯作者：
Chan FK
影响因子：
16.6
作者：
Kang YJ;Bang BR;Han KH;Hong L;Shim EJ;Ma J;Lerner RA;Otsuka M
通讯作者：
Otsuka M