CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis

被引：837

作者：

Zhang, Ting ^{[1
,2
]}

Zhang, Yan ^{[1
,2
]}

Cui, Mingyao ^{[1
,2
]}

Jin, Li ^{[1
,2
]}

Wang, Yimei ^{[1
,2
]}

Lv, Fengxiang ^{[1
,2
]}

Liu, Yuli ^{[1
,2
]}

Zheng, Wen ^{[1
,2
]}

Shang, Haibao ^{[1
,2
]}

Zhang, Jun ^{[1
,2
]}

Zhang, Mao ^{[1
,2
]}

Wu, Hongkun ^{[1
,2
]}

Guo, Jiaojiao ^{[1
,2
]}

Zhang, Xiuqin ^{[1
,2
]}

Hu, Xinli ^{[1
,2
]}

Cao, Chun-Mei ^{[1
,2
]}

Xiao, Rui-Ping ^{[1
,2
,3
,4
]}

机构：

[1] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China

[2] Peking Univ, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China

[3] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China

[4] Peking Univ, Beijing City Key Lab Cardiometab Mol Med, Beijing 100871, Peoples R China

来源：

NATURE MEDICINE | 2016年 / 22卷 / 02期

基金：

中国国家自然科学基金;

关键词：

MITOCHONDRIAL PERMEABILITY TRANSITION; RECEPTOR INTERACTING PROTEIN-3; MIXED LINEAGE KINASE; CELL-DEATH; PROGRAMMED NECROSIS; DOMAIN-LIKE; INDEPENDENT ACTIVATION; INHIBITION PROTECTS; CARDIAC-HYPERTROPHY; APOPTOSIS;

D O I：

10.1038/nm.4017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca2+-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.

引用

页码：175 / 182

页数：8

共 53 条

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