| Literature DB >> 26726877 |
Ting Zhang1,2, Yan Zhang1,2, Mingyao Cui1,2, Li Jin1,2, Yimei Wang1,2, Fengxiang Lv1,2, Yuli Liu1,2, Wen Zheng1,2, Haibao Shang1,2, Jun Zhang1,2, Mao Zhang1,2, Hongkun Wu1,2, Jiaojiao Guo1,2, Xiuqin Zhang1,2, Xinli Hu1,2, Chun-Mei Cao1,2, Rui-Ping Xiao1,2,3,4.
Abstract
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 Ca(2+)-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.Entities:
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Year: 2016 PMID： 26726877 DOI： 10.1038/nm.4017
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440