CaMKII is a RIP3 Substrate Mediating Ischemia- and Oxidative Stress-induced Myocardial Necroptosis

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2016 Jan 5

PMID 26726877

Citations 369

Authors

Ting Zhang

Yan Zhang

Mingyao Cui

Li Jin

Yimei Wang

Fengxiang Lv

Yuli Liu

Wen Zheng

Haibao Shang

Jun Zhang

Mao Zhang

Hongkun Wu

Jiaojiao Guo

Xiuqin Zhang

Xinli Hu

Chun-Mei Cao

Rui-Ping Xiao

Affiliations

Soon will be listed here.

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.

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