Journal Article

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

Liu, Yuli, Zhang, Ting, Zhang, Mao, Hu, Xinli, Wu, Hongkun, Xiao, Rui-Ping, Zhang, Xiuqin, Cui, Mingyao, Cao, Chun-Mei, Wang, Yimei, Guo, Jiaojiao, Zhang, Yan, Jin, Li, Shang, Haibao, Lv, Fengxiang, Zheng, Wen, Zhang, Jun

2016

Overview

Myocardial injury induced by ischemia-reperfusion or doxorubicin leads to cardiomyocyte necroptosis via RIP3-mediated phosphorylation of CaMKII and opening of the mitochondrial permeability transition pore. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/80/82/2344 / 692/699/75/230 / Animals / Antibiotics, Antineoplastic - toxicity / Apoptosis / Apoptosis - genetics / Biomedicine / Blotting, Western / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Cancer Research / Cardiomyocytes / Cardiovascular disease / Cell Survival / Doxorubicin - toxicity / Heart diseases / Heart Failure - chemically induced / Heart Failure - genetics / Heart Failure - pathology / Immunohistochemistry / In Situ Nick-End Labeling / Infectious Diseases / Ischemia / Medical research / Medicine, Experimental / Membrane Potential, Mitochondrial / Metabolic Diseases / Mice / Mice, Inbred C57BL / Mice, Knockout / Microscopy, Confocal / Mitochondrial Membrane Transport Proteins - metabolism / Molecular Medicine / Myocardial infarction / Myocardial Ischemia - complications / Myocardial Ischemia - genetics / Myocardial Ischemia - pathology / Myocardial Reperfusion Injury - genetics / Myocardial Reperfusion Injury - metabolism / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Necrosis / Necrosis - etiology / Necrosis - genetics / Necrosis - pathology / Neurosciences / Oxidation / Oxidative Stress / Permeability / Phosphorylation / Physiological aspects / Rats / Rats, Sprague-Dawley / Reactive Oxygen Species / Real-Time Polymerase Chain Reaction / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Signal transduction