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

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

doi:10.1038/nm.4017

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

Nat Med. 2016 Feb;22(2):175-82. doi: 10.1038/nm.4017. Epub 2016 Jan 4.

Authors

Ting Zhang^{1

2}, Yan Zhang^{1

2}, Mingyao Cui^{1

2}, Li Jin^{1

2}, Yimei Wang^{1

2}, Fengxiang Lv^{1

2}, Yuli Liu^{1

2}, Wen Zheng^{1

2}, Haibao Shang^{1

2}, Jun Zhang^{1

2}, Mao Zhang^{1

2}, Hongkun Wu^{1

2}, Jiaojiao Guo^{1

2}, Xiuqin Zhang^{1

2}, Xinli Hu^{1

2}, Chun-Mei Cao^{1

2}, Rui-Ping Xiao^{1

2

3

4}

Affiliations

¹ Institute of Molecular Medicine, Peking University, Beijing, China.
² State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
³ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
⁴ Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.

PMID: 26726877
DOI: 10.1038/nm.4017

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibiotics, Antineoplastic / toxicity
Apoptosis / genetics
Blotting, Western
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Cell Survival
Doxorubicin / toxicity
Heart Failure / chemically induced
Heart Failure / genetics*
Heart Failure / pathology
Immunohistochemistry
In Situ Nick-End Labeling
Membrane Potential, Mitochondrial
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Mitochondrial Membrane Transport Proteins / metabolism*
Mitochondrial Permeability Transition Pore
Myocardial Ischemia / complications
Myocardial Ischemia / genetics*
Myocardial Ischemia / pathology
Myocardial Reperfusion Injury / genetics*
Myocardial Reperfusion Injury / metabolism
Myocytes, Cardiac / metabolism*
Myocytes, Cardiac / pathology
Necrosis / etiology
Necrosis / genetics*
Necrosis / pathology
Oxidative Stress*
Phosphorylation
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

Substances

Antibiotics, Antineoplastic
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Reactive Oxygen Species
Doxorubicin
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse
Calcium-Calmodulin-Dependent Protein Kinase Type 2