title: CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis.
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.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Mingyao
authors.identifier: http://orcid.org/0000-0002-1701-2548
authors.initials: M
authors.lastname: Cui
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Lv
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Haibao
authors.initials: H
authors.lastname: Shang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Guo
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Cao
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.|Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D004317:Doxorubicin / Q000633:toxicity; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2