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

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

Zhang T1,2, Zhang Y1,2, Cui M1,2, Jin L1,2, Wang Y1,2, Lv F1,2, Liu Y1,2, Zheng W1,2, Shang H1,2, Zhang J1,2, Zhang M1,2, Wu H1,2, Guo J1,2, Zhang X1,2, Hu X1,2, Cao CM1,2, Xiao RP1,2,3,4.

Author information

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.


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.

[Indexed for MEDLINE]

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