期刊
NATURE MEDICINE
卷 22, 期 2, 页码 175-182出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4017
关键词
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资金
- National Basic Research Program of China [2013CB531200, 2012CB518000, 2012CB944500]
- National Natural Science Foundation of China [81170100, 81370234, 81130073, 81370233, 91439107, 81270190, 31221002]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2013ZX09508104]
- Specialized Research Fund for the Doctoral Program of Higher Education [20110001120119]
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 Ca2+-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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