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

T Zhang, Y Zhang, M Cui, LI Jin, Y Wang, F Lv, Y Liu… - Nature medicine, 2016 - nature.com
T Zhang, Y Zhang, M Cui, LI Jin, Y Wang, F Lv, Y Liu, W Zheng, H Shang, J Zhang, M Zhang
Nature medicine, 2016nature.com
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 …
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 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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