CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis
CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis
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CaMKII 是一种 RIP3 底物，介导缺血和氧化应激诱导的心肌坏死性凋亡。
DOI：
10.1038/nm.4017
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发表时间：
2016-02-01
期刊：
影响因子：
82.9
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
--
作者：
Zhang, Ting;Zhang, Yan;Xiao, Rui-Ping
调节性坏死（坏死性凋亡）和凋亡在严重的心脏病理状况中至关重要，包括心肌梗死、缺血-再灌注损伤和心力衰竭。尽管细胞凋亡信号已被很好地定义，但心肌细胞坏死凋亡的机制仍然难以捉摸。在这里，我们表明，受体相互作用蛋白3（RIP 3）触发心肌坏死性凋亡，除了细胞凋亡和炎症，通过激活钙离子-钙调蛋白依赖性蛋白激酶（CaMKII），而不是通过完善的RIP 3合作伙伴RIP 1和MLKL。在小鼠中，RIP 3缺陷或CaMKII抑制可改善缺血再灌注或阿霉素治疗诱导的心肌坏死性凋亡和心力衰竭。RIP 3诱导的CaMKII活化，通过磷酸化或氧化或两者，触发线粒体通透性转换孔的开放和心肌坏死性凋亡。这些发现确定CaMKII作为一种新的RIP 3底物，并描绘了RIP 3-CaMKII-mPTP心肌坏死凋亡途径，这是一种有前途的治疗缺血和氧化应激诱导的心肌损伤和心力衰竭的靶点。
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.