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CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis
Ting Zhang1,2, Yan Zhang1,2, Mingyao Cui1,2
1Institute of Molecular Medicine, Peking University, Beijing, China.
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.
Insights
Receptor-interacting protein 3 (RIP3) triggers heart cell death (necroptosis) by activating Ca(2+)-calmodulin-dependent protein kinase (CaMKII), not RIP1/MLKL. This pathway offers a new target for treating heart failure from ischemia and oxidative stress.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Death Research
Background:
- Regulated necrosis (necroptosis) and apoptosis are key in cardiac diseases like myocardial infarction and heart failure.
- Mechanisms of cardiomyocyte necroptosis are not fully understood, unlike well-defined apoptotic signaling.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying RIP3-mediated cardiomyocyte necroptosis.
- To identify novel therapeutic targets for ischemia- and oxidative stress-induced heart damage.
Main Methods:
- Investigated RIP3's role in myocardial necroptosis using mouse models.
- Utilized genetic deficiency (RIP3 knockout) and pharmacological inhibition (CaMKII inhibitors).
- Examined the activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) and mitochondrial permeability transition pore (mPTP) opening.
Main Results:
- Receptor-interacting protein 3 (RIP3) activates CaMKII, leading to myocardial necroptosis, distinct from RIP1/MLKL pathways.
- RIP3 deficiency or CaMKII inhibition significantly reduced necroptosis and heart failure in mouse models.
- RIP3-induced CaMKII activation triggers mPTP opening, causing cardiomyocyte necroptosis.
Conclusions:
- Identified CaMKII as a novel RIP3 substrate in myocardial necroptosis.
- Delineated a new RIP3-CaMKII-mPTP pathway crucial for necroptosis in cardiac pathology.
- This pathway represents a promising therapeutic target for heart failure and myocardial damage.
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