摘要：AIM:Programmed necrosis ( necroptosis ) and apoptosis are crucially involved in multiple severe cardiac pathological conditions , including myocardial infarction, ischemia/reperfusion (I/R) injury, and heart failure.Whereas apoptotic signaling is well defined, the mechanisms underlying cardiomyocyte necroptosis remain elusive .METHODS AND RESULTS:Here we show that both mRNA and protein levels of receptor-interacting protein 3 (RIP3) in the hearts are increased by I/R injury and doxorubicin (Dox) treatment. In mice, RIP3 deficiency ameliorates myocardial necroptosis and heart failure induced by I /R (30-min ischemia/4-h or 8-week reper-fusion) or Dox treatment (20 mg/kg or 5 mg/kg ×4, i.p.).RIP3 overexpression induces cardiomyocyte necroptosis evidenced by de-creased intracellular ATP level and increased lactate dehydrogenase concentration in cell culture medium .RIP3 triggers myocardial ne-croptosis via activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), rather than the well-established RIP3 partners, RIP1 and MLKL (mixed lineage kinase domain-like protein).Specifically, our data indicate that I/R and Dox markedly activate myo-cardial CaMKII in wild-type but not RIP3-deficient mice , and that CaMKII inhibition or RIP 3 deficiency protect the heart from I/R-and Dox-induced cardiomyocyte necroptosis , cardiac remodeling and heart failure .Mechanistically , RIP3 activates CaMKII via both di-rect phosphorylation and indirect reactive oxidative species-dependent oxidation , and subsequently triggers opening of the mitochondrial permeability transition pore ( mPTP) and myocardial necroptosis .CONCLUSION: These findings identify CaMKII as a novel RIP 3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway , a promising target for the treatment of cardiac ischemic and oxidative damage , and heart failure .