Abstract 17: A Critical Role of TRAF2 in Myocardial Survival and Homeostasis by Suppressing Necroptosis

Abstract

Programed cell death, including apoptosis and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain largely unkown. Here we identified TNF receptor-associated factor 2 (Traf2) as a key suppressor of myocardial necroptosis, which critically regulates myocardial survival and homeostasis. It has been shown that transgenic expression of Traf2 protects the heart against ischemia-reperfusion injury, but the underlying mechanisms remain unclear. Moreover, the role of Traf2 in myocardial necroptosis and pathological remodeling has not been investigated in a loss-of-function approach. By generating cardiac-specific Traf2 knockout mice, we found that ablation of Traf2 in the heart induced pathological remodeling and heart failure by promoting necroptotic myocyte death. Importantly, plasma TNFα level was significantly elevated in Traf2 -deficient mice, and genetic ablation of TNFR1 (TNF receptor-1) largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deficiency. Mechanistically, our data revealed that Traf2 critically regulates RIP1-RIP3-MLKL necroptosis signaling, with the adaptor protein TRADD (TNFR1-associated death domain protein) as an upstream regulator and TAK1 (TGFβ-activated kinase-1) as a downstream effector. Moreover, Traf2 prevents the degradation of key pro-survival signaling proteins TAK1, FLIP, cIAPs, and NFκB-p65 via the ubiquitin-proteasome pathway. Lastly, genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, further validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity. Taken together, these results identify an important Traf2-mediated, NFκB-independent, pro-survival pathway in the heart by suppressing necroptosis signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure.