Cardioprotective Role of TRAF2 by Suppressing Apoptosis and Necroptosis
Background—Programed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive.
Methods—We examined the role of Traf2 (TNF receptor-associated factor 2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling.
Results—We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma TNFα level was significantly elevated in Traf2-deficient mice and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates RIP1-RIP3-MLKL necroptotic signaling with the adaptor protein TRADD as an upstream regulator and TAK1 as a downstream effector. Importantly, genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity.
Conclusions—These results identify an important Traf2-mediated, NFκB-independent, pro-survival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure.
- Received November 2, 2016.
- Revision received May 1, 2017.
- Accepted May 19, 2017.