1. Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis.
- Author
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Xiaoyun Guo, Haifeng Yin, Lei Li, Yi Chen, Jing Li, Doan, Jessica, Steinmetz, Rachel, Qinghang Liu, Guo, Xiaoyun, Yin, Haifeng, Li, Lei, Chen, Yi, Li, Jing, and Liu, Qinghang
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TUMOR necrosis factors , *APOPTOSIS , *HEART failure , *CELLULAR signal transduction , *MYOCARDIAL infarction , *CELL metabolism , *ANIMAL populations , *ANIMALS , *CARDIOTONIC agents , *CARRIER proteins , *CELL culture , *CELL death , *CELLS , *MICE , *NECROSIS , *RATS , *RESEARCH funding , *VENTRICULAR remodeling , *PREVENTION - Abstract
Background: Programmed 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 tumor necrosis factor receptor-associated factor 2 (Traf2) 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 tumor necrosis factor α 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 receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor β-activated kinase 1 as a downstream effector. It is important to note that 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, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure. [ABSTRACT FROM AUTHOR]- Published
- 2017
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