Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis.
Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis.
复制标题
肿瘤坏死因子受体相关因子2的心脏保护作用通过抑制凋亡和坏死性。
DOI：
10.1161/circulationaha.116.026240
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发表时间：
2017-08-22
期刊：
影响因子：
37.8
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Guo X;Yin H;Li L;Chen Y;Li J;Doan J;Steinmetz R;Liu Q
缺血性细胞死亡，包括细胞凋亡、心肌坏死和坏死性凋亡，与缺血性心脏损伤、病理性心脏重塑和心力衰竭进展密切相关。尽管细胞凋亡和细胞凋亡介导的坏死信号转导已被很好地建立，但坏死性凋亡的调节机制及其在心力衰竭发病机制中的意义仍然难以捉摸。我们使用遗传小鼠模型研究了Traf 2（TNF受体相关因子2）在调节心肌坏死性凋亡和重塑中的作用。我们还进行了分子和细胞生物学研究，以阐明Traf 2调节坏死性凋亡信号传导的机制。我们确定了Traf 2通过抑制坏死性凋亡在心肌存活和体内平衡中的关键作用。小鼠心脏特异性Traf 2缺失引发坏死性心脏细胞死亡、病理性重塑和心力衰竭。Traf 2缺陷小鼠的血浆TNFα水平显著升高，TNFR 1的基因消融在很大程度上消除了与Traf 2缺失相关的病理性心脏重塑和功能障碍。Traf 2在机制上严格调节RIP 1-RIP 3-MLKL坏死性凋亡信号传导，衔接蛋白TRADD作为上游调节因子，TAK 1作为下游效应因子。重要的是，RIP 3的基因缺失在很大程度上挽救了由Traf 2缺失引发的心脏表型，验证了坏死性凋亡在调节病理性重塑和心力衰竭倾向中的关键作用。这些结果通过抑制坏死性凋亡信号在心脏中鉴定了一个重要的Traf 2介导的、NFκ B非依赖性的促存活通路，这可能作为病理性重塑和心力衰竭的新治疗靶点。
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. 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. 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. 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.