Pang Yanan, Ma Minglu, Wang Dong, Li Xun, Jiang Li
Division of Cardiology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiology, The First Affliated Hospital of Soochow University, Suzhou, China.
Front Cardiovasc Med. 2021 Sep 3;8:687540. doi: 10.3389/fcvm.2021.687540. eCollection 2021.
TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown. In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4-8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice. Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.
TANK（肿瘤坏死因子受体相关因子家族成员相关的核因子κB激活剂）作为支架蛋白家族的一员，参与多种疾病的发生发展。然而，其在心肌肥厚过程中的作用尚不清楚。在本研究中，我们观察到主动脉缩窄后小鼠肥厚心脏中TANK表达增加，提示TANK可能参与心肌肥厚的发病机制。我们构建了心脏特异性TANK基因敲除小鼠，随后进行4至8周的主动脉缩窄。与对照组相比，TANK基因敲除小鼠的心肌肥厚和功能障碍有所减轻。相反，心脏特异性TANK转基因小鼠表现出相反的体征。一致地，实验表明TANK基因敲低可减小细胞大小并降低肥厚标志物的表达。机制上，TANK基因敲除小鼠的AKT信号通路受到抑制，而主动脉缩窄后的TANK转基因小鼠中该信号通路被激活。用药物性AKT抑制剂阻断AKT信号通路可减轻TANK转基因小鼠的心肌肥厚和功能障碍。总体而言，我们确定TANK可加速病理性心肌肥厚的进展，是一个潜在的治疗靶点。
