Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.
Acta Pharmacol Sin. 2022 Oct;43(10):2562-2572. doi: 10.1038/s41401-022-00950-2. Epub 2022 Aug 10.
Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.
Tax1 结合蛋白 1（Tax1bp1）最初被鉴定为一种 NF-κB 调节蛋白，参与炎症、抗病毒和先天免疫过程。Tax1bp1 还作为自噬受体发挥作用，在自噬中起作用。我们之前的研究表明，Tax1bp1 可防止 STZ 诱导的糖尿病小鼠发生心肌病。在这项研究中，我们研究了 Tax1bp1 在心力衰竭中的作用。通过主动脉缩窄（AB）手术在小鼠中建立压力超负荷诱导的心力衰竭模型，并通过渗透微型泵输注血管紧张素 II（Ang II）4 周建立 Ang II 诱导的心力衰竭模型。我们显示，AB 手术后 2 周和 4 周，心脏中 Tax1bp1 的表达水平明显增加。在心脏中敲低 Tax1bp1 可显著改善 AB 和 Ang II 输注诱导的心力衰竭参数。相反，心脏特异性 Tax1bp1 转基因小鼠的 AB 诱导的心力衰竭加重。在 Ang II 损伤下的新生大鼠心肌细胞（NRCMs）中观察到类似的结果。我们证明 Tax1bp1 的促心力衰竭作用是由于其与 E3 连接酶 ITCH 相互作用，促进转录因子 P73 的泛素化和降解，导致增强 BCL2 相互作用蛋白 3（BNIP3）介导的心肌细胞凋亡所致。在 NRCMs 中敲低 ITCH 或 BNIP3 可显著减少体外 Ang II 诱导的凋亡。同样，BNIP3 敲低可减轻心脏特异性 Tax1bp1 转基因小鼠的心力衰竭。心力衰竭患者的左心室中，Tax1bp1 的表达水平显著增加；心力衰竭患者的 Tax1bp1 基因表达与左心室射血分数呈负相关。总之，心力衰竭时 Tax1bp1 的增加增强了 ITCH-P73-BNIP3 介导的心肌细胞凋亡并诱导心脏损伤。Tax1bp1 可能成为心力衰竭治疗的有效治疗靶点。
