TAX1结合蛋白1在心肌肥厚中的作用及机制

Cardiac hypertrophy is the common pathological process in the development of cardiac failure in various cardiovascular diseases. Thus, it is important to define downstream signaling mediators shared by several pathways and their regulatory mechanism. The regulation of autophagy and NF-κB signaling pathway is closely related to cardiac hypertrophy. TAX1 binding protein 1 (TAX1BP1) is an ubiquitin binding protein. TAX1BP1 regulates NF-κB and other inflammatory signaling pathways, which mediates inflammation, apoptosis and many other biological functions. Recent studies have found that TAX1BP1 was involved in autophagy. However, the effect of TAX1BP1 in cardiac hypertrophy remains unclear. Our preliminary results showed that TAX1BP1 was significantly down-regulated in the hypertrophic heart, which implies that TAX1BP1 may be involved in the pathology of cardiac hypertrophy. We intended to explore the effect of TAX1BP1 in cardiac hypertrophy by using TAX1BP1 cardiac specific knock out and transgene mice. We will further investigate cardiac autophagy and cellular signaling pathways to clear the mechanisms of TAX1BP1 on cardiac hypertrophy. In addition, cultured neonatal rat cardiomyocytes with overexpressed or silenced TAX1BP1 were used to observe the effects of TAX1BP1 on PE-induced cardiomyocyte hypertrophy, autophagy, and intracellular signaling pathways. The study is designed to elucidate the role and underlying mechanisms of TAX1BP1 in cardiac hypertrophy and provide new experimental evidence and targets for clinical intervention in cardiac hypertrophy and heart failure.

心肌肥厚是各种心血管疾病向心力衰竭发展的重要病理过程。明确多条信号通路共同的下游靶点及其调节机制对有效防治心肌肥厚至关重要。细胞自噬和NF-κB信号通路在心肌肥厚中发挥着关键调控作用。TAX1结合蛋白1（TAX1BP1）是一类泛素结合蛋白，其可调控NF-κB等炎症信号通路，介导细胞炎症、凋亡等多种生物学效应。近期研究发现TAX1BP1还参与细胞自噬的启动。但TAX1BP1 是否参与心肌肥厚的发生发展，目前尚无报道。我们的预实验结果显示，TAX1BP1在各种因素诱导的心肌肥厚模型中表达显著下调，提示TAX1BP1可能参与心肌肥厚的病理发展过程。本项目拟用心脏特异性TAX1BP1基因敲除和转基因小鼠构建在体心肌肥厚模型，并用TAX1BP1 沉默或过表达的心肌细胞建立离体心肌细胞肥大模型，以期明确TAX1BP1在心肌肥厚中的作用及其可能的作用机制，探寻防治心肌肥厚的新靶点和新策略。

近年来，尽管心肌肥厚的发生机制已取得重要进展，但是临床上尚无十分有效的防治方法，心力衰竭的发病率和死亡率仍居高不下。本项目采用心脏特异性TAX1BP1转基因小鼠构建在体心肌肥厚模型，探讨TAX1BP1在心里肥厚中的作用及机制。我们发现TAX1BP1在心力衰竭人体心脏组织、心肌肥厚小鼠心脏和心肌细胞中表达明显升高；TAX1BP1转基因小鼠加重压力负荷诱导的心肌肥厚、纤维化和心功能恶化，而心肌细胞特异性敲除TAX1BP1可减轻小鼠压力负荷下的心肌肥厚进程。通过机制研究我们发现TAX1BP1通过结合ITCH促进凋亡相关蛋白P73的泛素化降解，后者可负向调控促凋亡蛋白BNIP3的转录。BNIP3心肌特异性沉默可阻断TAX1BP1心肌沉默诱导的心脏保护作用。总之，心力衰竭中Tax1bp1的增加会增强ITCH-P73-BNIP3相关的心肌细胞凋亡并增加心脏损伤，阻断Tax1bp1可能会在将来成为心力衰竭的有效疗法。