TEA域转录因子1 (TEAD1) 诱导心脏纤维细胞细胞通过BRD4/Wnt4通路重塑
Shuai Song1,2,3,4,5, Xiaokai Zhang1,2,3,4,5, Zihang Huang1,2,3,4,5
1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Signal transduction and targeted therapy
|February 19, 2024
概括
在心力衰竭中,TEAD1通过促进纤维细胞转变为肌纤维细胞来驱动心脏重塑. 抑制TEAD1或其下游Wnt4通路可缓解纤维化并改善心脏功能.
科学领域:
- 心血管生物学 心血管生物学
- 分子心脏病学分子心脏病学
- 纤维化研究 纤维化研究
背景情况:
- 心脏纤维细胞 (CFs) 是对原重塑和心力衰竭 (HF) 的关键.
- TEAD1对心脏发育至关重要,但其在心脏重塑过程中对CF的作用尚不清楚.
- 压力过载模型显示CF中TEAD1增加.
研究的目的:
- 为了研究内源性TEAD1在心脏纤维细胞中在病态心脏重塑过程中的作用.
- 阐明TEAD1影响心脏纤维化的分子机制.
主要方法:
- 在心脏应激的小鼠模型中进行转录组分析 (RNA-seq) 和染色质免疫沉测序 (ChIP-seq).
- 条件TEAD1在CF和肌纤维细胞中的淘汰.
- 使用VT103.3进行TEAD1的药理抑制.
- 共同免疫沉,质谱和光酶测试以确定蛋白质相互作用和调节途径.
主要成果:
- 在压力过载下 (TAC,Ang-II) 的CF中,TEAD1的表达上调.
- 结核病特异性TEAD1缺陷或VT103治疗减弱的心脏重塑和纤维化.
- TEAD1直接准Wnt4,通过Wnt信号通路促进纤维细胞到肌纤维细胞的过渡.
- TEAD1与BRD4相互作用,以激活Wnt4促进体.
结论:
- TEAD1是病理性心脏重塑中的亲纤维性CFs表型的关键调节者.
- TEAD1-BRD4-Wnt4轴代表了心力衰竭的新型治疗标.
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