TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA‐143/145,FEBS Open Bio

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TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA‐143/145
FEBS Open Bio ( IF 2.8 ) Pub Date : 2021-01-20 , DOI: 10.1002/2211-5463.13092
Jing Zhang ₁ , Jie-Ru Guo ₁ , Xian-Li Wu ₁ , Xia Wang ₁ , Zhi-Ming Zhu ₂ , Yong Wang ₃ , Xia Gu ₄ , Ye Fan ₁

Affiliation

TWIST1 is an important basic helix‐loop‐helix protein linked to multiple physiological and pathological processes. Although TWIST1 is believed to be involved in vascular pathogenesis, its effects on homeostasis of smooth muscle cells (SMCs) remain poorly understood. Here, we show that TWIST1 protein levels were significantly elevated during SMC phenotypic switching in vivo and in vitro. TWIST1 overexpression promoted phenotypic switching of SMCs, while siRNA targeting of TWIST1 prevented cell transition. Mechanistically, TWIST1 decreased the level of microRNA‐143/145, which governs smooth muscle marker gene transcription. In addition, TWIST1 repressed p68 mRNA and protein expression, a crucial modulator of SMC behavior and microRNA biogenesis. Our co‐immunoprecipitation assay demonstrated a previously unrecognized molecular interaction between TWIST1 and p68 protein. Finally, we found that TWIST1 triggered SMC phenotypic switching and suppressed microRNA‐143/145 expression by promoting the proteasomal degradation of p68. These data suggest a novel role of TWIST1 in the regulation of SMC homeostasis by modulating p68/microRNA‐143/145 axis.

中文翻译：

TWIST1 通过下调 p68 和 microRNA-143/145 诱导血管平滑肌细胞的表型转换

TWIST1 是一种重要的基本螺旋-环-螺旋蛋白，与多种生理和病理过程相关。尽管 TWIST1 被认为与血管发病机制有关，但其对平滑肌细胞 (SMC) 稳态的影响仍知之甚少。在这里，我们表明在体内和体外SMC 表型转换期间 TWIST1 蛋白水平显着升高. TWIST1 过表达促进了 SMC 的表型转换，而 TWIST1 的 siRNA 靶向阻止了细胞转变。从机制上讲，TWIST1 降低了控制平滑肌标记基因转录的 microRNA-143/145 的水平。此外，TWIST1 抑制 p68 mRNA 和蛋白质表达，这是 SMC 行为和 microRNA 生物发生的关键调节剂。我们的免疫共沉淀试验证明了 TWIST1 和 p68 蛋白之间以前无法识别的分子相互作用。最后，我们发现 TWIST1 通过促进 p68 的蛋白酶体降解来触发 SMC 表型转换并抑制 microRNA-143/145 的表达。这些数据表明 TWIST1 通过调节 p68/microRNA-143/145 轴在调节 SMC 稳态中的新作用。

更新日期：2021-03-04

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