Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing, China.
FEBS Open Bio. 2021 Mar;11(3):932-943. doi: 10.1002/2211-5463.13092. Epub 2021 Feb 3.
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.
TWIST1 是一种与多种生理和病理过程相关的重要碱性螺旋-环-螺旋蛋白。虽然 TWIST1 被认为与血管发病机制有关，但它对平滑肌细胞（SMC）稳态的影响仍知之甚少。在这里，我们表明 TWIST1 蛋白水平在体内和体外 SMC 表型转换过程中显著升高。TWIST1 的过表达促进了 SMC 的表型转换，而 TWIST1 的 siRNA 靶向则阻止了细胞转变。在机制上，TWIST1 降低了 microRNA-143/145 的水平，后者调控平滑肌标记基因的转录。此外，TWIST1 抑制了 p68 mRNA 和蛋白质的表达，p68 是 SMC 行为和 microRNA 生物发生的关键调节剂。我们的共免疫沉淀实验证明了 TWIST1 和 p68 蛋白之间以前未被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 稳态方面发挥了新的作用。
