TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA-143/145.
TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA-143/145.
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DOI：
10.1002/2211-5463.13092
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发表时间：
2021-03
期刊：
影响因子：
2.6
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Zhang J;Guo JR;Wu XL;Wang X;Zhu ZM;Wang Y;Gu X;Fan Y
Twist1是一种重要的碱性螺旋-环-螺旋蛋白，与多种生理和病理过程有关。尽管Twist1被认为与血管发病有关，但其对平滑肌细胞(SMC)内稳态的影响仍然知之甚少。在此，我们发现在体内和体外SMC表型转换过程中，Twist1蛋白水平显著升高。Twist1的过表达促进了SMC的表型转换，而靶向Twist1的siRNA阻止了细胞的转换。机制上，Twist1降低了调控平滑肌标志物基因转录的microRNA-143/145的水平。此外，Twist1抑制了p68mRNA和蛋白的表达，p68mRNA和蛋白是SMC行为和microRNA生物发生的关键调节因子。我们的免疫共沉淀实验证明了Twist1和p68蛋白之间存在一种以前未知的分子相互作用。最后，我们发现Twist1通过促进p68蛋白酶体的降解，触发SMC表型转换，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动态平衡中发挥了新的作用。Twist1表达增加导致血管平滑肌细胞DDX5/microRNA-143/145通路被抑制，从而诱导血管平滑肌细胞表型转换，促进血管重塑的进展。因此，Twist1可能是抑制表型相关血管疾病的一个有吸引力的治疗靶点。
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. Increased TWIST1 expression leads to the suppression of the DDX5/microRNA‐143/145 pathway in VSMC, which induces phenotypic switching of VSMC and promotes the progression of vascular remodeling. Therefore, TWIST1 might be a attractive therapeutic target for inhibiting phenotype‐related vascular disorders.
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影响因子：
82.9
作者：
Murgai M;Ju W;Eason M;Kline J;Beury DW;Kaczanowska S;Miettinen MM;Kruhlak M;Lei H;Shern JF;Cherepanova OA;Owens GK;Kaplan RN
通讯作者：
Kaplan RN
影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
通讯作者：
Srivastava D
影响因子：
4.5
作者：
Nurnberg, Sylvia T.;Guerraty, Marie A.;Rader, Daniel J.
通讯作者：
Rader, Daniel J.
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko
影响因子：
20.1
作者：
Torella, Daniele;Iaconetti, Claudio;Indolfi, Ciro
通讯作者：
Indolfi, Ciro