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同源框A4通过抑制YAP/TEAD转录活性来抑制血管重塑。

Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity.

作者信息

Kimura Masahiro, Horie Takahiro, Baba Osamu, Ide Yuya, Tsuji Shuhei, Ruiz Rodriguez Randolph, Watanabe Toshimitsu, Yamasaki Tomohiro, Otani Chiharu, Xu Sijia, Miyasaka Yui, Nakashima Yasuhiro, Kimura Takeshi, Ono Koh

机构信息

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

EMBO Rep. 2020 Apr 3;21(4):e48389. doi: 10.15252/embr.201948389. Epub 2020 Mar 9.

DOI:10.15252/embr.201948389
PMID:32147946
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7132199/
Abstract

The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD-mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD-mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD-induced phenotypic switching. We generated Hoxa4-deficient mice and confirmed the downregulation of smooth muscle-specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD-mediated transcription.

摘要

河马信号通路参与多种心血管疾病的病理生理学过程。Yes相关蛋白（YAP）和转录增强激活域（TEAD）转录因子是河马通路的主要转录复合物，最近被确定为血管平滑肌细胞（VSMC）表型转换的调节因子。然而，参与血管病理生理学的YAP/TEAD介导的基因表达的内在调节因子仍有待阐明。在这里，我们通过慢病毒shRNA筛选确定同源框A4（HOXA4）是YAP/TEAD转录活性的有效抑制因子。从机制上讲，HOXA4与TEAD相互作用，并通过与YAP竞争TEAD结合来减弱YAP/TEAD介导的转录。我们还阐明，HOXA4在脉管系统中，尤其是在VSMC中表达相对丰富。在人VSMC中的体外实验表明，HOXA4通过抑制YAP/TEAD诱导的表型转换来维持VSMC的分化状态。我们生成了Hoxa4基因缺陷小鼠，并证实体内颈动脉结扎后平滑肌特异性收缩基因的下调和血管重塑的加剧。我们的结果表明，HOXA4通过抑制YAP/TEAD介导的转录来抑制VSMC表型转换。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d2c/7132199/7b3cd426867e/EMBR-21-e48389-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d2c/7132199/46077d6aaa69/EMBR-21-e48389-g010.jpg
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