Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
Int J Biochem Cell Biol. 2022 Oct;151:106278. doi: 10.1016/j.biocel.2022.106278. Epub 2022 Aug 17.
Enhancer of zeste homolog 2 (EZH2) was recently found to play an important role in cardiovascular disease. However, the role of EZH2 in vascular remodeling induced by mechanical stretch is poorly understood. The aim of the present work was to investigate the role of EZH2 in regulating smooth muscle cell function through mechanical stretch assays and to explore the underlying mechanisms.
WT C57BL/6 J mice underwent sham surgery or abdominal aortic constriction. The level of EZH2 expression was determined by Western blotting and immunohistochemical staining. We demonstrated the thickness of vascular remodeling by HE staining. JASPAR was used to predict transcription factors that could affect EZH2. Chromatin immunoprecipitation was used to substantiate the DNAprotein interactions. Promoter luciferase assays were performed to demonstrate the activity of the transcription factors.
We found that in vivo, AAC significantly reduced EZH2 protein levels in the thoracic aorta. Smooth muscle-specific overexpression of EZH2 was sufficient to attenuate the AAC-induced reduction in trimethylation of Lys-27 in histone 3 and thickening of the arterial media. Administration of GSK-J4 (an inhibitor of H3K27me3 demethylase) induced the same effects. In addition, we found that mechanical stretch regulated the expression of EZH2 through the Yes-associated protein (YAP)- transcriptional factor TEA domain 1 (TEAD) pathway. TEAD1 bound directly to the promoter of EZH2, and blocking the YAP-TEAD1 interaction inhibited EZH2 downregulation due to mechanical stretch.
This study reveals that mechanical stretch downregulates EZH2 through the YAP-TEAD1 pathway, thereby aggravating smooth muscle cell apoptosis and vascular remodeling.
最近发现，胚胎外胚层发育蛋白同源物 2（EZH2）在心血管疾病中发挥重要作用。然而，EZH2 在机械拉伸诱导的血管重构中的作用知之甚少。本研究旨在通过机械拉伸实验研究 EZH2 在调节平滑肌细胞功能中的作用，并探讨其潜在机制。
WT C57BL/6J 小鼠接受假手术或腹主动脉缩窄。通过 Western blot 和免疫组化染色测定 EZH2 表达水平。通过 HE 染色显示血管重构的厚度。JASPAR 用于预测可能影响 EZH2 的转录因子。染色质免疫沉淀用于证实 DNA-蛋白质相互作用。启动子荧光素酶实验用于证明转录因子的活性。
我们发现，在体内，AAC 显著降低了胸主动脉中的 EZH2 蛋白水平。EZH2 的平滑肌特异性过表达足以减轻 AAC 诱导的组蛋白 3 赖氨酸 27 三甲基化的减少和动脉中膜的增厚。H3K27me3 去甲基酶抑制剂 GSK-J4 的给药也产生了相同的效果。此外，我们发现机械拉伸通过 Yes 相关蛋白（YAP）-转录因子 TEA 结构域 1（TEAD）途径调节 EZH2 的表达。TEAD1 直接结合到 EZH2 的启动子上，阻断 YAP-TEAD1 相互作用抑制了机械拉伸导致的 EZH2 下调。
这项研究揭示了机械拉伸通过 YAP-TEAD1 途径下调 EZH2，从而加重平滑肌细胞凋亡和血管重构。
