Mechanical stretch aggravates vascular smooth muscle cell apoptosis and vascular remodeling by downregulating EZH2.
Mechanical stretch aggravates vascular smooth muscle cell apoptosis and vascular remodeling by downregulating EZH2.
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DOI：
10.1016/j.biocel.2022.106278
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发表时间：
2022-08
期刊：
影响因子：
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通讯作者：
Hong-yu Zhong;Chong Yuan;Xiao-lin Liu;Qian-qian Wang;Xiao Li;Ya-chao Zhao;Xuan Li;Dong-dong Liu;Teng-fei Zheng;Mei Zhang
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作者：
Hong-yu Zhong;Chong Yuan;Xiao-lin Liu;Qian-qian Wang;Xiao Li;Ya-chao Zhao;Xuan Li;Dong-dong Liu;Teng-fei Zheng;Mei Zhang
背景Zeste增强子2（Enhancer of zeste homolog 2，EZH 2）是近年来发现的在心血管疾病中发挥重要作用的基因。然而，EZH 2在机械牵张诱导的血管重塑中的作用知之甚少。本工作的目的是研究EZH 2在调节平滑肌细胞功能，通过机械拉伸试验的作用，并探讨潜在的mechanism.MethodsWT C57 BL/6 J小鼠进行假手术或腹主动脉缩窄。Western blotting和免疫组织化学染色检测EZH 2的表达水平。HE染色显示血管重塑厚度。JASPAR用于预测可能影响EZH 2的转录因子。染色质免疫沉淀用于证实DNA蛋白相互作用。启动子荧光素酶测定进行证明的转录factors.ResultsWe的活动发现，在体内，AAC显着降低EZH 2蛋白水平在胸主动脉。平滑肌特异性EZH 2过表达足以减弱AAC诱导的组蛋白3中Lys-27三甲基化减少和动脉中层增厚。GSK-J 4（H3 K27 me 3去甲基化酶的抑制剂）的施用诱导了相同的效果。另外，我们发现机械牵张通过Yes相关蛋白（雅普）-转录因子TEA结构域1（TEAD）途径调控EZH 2的表达。TEAD 1直接与EZH 2的启动子结合，阻断YAP与TEAD 1的相互作用可抑制机械牵张引起的EZH 2下调，从而加重平滑肌细胞凋亡和血管重构。
BackgroundEnhancer 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.MethodsWT 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.ResultsWe 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.ConclusionThis study reveals that mechanical stretch downregulates EZH2 through the YAP-TEAD1 pathway, thereby aggravating smooth muscle cell apoptosis and vascular remodeling.