Exendin-4 通过 AMPK/SIRT1/FOXO3a 信号通路促进血管平滑肌细胞再分化。

Exendin-4 promotes the vascular smooth muscle cell re-differentiation through AMPK/SIRT1/FOXO3a signaling pathways.

机构信息

Institute of Cardiovascular Science, Beijing, 100191, China; Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.

出版信息

Atherosclerosis. 2018 Sep;276:58-66. doi: 10.1016/j.atherosclerosis.2018.07.016. Epub 2018 Jul 21.

DOI:10.1016/j.atherosclerosis.2018.07.016

PMID:30036742

Abstract

BACKGROUND AND AIMS

The phenotype switching of vascular smooth muscle cells (VSMCs) plays a key role during development and progression of vascular remodeling diseases. Recent studies show that GLP-1 can inhibit intima thickening to delay the progression of atherosclerotic plaques. The purpose of this study was to investigate the role of Exendin-4, a GLP-1 receptor agonist, in VSMCs phenotype switching and the related mechanisms.

METHODS

Immunohistochemistry and Western blot were used to detect the effect of Exendin-4 on expression of markers of contractile VSMCs. Phalloidin staining was performed to observe the effect of Exendin-4 on morphology of VSMCs.

RESULTS

Exendin-4 significantly increased the protein levels of contractile VSMCs markers like Calponin and SM22α. After treatment of Exendin-4, VSMCs showed more typical characteristic spindle shape. In addition, Exendin-4 significantly upregulated the phosphorylation of AMPK as well as the protein levels of Sirtuin1 (SIRT1) and FOXO3a in VSMCs. After inhibiting AMPK activity with compound C and SIRT1 activity with EX527, and knocking down FOXO3a expression through RNAi technique, Exendin-4 increased the protein levels of Calponin and SM22α and promoted the redifferentiation of VSMCs mainly through AMPK/SIRT1/FOXO3a signaling pathways.

CONCLUSIONS

Exendin-4 can regulate the phenotype switching of VSMCs and promote redifferentiation of VSMCs through AMPK/SIRT1/FOXO3a signaling pathways.

摘要

背景与目的

血管平滑肌细胞（VSMCs）的表型转换在血管重塑疾病的发展和进展中起着关键作用。最近的研究表明，GLP-1 可以抑制内膜增厚，从而延缓动脉粥样硬化斑块的进展。本研究旨在探讨 GLP-1 受体激动剂 Exendin-4 在 VSMCs 表型转换中的作用及其相关机制。

方法

采用免疫组织化学和 Western blot 检测 Exendin-4 对收缩型 VSMCs 标志物表达的影响。用鬼笔环肽染色观察 Exendin-4 对 VSMCs 形态的影响。

结果

Exendin-4 显著增加了收缩型 VSMCs 标志物如 Calponin 和 SM22α 的蛋白水平。经 Exendin-4 处理后，VSMCs 呈现出更典型的特征性梭形。此外，Exendin-4 显著上调了 VSMCs 中 AMPK 的磷酸化以及 Sirtuin1（SIRT1）和 FOXO3a 的蛋白水平。用化合物 C 抑制 AMPK 活性、用 EX527 抑制 SIRT1 活性、用 RNAi 技术敲低 FOXO3a 表达后，Exendin-4 增加了 Calponin 和 SM22α 的蛋白水平，并通过 AMPK/SIRT1/FOXO3a 信号通路主要促进 VSMCs 的再分化。