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

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.