Metformin Inhibits the Phenotypic Transformation of Aortic Vascular Smooth Muscle Cells Induced by Hyperglycemia Through Regulation of the Mir-21-mediated PTEN/pAKT/Egr-1 Pathway

Abstract

Background The phenotypic transformation of arterial vascular smooth muscle cells (VSMC) is one of the key mechanisms in the formation of atherosclerotic plaque. It is unclear whether metformin can inhibit the phenotypic transformation of VSMC. In this study, we observed the effect of metformin on the phenotypic transformation of VSMC in vivo and in vitro and its mechanism.Methods Patients who underwent simple coronary artery bypass grafting (CABG) were divided into non-diabetic(non-DM) group and diabetes (DM) group according to whether diabetes was combined. The miR-21 and VSMC contractile marker protein, smooth muscle contractile protein (αSMA) and synthetic marker protein osteopontin (OPN) were isolated from the internal mammary artery.30 male, clean, and 6 week old wild type C57/BL6J mice were randomly divided into 3 groups:the control group (NC), the diabetes mellitus group (DM) and the metformin intervention group(DM+MET).Diabetic mice model was established by high-fat diet combined with low-dose streptozotocin. Metformin was given by gavage for 8 weeks.The aortic tissue from aortic root to renal artery was retained, miR-21 was determined by real-time PCR, and SMC and OPN were determined by Western Blotting (WB). In vitro, human aortic smooth muscle cells (HA-SMC) were divided into three groups: control group, HG group and HG+ group. The content of miR-21/PTEN/pAKT/Egr-1 protein was determined by WB, the migration ability was determined by MTT and scratch method.Results 1.In vivo, the expression of miR-21 and OPN in the aortic VSMC of DM petients and diabetic mice increased and the intima media thickness increased. Metformin treatment reduced the expression of miR-21 and OPN in the aorta and decreased the thickness of intima media. 2.In vitro, glucose concentration dependently upregulates the expression of miR-21 and osteopontin in HA-SMC.Conclusion Metformin can inhibit the phenotype transformation of VSMC induced by HG, which may inhibit the migration of VSMC through miR-21/PTEN/pAkt/Egr-1.