Metformin attenuates carotid neointimal hyperplasia by modulating the vascular smooth muscle cell phenotype transformation through upregulation of TET2, Nur77 and calponin

Abstract

Metformin is a drug used to treat type 2 diabetes based on its effectiveness as well as cardiovascular safety. Metformin has been shown to modulate proliferation and migration of vascular smooth muscle cells (VSMCs), but the underlying mechanisms of the effect of metformin on VSMC function remains unclear. We found that metformin inhibits VSMC proliferation and migration and upregulates the expression of nuclear receptor subfamily 4 group A member 1 (Nur77), ten-eleven translocation 2 (TET2), and calponin in vitro. In the carotid artery balloon injury model of rats, metformin effectively prevented neointimal hyperplasia in the carotid artery, including neointimal thickness, increased neointimal area, and the neointimal area/medial area ratio. It also reduced the number of proliferating cell nuclear antigen (PCNA)+cells and increased the expression of Nur77, calponin and alpha-smooth muscle actin (α-SMA). These results show that metformin attenuates neointimal hyperplasia in balloon-injured carotid arteries via increased expression of TET2, Nur77 and calponin, and reduced expression of matrix metallopeptidase 9 (MMP-9).