Abstract
We investigated the protective effects and mechanism of action of metformin on high glucose-induced smooth muscle cell proliferation and migration. Vascular smooth muscle cells (VSMCs) were subjected to a series of concentrations (0-10 mM) of metformin. CCK-8, wound healing, and transwell assays were performed. Correlations between metformin concentration and high-mobility group box 1 (HMGB1) and miR-142-3p levels were assessed. In addition, miR-142-3p mimic and siRNA were used to investigate VSMC migration in the presence or absence of metformin. In the high-glucose condition, metformin decreased cell growth and inhibited cell migration. HMGB1 gene expression correlated negatively with metformin concentration, whereas miR-142-3p expression correlated positively with metformin concentration. In addition, mimic-induced miR-142-3p elevation resulted in decreased HMGB1 and LC3II levels and elevated p62 levels in the high-glucose condition, whereas miR-142-3p knockdown had the reverse effects, and metformin abolished those effects. Metformin inhibits high glucose–induced VSMC hyperproliferation and increased migration by inducing miR-142-3p-mediated inhibition of HMGB1 expression via the HMGB1-autophagy related pathway.
Highlights
Arteriosclerosis obliterans (ASO) is a major cause of death and disability, in patients with diabetes mellitus (DM) [1, 2]
Metformin was added, and the results showed that metformin at concentrations of 1, 5, and 10 mM significantly inhibited high glucose–induced vascular smooth muscle cells (VSMCs) hyperproliferation (Figure 1B)
We evaluated the expression of High-mobility group box 1 (HMGB1)-autophagy related pathway molecules and found that metformin treatment resulted in inhibition of the elevated HMGB1 and LC3II levels and the decreased p62 level found in the high-glucose condition
Summary
Arteriosclerosis obliterans (ASO) is a major cause of death and disability, in patients with diabetes mellitus (DM) [1, 2]. This is because the inflammation underlying atherosclerosis exacerbated by hyperglycemic states [3]. Abundant HMGB1 within carotid and coronary atherosclerotic plaques [8] contributes to the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) [9, 10]. This makes HMGB1 inhibition potentially effective theraputic approach to atherosclerosis. Inhibiting HMGB1 expression via microRNAs in VSMCs may be a therapeutic approach to reduce atherothrombotic events
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