Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1...

Metformin is a widely used classic antidiabetic drug. However, its clinical pharmacologic mechanism remains poorly understood. In the present study, we investigated the anti-inflammatory effects of metformin on circulating peripheral blood mononuclear cells (MNCs) of patients with carotid artery atherosclerosis (AS). A total of 42 patients with carotid artery AS were randomly assigned to metformin (500 mg twice a day; Met; n = 21) or placebo control (Con; n = 21) groups. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) significantly decreased in the Met group compared with the Con group. In addition, treatment with metformin significantly reduced the expression of IL-6 and TNF-α at the messenger RNA level and attenuated nuclear factor kappa B (NF-κB) DNA binding activity in MNCs. Intriguingly, metformin did not alter the expression of NF-κB p65 subunit, but markedly inhibited its acetylation. Furthermore, metformin significantly induced sirtuin 1 (SIRT1) expression in MNCs. Moreover, we found that metformin treatment dramatically induced SIRT1 expression, blocked p65 acetylation, and inhibited NF-κB activity and the expression of inflammatory factors in MNCs in vitro. We conclude that metformin has a novel direct protective role to ameliorate the proinflammatory response through SIRT1 induction, p65 acetylation reduction, NF-κB inactivation, and inflammatory inhibition in peripheral blood MNCs of patients with carotid artery AS.