title: Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiovascular Department of Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Deng
authors.affiliation: Cardiovascular Department of Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China; Department of Vascular Surgery, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Sijia
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Prabindra
authors.initials: P
authors.lastname: Maharjan
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiovascular Department of Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China. Electronic address: zuyiyuan@mail.xjtu.edu.cn.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiovascular Department of Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China. Electronic address: imyuewu@gmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000368:Aged; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D056564:Sirtuin 1 / Q000096:biosynthesis*
chemical_list: D010919:Placebos; D008687:Metformin; C447939:SIRT1 protein, human; D056564:Sirtuin 1