Metformin suppresses cardiac fibroblast proliferation under high-glucose conditions via regulating the mitochondrial complex I protein Grim-19 involved in the Sirt1/Stat3 signaling pathway

被引：8

作者：

Li, Yongguang ^{[1
]}

Liu, Xiangdong ^{[2
]}

Wan, Lili ^{[3
]}

Han, Beibei ^{[1
]}

Ma, Shixin ^{[1
]}

Pan, Hongyuan ^{[4
]}

Wei, Junbo ^{[1
,5
]}

Cui, Xiaofang ^{[6
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, Dept Cardiol, 600 Yishan Rd, Shanghai 200233, Peoples R China

[2] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Cardiol, 301 Yanchang Rd, Shanghai 200072, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, Div Pharm, 600 Yishan Rd, Shanghai 200233, Peoples R China

[4] St Pauls Sch, 325 Pleasant St, Concord, NH 03301 USA

[5] Renhe Hosp, Dept Cardiol, 1999 Changjiang West Rd, Shanghai 200431, Peoples R China

[6] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2023年 / 206卷

基金：

中国国家自然科学基金;

关键词：

Cardiac fibroblasts; Grim-19; Metformin; Migration; Proliferation; Sirt1; Stat3; OXIDATIVE STRESS; METABOLISM; FIBROSIS; NAD(+); CANCER; SIRT1; CARDIOMYOCYTES; BIOGENESIS; ACTIVATION; MECHANISMS;

D O I：

10.1016/j.freeradbiomed.2023.06.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hyperglycemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Currently, no approved drug is available for preventing or treating diabetes-induced cardiac fibrosis. Metformin has been reported to improve glycemic control and ameliorate diabetic cardiomyopathy. This study aimed to investigate the effects and mechanism of metformin on diabetes-induced cardiac fibrosis and high glucose-induced proliferation of cardiac fibroblasts (CFs). In this study, db/db mice were treated with metformin [250 mg/kg center dot d, gavage]. CFs were cultured in high-glucose medium to mimic an in vitro diabetes model and then subjected to treatment with or without metformin. Cardiac fibrosis was analyzed using immunohistochemistry, Masson's trichrome staining, and Western blot analysis. Cell Counting Kit-8 (CCK-8) assays and cell colony formation assays were used to examine cell proliferation capacity. Transwell and scratch-wound assays were used to detect the migration ability of CFs. Retinoid-interferon-induced mortality-19 (Grim-19), sirtuin1 (Sirt1), and signal transducer and activator of transcription 3 (Stat3) were detected using Western blot analysis. The genes downstream of the Stat3 pathway were detected using quantitative reverse transcription PCR (qRT-PCR). Metformin treatment markedly attenuated cardiac fibrosis in db/db mice and the proliferation and migration of CFs under high-glucose conditions. Mechanistically, we found an intersection between metformin and Grim-19 using bioinformatics. Metformin was found to suppress the expression of p-Stat3 and elevate the expression of mitochondrial complex I protein Grim-19 and Sirt1, thus inhibiting the proliferation and migration of CFs under high-glucose conditions. Our data suggested that metformin inhibited the proliferation and migration of CFs by regulating the expression of mitochondrial complex I Grim-19 protein involved in the Sirt1/Stat3 signaling pathway under high-glucose conditions, thus providing new ideas for treating diabetes-induced cardiac fibrosis.

引用

页码：1 / 12

页数：12