Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages

被引：85

作者：

Fei, Qin ^{[1
,2
]}

Ma, Heng ^{[1
,2
]}

Zou, Jiang ^{[1
,2
]}

Wang, Wenmei ^{[1
,2
]}

Zhu, Lili ^{[1
,2
]}

Deng, Huafei ^{[1
,2
]}

Meng, Meng ^{[1
,2
]}

Tan, Sipin ^{[1
,2
]}

Zhang, Huali ^{[1
,2
]}

Xiao, Xianzhong ^{[1
,2
]}

Wang, Nian ^{[1
,2
,3
]}

Wang, Kangkai ^{[1
,2
]}

机构：

[1] Cent South Univ, Sch Basic Med Sci, Dept Pathophysiol, Changsha 410008, Hunan, Peoples R China

[2] Cent South Univ, Hunan Key Lab Sepsis Translat Med, Changsha 410008, Hunan, Peoples R China

[3] Cent South Univ, Xiangya Sch Med, Res Ctr China Africa Infect Dis, Changsha 410008, Hunan, Peoples R China

来源：

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY | 2020年 / 145卷

基金：

中国国家自然科学基金;

关键词：

Metformin; NLRP3; Autophagy; ROS; Macrophages; Inflammation; Myocardial infarction; NLRP3; INFLAMMASOME; ACTIVATION; INFARCTION; AUTOPHAGY; INHIBITION; KINASE; ROS; DYSFUNCTION; RELEASE; CANCER;

D O I：

10.1016/j.yjmcc.2020.05.016

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Myocardial ischaemia is usually accompanied by inflammatory response which plays a critical role in the myocardial healing and scar formation, while persistent inflammatory response contributes greatly to the myocardial remodeling and consequent heart failure. Metformin (Met), a widely used hypoglycemic drug, has increasingly been shown to exert remarkable cardioprotective effect on ischaemic myocardial injury such as acute myocardial infarction (AMI). However, the underlying mechanisms are still far from being fully understood. In this study, a mouse model of AMI was established through ligating the left anterior descending coronary artery (LAD), 100 mg/kg Met was given immediately after operation once daily for 3 days. It was demonstrated that Met effectively improved the cardiac haemodynamics (LVSP, LVEDP, + dp/dt, - dp/dt), diminished the infarct size, alleviated the disarrangement of myocardial cells and reduced the infiltration of inflammatory cells (macrophages, neutrophils and lymphocytes) in the heart of AMI mice. Mechanistically, Met decreased the expression of NLRP3 and enhanced the accumulation of LC3 puncta in F4/80-positive macrophages in the heart of AMI mice. Single cell suspension of cardiac macrophages was prepared from AMI mice and exhibited increased NLRP3 mRNA and protein expression. In contrast, Met decreased the expression of NLRP3 and p62, whereas increased the ratio of LC3II/LC3I. Additionally, both conditioned medium from H9c2 cardiomyocytes exposed to hydrogen peroxide (H9c2-H2O2-CM) and combination of mtDNA and ATP (mtDNA-ATP) increased the expression of NLRP3 and cleaved caspase-1 (p10) as well as intracellular ROS production in RAW264.7 macrophages, which were abrogated by Met treatment. Strikingly, chloroquine (CQ), 3-methyladenine (3-MA) and knockdown of autophagy-related gene (Atg5) abrogated the inhibitory effects of Met on H9c2-H2O2-CM and mtDNA-ATP-induced NLRP3 expression, release of IL-1 beta and IL-18 as well as ROS production in RAW264.7 macrophages. Collectively, these findings suggest that Met protects against ischaemic myocardial injury through alleviating autophagy-ROS-NLRP3 axis-mediated inflammatory response in macrophages.

引用

页码：1 / 13

页数：13

共 52 条

[1]

Metformin improves the angiogenic potential of human CD34+ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction [J].