Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms

Cardiovascular Diabetology

Original Investigation

Hang Yu¹  Tao Chen¹  Juan Zhou¹  Yanjie Yang¹  Wei Zhang¹  Jiahao Feng¹  Zuyi Yuan¹  Yue Wu¹  Yan Wu¹  Xiaojuan Fan¹  Yuling Tian¹  Lijun Wang¹  Lin Yang² 

[1] Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, 710061, Xi’an, Shaanxi, China;Department of Vascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;

关键词: Pioglitazone;    AMPK;    T cell;    Signaling;    Atherosclerosis;   

DOI  :  10.1186/s12933-017-0623-6

 received in 2017-07-21, accepted in 2017-10-18,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPioglitazone (PIO), a thiazolidinediones drug, is a well-known anti-diabetic medicine, but its anti-atherosclerotic effects remain controversial. Thus it is important to investigate the effects of PIO on atherogenesis and the relevant mechanisms.MethodsFor in vitro studies, primary cultured or AMP-activated protein kinase (AMPK) inhibited splenocytes were treated with oxidized low density lipoprotein (ox-LDL) or ox-LDL plus PIO. Percentage of T helper 17 (Th17) and regulatory T (Treg) cells were determined by flow cytometry. Expression of AMPK, interleukin-17 (IL-17) and forkhead box P3 (FoxP3) were detected by Western blots. For in vivo studies, apolipoprotein E–deficient (apoE−/−) mice fed with western diet were treated with PIO or vehicle for 8 weeks respectively. Percentage of Th17 and Treg cells in spleen were measured by immunohistochemical analysis. The atherosclerotic lesions were analyzed using oil red O staining, and collagen types I and III in atherosclerotic lesions were stained by Sirius red. Expression of IL-17 and FoxP3 were determined by quantitative polymerase chain reaction.ResultsIn cultured primary splenocytes, PIO dramatically inhibited Th17 and raised Treg. Intriguingly, pharmacological and genetic AMPK inhibitions abolished PIO-induced Treg elevation and Th17 inhibition. Moreover, PIO significantly induced AMPK phosphorylation, decreased IL-17+ and increased FoxP3+ cells in spleen of apoE−/− mice. Finally, PIO did not alter plaque area, but intriguingly, stabilized atherosclerotic plaque through collagen induction in apoE−/− mice. PIO treatment also improved Th17/Treg balance in atherosclerotic lesions.ConclusionsPIO exhibits anti-atherosclerotic effects for stabilization of atherosclerotic plaque through regulating the Th17/Treg balance in an AMPK-dependent manner.

【 授权许可】

CC BY   
© The Author(s) 2017