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

Pioglitazone (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. For in vitro studies, primary cultured or AMP-activat...

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Published in:	Cardiovascular diabetology 2017-10, Vol.16 (1), p.140-140, Article 140
Main Authors:	Tian, Yuling, Chen, Tao, Wu, Yan, Yang, Lin, Wang, Lijun, Fan, Xiaojuan, Zhang, Wei, Feng, Jiahao, Yu, Hang, Yang, Yanjie, Zhou, Juan, Yuan, Zuyi, Wu, Yue
Format:	Article
Language:	eng
Subjects:	AMP-activated protein kinase AMPK Apolipoprotein E Apolipoproteins Arteriosclerosis Atherogenesis Atherosclerosis Collagen Coronary vessels Diabetes Diabetes mellitus Flow cytometry Forkhead protein Foxp3 protein Helper cells Interleukin 17 Kinases Laboratory animals Lesions Low density lipoprotein Lymphocytes Lymphocytes T Mice Microscopy Oils & fats Original Investigation Phosphorylation Pioglitazone Polymerase chain reaction Proteins Rodents Signaling Spleen Splenocytes Studies T cell Thiazolidinediones Western blotting
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Summary:	Pioglitazone (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. For 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. In 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. PIO exhibits anti-atherosclerotic effects for stabilization of atherosclerotic plaque through regulating the Th17/Treg balance in an AMPK-dependent manner.
ISSN:	1475-2840 1475-2840