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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

PIO exhibits anti-atherosclerotic effects for stabilization of atherosclerotic plaque through regulating the Th17/Treg balance in an AMPK-dependent manner.

• Authors: Yuling Tian, Tao Chen, Yan Wu, Lin Yang, Lijun Wang, Xiaojuan Fan, Wei Zhang, Jiahao Feng, Hang Yu, Yanjie Yang, Juan Zhou, Zuyi Yuan, Yue Wu
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 16 Issue 1 Pg. 140 (10 30 2017) ISSN: 1475-2840 [Electronic] England
• PMID: 29084546 (Publication Type: Journal Article)

Chemical References

• Hypoglycemic Agents
• Thiazolidinediones
• Protein Kinases
• AMP-Activated Protein Kinase Kinases
• Pioglitazone

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Atherosclerosis (drug therapy, enzymology, physiopathology)
• Cells, Cultured
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Mice
• Mice, 129 Strain
• Mice, Knockout
• Pioglitazone
• Protein Kinases (biosynthesis)
• T-Lymphocytes, Regulatory (drug effects, physiology)
• Th17 Cells (drug effects, physiology)
• Thiazolidinediones (pharmacology, therapeutic use)