Abstract
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.
Highlights
Pioglitazone (PIO) belongs to a class of drugs named thiazolidinediones (TZDs), which are the agonists of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-γ. and has been widely used as anti-diabetic drugs
PIO attenuates ox‐LDL‐enhanced IL‐17 expression in cultured primary splenocytes We first investigated whether PIO could influence T helper 17-cells (Th17) cell population in cultured splenocytes isolated from apoE−/− mice
D, oxidized low density lipoprotein (ox-LDL) dramatically decreased regulatory T (Treg) cells, which can be blocked by PIO. These data suggested that PIO improved the balance of Th17/Treg disturbed by ox-LDL in vitro
Summary
Pioglitazone (PIO) belongs to a class of drugs named thiazolidinediones (TZDs), which are the agonists of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-γ. and has been widely used as anti-diabetic drugs. Pioglitazone (PIO) belongs to a class of drugs named thiazolidinediones (TZDs), which are the agonists of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-γ. Several possible mechanisms, including amelioration of atherosclerosis [4,5,6], and modulating effects on the immune system [7,8,9,10], have been proposed. Since the immune response plays a pathogenic role in atherosclerosis [11], the anti-inflammatory properties of TZDs may contribute to its cardiovascular protective effects, including anti-atherosclerosis. Pioglitazone (PIO), a thiazolidinediones drug, is a well-known anti-diabetic medicine, but its anti-atherosclerotic effects remain controversial. It is important to investigate the effects of PIO on atherogenesis and the relevant mechanisms
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have