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

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.

Aged garlic extract reduces low attenuation plaque in coronary arteries of patients with diabetes: A�randomized, double‑blind, placebo‑controlled study

“…Previous studies demonstrated that statin and anti-diabetic therapies may decrease the rate of coronary plaque progression and may participate in plaque stabilization (7)(8)(9). Previous experiments performed in our laboratory have shown that the use of aged garlic extract (AGE) is associated with a significant reduction in low attenuation plaque (LAP) progression as compared to the placebo using CCTA in patients with metabolic syndrome (10).…”

Glitazones and alpha-glucosidase inhibitors as the second-line oral anti-diabetic agents added to metformin reduce cardiovascular risk in Type 2 diabetes patients: a nationwide cohort observational study

“…Although prospective randomized controlled trials (RCTs) have provided cardiovascular safety data on various ADAs including sulphonylureas (SU) [ 7 ], thiazolidinediones (TZD) [ 8 – 10 ], alpha-glucosidase inhibitors (AGI) [ 11 , 12 ], and dipeptidyl peptidase-4 inhibitors (DPP-4I) [ 13 – 15 ], these trials were not designed to compare the individual ADAs as the add-on medication to baseline metformin monotherapy [ 16 ]. A landmark RCT comparing cardiovascular outcomes of SU, DPP-4I, glucagon-like peptide-1 analogues and insulin as second-line agents to metformin in newly diagnose T2DM patients is expected to be completed in 2020 [ 17 ].…”

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis

“…Some studies have reported that the proportions of circulating Tregs in AITDs tended to be lower than those in HCs [11][12][13][14][15][16][17][18][19][20][21][22], while others reported the opposite result [23,24]. Considering that drugs including methimazole [25] might affect the differentiation and proliferation of Tregs through regulation of AMP-activated protein kinase (AMPK) [26] and signal transducer and activator of transcription 3 (STAT3) [27], we speculated that the origins of these differences between results lie in differences in the treatment statuses of the AITDs involved in the studies. Therefore, we performed a meta-analysis of the proportions of peripheral blood Tregs among CD4+ T cells of untreated and treated AITDs to explore how Tregs function in the pathogenesis of AITD.…”