Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms.
Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms.
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吡格列酮通过调节 AMPK 依赖性机制中的 Th17/Treg 平衡来稳定动脉粥样硬化斑块。
DOI：
10.1186/s12933-017-0623-6
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发表时间：
2017-10-30
影响因子：
9.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Tian Y;Chen T;Wu Y;Yang L;Wang L;Fan X;Zhang W;Feng J;Yu H;Yang Y;Zhou J;Yuan Z;Wu Y
吡格列酮（PIO）是一种噻唑烷二酮类药物，是一种著名的抗糖尿病药物，但其抗动脉粥样硬化作用仍存在争议。因此，研究PIO在动脉粥样硬化形成中的作用及其机制具有重要意义。对于体外研究，原代培养或AMP活化蛋白激酶（AMPK）抑制的脾细胞用氧化低密度脂蛋白（ox-LDL）或ox-LDL加PIO处理。通过流式细胞术测定T辅助性17（Th 17）和调节性T（Treg）细胞的百分比。Western blot检测AMPK、白细胞介素17（IL-17）和叉头盒P3（FoxP 3）的表达。对于体内研究，分别用PIO或溶剂处理喂食西方饮食的载脂蛋白E缺陷（apoE−/−）小鼠8周。免疫组化法检测脾脏中Th 17和Treg细胞的百分比。采用油红O染色法对动脉粥样硬化病变进行分析，天狼星红染色法对动脉粥样硬化病变中的I型和III型胶原进行染色。用定量聚合酶链反应测定IL-17和FoxP 3的表达。在培养的原代脾细胞中，PIO显著抑制Th 17并升高Treg。有趣的是，药理学和遗传AMPK抑制消除PIO诱导的Treg升高和Th 17抑制。此外，PIO显著诱导AMPK磷酸化，降低apoE−/−小鼠脾脏中的IL-17+和FoxP 3+细胞。最后，PIO没有改变斑块面积，但有趣的是，通过apoE−/−小鼠的胶原诱导稳定了动脉粥样硬化斑块。PIO治疗还改善了动脉粥样硬化病变中的Th 17/Treg平衡。PIO通过AMPK依赖性调节Th 17/Treg平衡，发挥抗动脉粥样硬化作用。
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.
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影响因子：
82.9
作者：
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