[1]田雨灵,王丽君,吴岳,等.吡格列酮通过调控TGF-β信号通路和T细胞调节性免疫机制缓解ApoE-/-小鼠动脉粥样硬化[J].南方医科大学学报,2017,(08):1003.
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吡格列酮通过调控TGF-β信号通路和T细胞调节性免疫机制缓解ApoE-/-小鼠动脉粥样硬化()
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《南方医科大学学报》[ISSN:/CN:]

卷:
期数:
2017年08期
页码:
1003
栏目:
出版日期:
2017-08-06

文章信息/Info

Title:
Pioglitazone ameliorates atherosclerosis in apoE knockout mice through transforming growth factor-β/Smad signaling and adaptive T cell immunity
作者:
田雨灵王丽君吴岳张卫萍梁萧袁祖贻
关键词:
吡格列酮PPARγT细胞TGF-β/Smad信号通路动脉粥样硬化
Keywords:
pioglitazone nuclear receptor peroxisome proliferator-activated receptor-γ T cells transforming growth factor-β/Smad signaling atherosclerosis
摘要:
目的研究ApoE-/-小鼠体内吡格列酮(PIO)是否通过TGF-β信号通路和T细胞调节性免疫机制来发挥抗动脉粥样硬化的
作用。方法动脉粥样硬化ApoE-/-小鼠模型连续8周每日灌胃给予PIO(日剂量20 mg/kg)。免疫组化对动脉病变组织中TGF-β
信号通路相关因子、IFN-γ+细胞及Foxp3+细胞的表达水平进行检测。体外研究中,用特异性抗原氧化低密度脂蛋白(oxLDL)刺
激原代培养的ApoE-/-小鼠脾脏细胞,并与PIO或PIO+PPARγ阻断剂GW9662 共同孵育。流式细胞术检测CD4+IFN-γ+细胞和
CD4+CD25+Foxp3+细胞的水平。结果PIO可通过提高TGFβ1(P<0.01),TGFβRII(P<0.05)和p-Smad3(P<0.05)的表达量、抑制
Smad7(P<0.05)的表达量来缓解ApoE-/-小鼠动脉粥样硬化的病变程度。体外实验表明,PIO处理后原代小鼠脾细胞中IFN-γ的
mRNA水平显著下调(P<0.05),而Foxp3的mRNA水平显著上调(P<0.05)。流式细胞术表明PIO处理后CD4+IFN-γ+细胞(P<0.05)
和CD4+CD25+Foxp3+细胞(P<0.05)的表达量明显上升,而PPARγ阻断剂GW9662 可阻断PIO 对两种细胞的调控作用。结论
PIO可能通过调控TGF-β/Smad信号通路及PPARγ介导的Th1/Treg细胞水平抑制ApoE-/-小鼠的动脉粥样硬化病变。
Abstract:
Objective To examine whether transforming growth factor-β (TGF-β) pathway and adaptive T cell immunity play
roles in the anti-atherosclerotic effects of pioglitazone (PIO) in ApoE-/- mice. Methods ApoE-/- mice with atherosclerosis induced
by high-fat feeding were treated daily with PIO (20 mg/kg) or vehicle for 8 weeks. The protein expressions of TGF-β pathway
in the atheromatous lesions of the aorta and the percentages of IFN-γ+ and Foxp3+ cells in the spleen of the mice were examined
with immunohistochemical staining. In the in vitro experiment, primary cultured splenocytes were stimulated with oxidized
low-density lipoproteins (oxLDL) and treated with PIO either alone or in combination with the PPARγ antagonist GW9662,
after which the changes in percentages of CD4+IFN-γ+ cells and CD4+CD25+Foxp3+ cells were analyzed with flow cytometry.
Results PIO treatment of ApoE-/- mice with high-fat feeding significantly attenuated the progression of atheromatous lesions
(P<0.05) and resulted in increased expressions of TGFβ1 (P<0.01), TGFβRII (P<0.05), and p-Smad3 (P<0.05) and a decreased
expression of Smad7 (P<0.05) in the lesions. PIO treatment also led to decreased percentage of IFN-γ + cells (P<0.05) and
increased percentage of Foxp3+ cells (P<0.01) in the spleen of the mice. In primary cultured splenocytes, PIO treatment caused
significant down-regulation of IFN-γ mRNA (P<0.05) and up-regulation of Foxp3 mRNA (P<0.05) and obviously increased the
percentages of CD4+IFN-γ+ cells (P<0.05) and CD4+CD25+Foxp3+ (P<0.05); the effects of PIO on CD4+IFN-γ+ and CD4+CD25+
Foxp3 + cells were abolished by treatment of the cells with GW9662. Conclusion The anti-atherosclerotic effect of PIO is
probably mediated by the TGF-β/Smad signaling pathway and PPAR-γ-dependent modulation of Th1/Treg population.

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更新日期/Last Update: 1900-01-01