南方医科大学学报

南方医科大学学报 ›› 2017, Vol. 37 ›› Issue (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

田雨灵，王丽君，吴岳，张卫萍，梁萧，袁祖贻   

  • 出版日期:2017-08-20 发布日期:2017-08-20

Pioglitazone ameliorates atherosclerosis in apoE knockout mice through transforming growth factor-β/Smad signaling and adaptive T cell immunity

  • Online:2017-08-20 Published:2017-08-20

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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.