Antiatherogenic effect of pioglitazone on uremic apolipoprotein E knockout mice by modulation of the balance of regulatory and effector T cells
Antiatherogenic effect of pioglitazone on uremic apolipoprotein E knockout mice by modulation of the balance of regulatory and effector T cells
复制标题
吡格列酮通过调节调节性 T 细胞和效应 T 细胞的平衡对尿毒症载脂蛋白 E 敲除小鼠的抗动脉粥样硬化作用
DOI：
10.1016/j.atherosclerosis.2011.07.112
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发表时间：
2011-10-01
期刊：
影响因子：
5.3
通讯作者：
Kishimoto, Chiharu
中科院分区：
文献类型：
--
作者：
Shen, Yan;Yuan, Zuyi;Kishimoto, Chiharu
目的：尿毒症明显加速动脉粥样硬化的形成，但其发病机制仍有待阐明，需要有效的抗动脉粥样硬化治疗。本研究的目的是探讨尿毒症载脂蛋白E基因敲除（apoE-/-）小鼠中加速动脉粥样硬化（AS）和调节性/效应性T细胞（Treg/Teff）平衡之间的关系，以及吡格列酮对尿毒症AS的影响和可能的机制。诱导尿毒症后两周，将小鼠随机接受吡格列酮（每日口服灌胃20 mg/kg）或溶媒。对照apoE-/-小鼠进行假手术并接受载体。治疗8周后，处死所有小鼠。与对照组相比，尿毒症小鼠主动脉根部动脉粥样硬化病变的横截面积显著更大，斑块不稳定，这与Treg/Teff失衡（Treg下调/Teff上调）相关。在对照组和接受溶媒的尿毒症小鼠中，肾功能和脾细胞中Treg细胞的百分比呈负相关。吡格列酮治疗可显著抑制AS进展，稳定斑块，并调节尿毒症小鼠中Treg/Teff失衡（上调Treg/下调Teff），而不影响血脂谱和血糖。在体外，氧化低密度脂蛋白诱导尿毒症小鼠脾细胞Treg/Teff失衡。吡格列酮通过上调Treg细胞和下调Teff细胞来调节失衡。过氧化物酶体增殖物激活受体（peroxisomeproliferator-activatedreceptor，PPAR γ）拮抗剂GW 9662不能阻断前者，而后者可完全阻断。结论：吡格列酮可改善尿毒症apoE-/-小鼠加速型动脉粥样硬化，其机制可能是通过调节PPAR γ非依赖性和依赖性调节Treg/Teff失衡。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Objective: Uremia markedly accelerates atherogenesis, but the pathogenesis remains to be elucidated and effective anti-atherogenic treatments are needed. The aim of this study was to investigate the relationship between accelerated atherosclerosis (AS) and the balance of regulatory/effector T cells (Treg/Teff) in uremic apolipoprotein E knockout (apoE-/-) mice, and the effect of pioglitazone on uremic AS and possible mechanisms.Methods and results: Uremia was induced surgically in 8-week-old male apoE-/- mice. Two weeks after induction of uremia, the mice were randomized to receive pioglitazone (daily oral gavage with 20 mg/kg) or vehicle. Control apoE-/- mice were sham-operated and received vehicle. After 8 weeks' treatment, all mice were sacrificed. The cross-sectional area of atherosclerotic lesions at the aortic root was significantly larger and plaques were unstable in uremic mice, which was associated with a Treg/Teff imbalance (Treg down-regulated/Teff up-regulated) compared with controls. Renal function and the percentage of Treg cells in splenocytes were negatively correlated in control and uremic mice that received vehicle. Treatment with pioglitazone dramatically inhibited AS progression, stabilized plaque and modulated the Treg/Teff imbalance (up-regulated Treg/down-regulated Teff) in uremic mice, without influencing serum lipid profiles and blood glucose. In vitro, oxidized low density lipoprotein induced a Treg/Teff imbalance in splenocytes from uremic mice. Pioglitazone modulated the imbalance by upregulating Treg cells and downregulating Teff cells. The former was not abolished by the peroxisome proliferator-activated receptor (PPAR)gamma antagonist GW9662, whereas the latter was completely abolished by GW9662.Conclusion: Pioglitazone ameliorates accelerated AS in uremic apoE-/- mice, probably through PPAR gamma-independent and -dependent mechanisms to modulate the Treg/Teff imbalance. (C) 2011 Elsevier Ireland Ltd. All rights reserved.