Department of Cardiovascular Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Atherosclerosis. 2011 Oct;218(2):330-8. doi: 10.1016/j.atherosclerosis.2011.07.112. Epub 2011 Aug 4.
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.
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 20mg/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)γ antagonist GW9662, whereas the latter was completely abolished by GW9662.
Pioglitazone ameliorates accelerated AS in uremic apoE-/- mice, probably through PPARγ-independent and -dependent mechanisms to modulate the Treg/Teff imbalance.
尿毒症显著加速动脉粥样硬化形成，但发病机制尚不清楚，需要有效的抗动脉粥样硬化治疗。本研究旨在探讨尿毒症载脂蛋白 E 基因敲除（apoE-/-）小鼠加速动脉粥样硬化（AS）与调节/效应 T 细胞（Treg/Teff）平衡的关系，以及吡格列酮对尿毒症 AS 的影响及可能的机制。
通过手术在 8 周龄雄性 apoE-/-小鼠中诱导尿毒症。尿毒症诱导 2 周后，将小鼠随机分为吡格列酮（每天口服 20mg/kg）或载体治疗组。假手术对照组apoE-/-小鼠给予载体。治疗 8 周后，所有小鼠均被处死。与对照组相比，尿毒症小鼠主动脉根部粥样硬化病变的横截面积明显增大，斑块不稳定，与 Treg/Teff 失衡（Treg 下调/Teff 上调）有关。与对照组相比，尿毒症未接受治疗的小鼠肾功能与脾细胞 Treg 细胞的百分比呈负相关。吡格列酮治疗可显著抑制尿毒症小鼠 AS 进展，稳定斑块，调节 Treg/Teff 失衡（上调 Treg/下调 Teff），而不影响血清脂质谱和血糖。体外，氧化型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。前者不受过氧化物酶体增殖物激活受体（PPAR）γ拮抗剂 GW9662 的影响，而后者则完全被 GW9662 所抑制。
吡格列酮改善尿毒症 apoE-/-小鼠加速的 AS，可能通过 PPARγ 非依赖性和依赖性机制来调节 Treg/Teff 失衡。
