Antiatherogenic effect of pioglitazone on uremic apolipoprotein E knockout mice by modulation of the balance of regulatory and effector T cells

被引：14

作者：

Shen, Yan ^{[1
,2
]}

Yuan, Zuyi ^{[1
,3
]}

Yin, Aiping ^{[2
]}

Liu, Yan ^{[1
]}

Xiao, Yan ^{[1
]}

Wu, Yue ^{[1
]}

Wang, Lijun ^{[3
]}

Liang, Xiao ^{[1
]}

Zhao, Yan ^{[1
]}

Tian, Yuling ^{[1
]}

Liu, Weimin ^{[1
]}

Chen, Tao ^{[1
]}

Kishimoto, Chiharu ^{[4
]}

机构：

[1] Xi An Jiao Tong Univ, Dept Cardiovasc Med, Affiliated Hosp 1, Sch Med, Xian 710061, Shaanxi, Peoples R China

[2] Xi An Jiao Tong Univ, Dept Nephrol, Affiliated Hosp 1, Nephropathy Ctr,Med Sch, Xian 710061, Shaanxi, Peoples R China

[3] Xi An Jiao Tong Univ, Minist Educ, Lab Environm & Genes Related Dis, Xian 710061, Shaanxi, Peoples R China

[4] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto 6068507, Japan

来源：

ATHEROSCLEROSIS | 2011年 / 218卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Uremia; Atherosclerosis; Regulatory T cells; Effector T cells; Pioglitazone; PPAR gamma; ACTIVATED-RECEPTOR-GAMMA; CHRONIC KIDNEY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; MAINTENANCE HEMODIALYSIS; DEFICIENT MICE; RENAL-FAILURE; PPAR-GAMMA; ATHEROSCLEROSIS; ATHEROGENESIS; EXPRESSION;

D O I：

10.1016/j.atherosclerosis.2011.07.112

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：330 / 338

页数：9

共 31 条

[1] Natural regulatory T cells control the development of atherosclerosis in mice [J].

Ait-Oufella, H ;

Salomon, BL ;

Potteaux, S ;

Robertson, AKL ;

Gourdy, P ;

Zoll, J ;

Merval, R ;

Esposito, B ;

Cohen, JL ;

Fisson, S ;

Flavell, RA ;

Hansson, GK ;

Klatzmann, D ;

Tedgui, A ;

Mallat, Z .

NATURE MEDICINE, 2006, 12 (02) :178-180

[2] Low Numbers of FOXP3 Positive Regulatory T Cells Are Present in all Developmental Stages of Human Atherosclerotic Lesions [J].

de Boer, Onno J. ;

van der Meer, Jelger J. ;

Teeling, Peter ;

van der Loos, Chris M. ;

van der Wal, Allard C. .

PLOS ONE, 2007, 2 (08)

[3] Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events):: a randomised controlled trial [J].

Dormandy, JA ;

Charbonnel, B ;

Eckland, DJA ;

Erdmann, E ;

Massi-Benedetti, M ;

Kmoules, IK ;

Skene, AM ;

Tan, MH ;

Lefébvre, PJ ;

Murray, GD ;

Standl, E ;

Wilcox, RG ;

Wlhelmsen, L ;

Betteridge, J ;

Birkeland, K ;

Golay, A ;

Heine, RJ ;

Korányi, L ;

Laakso, M ;

Mokán, M ;

Norkus, A ;

Pirags, V ;

Podar, T ;

Scheen, A ;

Scherbaum, W ;

Schernthaner, G ;

Schmitz, O ;

Skrha, J ;

Smith, U ;

Taton, J .

LANCET, 2005, 366 (9493) :1279-1289

[4] Peroxisome proliferator-activated receptor-γ-mediated effects in the vasculature [J].

Duan, Sheng Zhong ;

Usher, Michael G. ;

Mortensen, Richard M. .

CIRCULATION RESEARCH, 2008, 102 (03) :283-294

[5] CHARACTERIZATION OF A MOUSE MODEL OF CHRONIC UREMIA [J].

GAGNON, RF ;

GALLIMORE, B .

UROLOGICAL RESEARCH, 1988, 16 (02) :119-126

[6] Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice [J].

Gough, PJ ;

Gomez, IG ;

Wille, PT ;

Raines, EW .

JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (01) :59-69

[7] The immune response in atherosclerosis: a double-edged sword [J].

Hansson, Goran K. ;

Libby, Peter .

NATURE REVIEWS IMMUNOLOGY, 2006, 6 (07) :508-519

[8] Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells [J].

Heller, Eric A. ;

Liu, Emerson ;

Tager, Andrew M. ;

Yuan, Qian ;

Lin, Alexander Y. ;

Ahluwalia, Neil ;

Jones, Krister ;

Koehn, Stephanie L. ;

Lok, Vincent M. ;

Aikawa, Elena ;

Moore, Kathryn J. ;

Luster, Andrew D. ;

Gerszten, Robert E. .

CIRCULATION, 2006, 113 (19) :2301-2312

[9] End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells [J].

Hendrikx, Thijs K. ;

van Gurp, Eveline A. F. J. ;

Mol, Wendy M. ;

Schoordijk, Wenda ;

Sewgobind, Varsha D. K. D. ;

IJzermans, Jan N. M. ;

Weimar, Willem ;

Baan, Carla C. .

NEPHROLOGY DIALYSIS TRANSPLANTATION, 2009, 24 (06) :1969-1978

[10] Peroxisome proliferator-activated receptor γ is required for regulatory CD4+ T cell-mediated protection against colitis [J].

Hontecillas, Raquel ;

Bassaganya-Riera, Josep .

JOURNAL OF IMMUNOLOGY, 2007, 178 (05) :2940-2949

← 1 2 3 4 →