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

Abstract 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 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. Conclusion Pioglitazone ameliorates accelerated AS in uremic apoE−/− mice, probably through PPARγ-independent and -dependent mechanisms to modulate the Treg/Teff imbalance.