Pioglitazone ameliorates atherosclerosis in apoE knockout mice through transforming growth factor-β/Smad signaling and adaptive T cell immunity.
- Author:
Yu-Ling TIAN
1
;
Li-Jun WANG
;
Yue WU
;
Wei-Ping ZHANG
;
Xiao LIANG
;
Zu-Yi YUAN
Author Information
- Publication Type:Journal Article
- From: Journal of Southern Medical University 2017;37(8):1003-1009
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo 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 ApoEmice.
METHODSApoEmice 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-γand Foxp3cells 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 CD4IFN-γcells and CD4CD25Foxp3cells were analyzed with flow cytometry.
RESULTSPIO treatment of ApoEmice 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-γcells (P<0.05) and increased percentage of Foxp3cells (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 CD4IFN-γcells (P<0.05) and CD4CD25Foxp3(P<0.05); the effects of PIO on CD4IFN-γand CD4CD25Foxp3cells were abolished by treatment of the cells with GW9662.
CONCLUSIONThe anti-atherosclerotic effect of PIO is probably mediated by the TGF-β/Smad signaling pathway and PPAR-γ-dependent modulation of Th1/Treg population.