Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-γ in vascular smooth muscle cells

被引:179
作者
Sugawara, A [1 ]
Takeuchi, K [1 ]
Uruno, A [1 ]
Ikeda, Y [1 ]
Arima, S [1 ]
Kudo, M [1 ]
Sato, K [1 ]
Taniyama, Y [1 ]
Ito, S [1 ]
机构
[1] Tohoku Univ, Grad Sch Med,Dept Med, Div Nephrol Endocrinol & Vasc Med, Mol Biol Unit,Aoba Ku, Sendai, Miyagi 9808574, Japan
关键词
D O I
10.1210/en.142.7.3125
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15deoxy-(Delta 12,14)-prostaglandin J(2) and thiazolidinediones have been shown to be ligands for peroxisome proliferator-activated receptor (PPAR)-gamma and activate PPAR-gamma. In the present work, we have studied the effect of PPAR-gamma on AT1R expression in rat vascular smooth muscle cells (VSMCs). We observed that: 1) endogenous AT1R expression was significantly decreased by PPAR-gamma ligands both at messenger RNA and protein levels, whereas AT1R messenger RNA stability was not affected; 2) AII-induced increase of H-3-thymidine incorporation into VSMCs was inhibited by PPAR-gamma ligands; 3) rat AT1R gene promoter activity was significantly suppressed by PPAR-gamma ligands, and PPAR-gamma overexpression further suppressed the promoter activity; 4) transcriptional analyses using AT1R gene promoter mutants revealed that a GC-box-related sequence within the -58/-34 region of the AT1R gene promoter was responsible for the suppression; 5) Spl overexpression stimulated AT1R gene transcription via the GC-box-related sequence, which was inhibited by additional PPAR-gamma overexpression; 6) electrophoretic mobility shift assay suggested that Spl could bind to the GC-box-related sequence whereas PPAR-gamma could not; 7) antibody supershift experiments using VSMC nuclear extracts revealed that protein-DNA complexes formed on the GC-box-related sequence, which were decreased by PPAR-gamma coincubation, were mostly composed of Spl; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-gamma and Spl. Taken together, it is suggested that activated PPAR-gamma suppresses AT1R gene at a transcriptional level by inhibiting Spl via a protein-protein interaction. PPAR-gamma ligands, thus, may inhibit AII-induced cell growth and hypertrophy in VSMCs by AT1R expression suppression and possibly be beneficial for treatment of diabetic patients with hypertension and atherosclerosis.
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页码:3125 / 3134
页数:10
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