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Endocrinology Vol. 142, No. 7 3125-3134
Copyright © 2001 by The Endocrine Society

ARTICLES

Transcriptional Suppression of Type 1 Angiotensin II Receptor Gene Expression by Peroxisome Proliferator-Activated Receptor-{gamma} in Vascular Smooth Muscle Cells1

Akira Sugawara, Kazuhisa Takeuchi, Akira Uruno, Yukio Ikeda, Shuji Arima, Masataka Kudo, Kazunori Sato, Yoshihiro Taniyama and Sadayoshi Ito

Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan

Address all correspondence and requests for reprints to: Dr. Akira Sugawara, Molecular Biology Unit, Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574 Japan. E-mail: akiras2i{at}mail.cc.tohoku.ac.jp

Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15-deoxy-{Delta}12,14-prostaglandin J2 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 3H-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) Sp1 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 Sp1 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 Sp1; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-{gamma} and Sp1. Taken together, it is suggested that activated PPAR-{gamma} suppresses AT1R gene at a transcriptional level by inhibiting Sp1 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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