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(Circulation Research. 2002;90:348.)
© 2002 American Heart Association, Inc.

Molecular Medicine

PPAR Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells

Yuko Oyama, Nobuhiro Akuzawa, Ryozo Nagai, Masahiko Kurabayashi

From the Second Department of Internal Medicine (Y.O., N.A., M.K.), Gunma University School of Medicine, Maebashi, Gunma, Japan; and Department of Cardiovascular Medicine (R.N.), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Correspondence to Masahiko Kurabayashi, MD, PhD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, 371-8511, Japan. E-mail mkuraba{at}med.gunma-u.ac.jp

Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily that acts as a key player in adipocyte differentiation, glucose metabolism, and macrophage differentiation. Osteopontin (OPN), a component of extracellular matrix, is elevated during neointimal formation in the vessel wall and is synthesized by macrophages in atherosclerotic plaques. In the present study, we investigated the molecular mechanisms regulating OPN gene expression by PPAR in THP-1 cells, a cell line derived from human monocytic leukemia cells. Northern and Western blot analyses showed that exposure of THP-1 cells to PMA (phorbol 12-myristate 13-acetate) increases OPN mRNA and protein levels in a time-dependent manner. PMA-induced OPN expression was significantly decreased by troglitazone (Tro) and other PPAR ligands. Transient transfection assays of the human OPN promoter/luciferase construct showed that PPAR represses OPN promoter activity, and the PPAR-responsive region within the OPN promoter lies between -1000 and -970 relative to the transcription start site. Site-specific mutation analysis and electrophoretic mobility shift assays indicated that a homeobox-like A/T-rich sequence between -990 and -981, which functions as a binding site for PMA-induced nuclear factors other than PPAR, mediates the repression of OPN expression by Tro. Furthermore, concatenated A/T-rich sequences conferred the PPAR responsiveness on the heterologous promoter. Taken together, these data suggest that PPAR ligand inhibits OPN gene expression through the interference with the binding of nuclear factors to A/T-rich sequence in THP-1 cells.

Key Words: peroxisome proliferator-activated receptor • osteopontin • macrophage • transcription factors

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