Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-γ via an interaction with Sp1 in vascular smooth muscle cells

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

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Thromboxane (TX) A2 exerts contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. A nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-γ, has recently been reported to be expressed in VSMCs. Here we examined a role of PPAR-γ in TXR gene expression in VSMCs. PPAR-γ ligands 15-deoxy-Γ12,14-prostaglandin J2 and troglitazone reduced TXR mRNA expression levels as well as cell growth as assessed by [3H]thymidine incorporation. Transcriptional activity of the TXR gene promoter was suppressed with PPAR-γ ligands, and the suppression was augmented further by PPAR-γ overexpression. By deletion and mutation analyses, the transcription suppression was shown to be the result of a -22/-7 GC box-related sequence (upstream of transcription start site). Electrophoretic mobility shift assays also showed that the sequence was bound by Sp1 but not by PPAR-γ, and the formation of a Sp1·DNA complex was inhibited either by coincubation with PPAR-γ or PPAR-γ ligand treatment of VSMCs. Moreover, glutathione S-transferase pull-down assays demonstrated a direct interaction between PPAR-γ and Sp1. In conclusion, PPAR-γ suppresses TXR gene transcription via an interaction with Sp1. PPAR-γ may possibly have an antiatherosclerotic action by inhibiting TXR gene expression in VSMCs.

Original languageEnglish
Pages (from-to)9676-9683
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number12
DOIs
Publication statusPublished - 2002 Mar 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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