Identification of the inhibitory factor for the transcription of inflammatory genes in vascular smooth muscle cells

• Project/Area Number: 16590877
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Shiga University of Medical Science
• Principal Investigator: NISHIO Yoshihiko Shiga University of Medical Science, Department of Medicine, assistant professor, 医学部, 講師 (40281084)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: NO / CHOP / MCP-1 / C / EBP / Insulin / 血管平滑筋細胞 / 炎症 / 血管平滑筋

Research Abstract

We have reported that chronic activation of phosphatidylinositol 3-kinase (PI3K) by the overexpression of membrane-targeted p110CAAX induces proinflammatory gene expression in rat vascular smooth muscle cells (VSMCs) through the induction of CCAAT/enhancer binding protein-β (C/EBP-β) and C/EBP-δ. To examine the antiinflammatory effect of nitric oxide (NO) on the proinflammatory gene expression, we investigated the effects of sodium nitroprusside (SNP) on the monocyte chemoattractant protein-1 (MCP-1) gene expression in VSMCs under chronic activation of PI3K. At low concentration (0.05 mM) of SNP, but not at high concentration (0.5-1.0 mM), it significantly reduced MCP-1 mRNA and protein expression as well as its transcriptional activity. We found that SNP induced C/EBP homologous protein (CHOP) expression, which inhibited C/EBP binding activity and reduced the C/EBP activity induced by chronic activation of PI3K in a dose-dependent manner up to 1.0 mM. Consistently, the increase in CHOP expression significantly reduced the MCP-1 promoter activity induced by PI3K. However, the overexpression of CHOP alone up-regulated MCP-1 promoter activity in a dose-dependent manner up to high concentration. Deletion analysis of MCP-1 promoter and electrophoretic mobility shift assay identified the CHOP-response element (CHOP-RE) at the region between -190 and -179 bp of MCP-1 promoter. By CHOP-RE used as a decoy, the increase in promoter activity of MCP-1 induced by either CHOP or SNP was suppressed significantly. Thus, CHOP induced by an NO-donor has bidirectional effects on MCP-1 gene expression : it decreases the gene expression by inhibition of C/EBPs, and it increases the gene expression through the CHOP-RE.

Research Products

• [Journal Article] The Transcription Factor AP-2{beta}Causes Cell Enlargement and insulin Resistance in 3T3-L1 Adipocytes. (2006)
  • Author(s): Tao Y, Maegawa H, Ugi S, Ikeda K, Nagai Y, Egawa K, Nakamura T, Tsukada S, Nishio Y, Maeda S, Kashiwagi A
  • Journal Title: Endocrinology 147 Pages: 1685-96
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Transcription Factor AP-2 {beta} Causes Cell Enlargement and Insulin Resistance in 3T3-L1 Adipocytes. (2006)
  • Author(s): Tao Y, Maegawa H, Ugi S, Ikeda K, Nagai Y, Egawa K, Nakamura T, Tsukada S, Nishio Y, Maeda S, Kashiwagi A
  • Journal Title: Endocrinology 147 Pages: 1685-1696
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The Transcription Factor AP-2{beta} Causes Cell Enlargement and Insulin Resistance in 3T3-L1 Adipocytes. (2006)
  • Author(s): Tao Y, Maegawa H, Ugi S, Ikeda K, Nagai Y, Egawa K, Nakamura T, Tsukada S, Nishio Y, Maeda S, Kashiwagi A
  • Journal Title: Endocrinology 147 Pages: 1685-1696
• [Journal Article] Bidirectional regulation of monocyte chemoattractant protein-1 gene at distinctsites of its promoter by nitric oxide in vascular smooth muscle cells (2005)
  • Author(s): Kodama K, Nishio Y, Sekine O, Sato Y, Egawa K, Maegawa H, Kashiwagi A
  • Journal Title: Am J Physiol Cell Physiol 289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Supplement oftetrahydrobiopterin by a gene transfer of GTP cyclohydrolase IcDNA improves vascular dysfunction in insulin-resistant rats. (2005)
  • Author(s): Shinozaki K, Nishio Y, Yoshida Y, Koya D, Ayajiki K, Masada M, Kashiwagi A, Okamura T
  • Journal Title: J Cardiovasc Pharmacol 46 Pages: 505-12
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bidirectional regulation of monocyte chemoattractant protein-1 gene at distinctsites of its promoter by nitric oxide in vascular smooth muscle cells (2005)
  • Author(s): Kodama K, Nishio Y, Sekine 0, Sato Y, Egawa K, Maegawa H, Kashiwagi A
  • Journal Title: Am J Physiol Cell Physiol 289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Supplement of tetrahydrobiopterin by a gene transfer of GTP cyclohydrolase IcDNA improves vascular dysfunction in insulin-resistant rats. (2005)
  • Author(s): Shinozaki K, Nishio Y, Yoshida Y, Koya D, Ayajiki K, Masada M, Kashiwagi A, Okamura T
  • Journal Title: J Cardiovasc Pharmacol 46 Pages: 505-512
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Single nucleotide polymorphism (-468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis (2004)
  • Author(s): Nagata R, Nishio Y et al.
  • Journal Title: J Biol Chem 279・28 Pages: 29031-29042
• [Journal Article] Stiffness and impaired blood flow in lower-leg arteries are associated with severity of coronary artery calcification among asymptomatic type 2 diabetic patients. (2004)
  • Author(s): Tsuchiya M et al.
  • Journal Title: Diabetes Care 27・10 Pages: 2409-2415
• [Journal Article] Regulation of ATP-sensitive potassium channel subunit Kir6.2 expression in rat intestinal insulin-producing progenitor cells.
  • Author(s): Hashimoto T et al.
  • Journal Title: J Biol Chem (in press)
• [Book] Mitochondorial Pathogenesis (2004)
  • Author(s): Nishio Y et al.
  • Total Pages: 352
  • Publisher: The New York Academy of Sciences