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

血管平滑肌细胞炎症基因转录抑制因子的鉴定

• 批准号: 16590877
• 负责人: NISHIO Yoshihiko
• 金额: $ 2.3万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590877/
• 关键词: NO; CHOP; MCP-1; C; EBP; Insulin; 血管平滑筋細胞; 炎症; 血管平滑筋

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.

我们已报道，通过膜靶向p110CAAX的过度表达慢性激活磷脂酰肌醇3-激酶(PI3K)，通过诱导CCAAT/增强子结合蛋白-β(C/eBP-β)和C/eBP-δ诱导大鼠血管平滑肌细胞(VSMC)的促炎基因表达。为探讨一氧化氮(NO)对促炎症基因表达的影响，我们观察了硝普钠(SNP)对PI3K慢性激活的VSMC单核细胞趋化蛋白-1(MCP-1)基因表达的影响。低浓度(0.05 mM)的SNP可显著降低MCP-1mRNA和蛋白的表达及其转录活性，而高浓度(0.5-1.0 mM)的SNP对MCP-1的转录活性无影响。我们发现，SNP诱导C/EBP同源蛋白(CHOP)表达，抑制C/EBP结合活性，并以剂量依赖的方式降低PI3K慢性激活所诱导的C/EBP活性，最大剂量可达1.0 mM。一致地，CHOP表达的增加显著降低了PI3K诱导的MCP-1启动子活性。然而，CHOP单独过表达可剂量依赖性地上调MCP-1启动子的活性，直至高浓度。MCP-1启动子缺失分析和凝胶迁移率改变分析表明，CHOP-RE位于MCP-1启动子-190~-179碱基之间。以CHOP-RE为诱饵，可显著抑制CHOP或SNP诱导的MCP-1启动子活性的升高。因此，NO供体诱导的CHOP对MCP-1基因表达具有双向作用：通过抑制C/EBPs降低基因表达，通过CHOP-RE促进基因表达。

项目成果

Mitochondorial Pathogenesis

线粒体发病机制

• 发表时间: 2004
• 作者: Nagata R;Nishio Y et al.;Tsuchiya M et al.;Hashimoto T et al.;Nishio Y et al.
• 通讯作者: Nishio Y et al.

Stiffness and impaired blood flow in lower-leg arteries are associated with severity of coronary artery calcification among asymptomatic type 2 diabetic patients.

• DOI: 10.2337/diacare.27.10.2409
• 发表时间: 2004-10
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: M. Tsuchiya;E. Suzuki;K. Egawa;Y. Nishio;H. Maegawa;S. Inoue;K. Mitsunami;S. Morikawa;T. Inubushi;A. Kashiwagi

The transcription factor AP-2beta causes cell enlargement and insulinresistance in 3T3-L1 adipocytes.

转录因子 AP-2beta 导致 3T3-L1 脂肪细胞细胞增大和胰岛素抵抗。

• 发表时间: 2006
• 期刊: Endocrinology 147
• 作者: Tao Y;Maegawa H;Ugi S;他
• 通讯作者: 他

Supplement of tetrahydrobiopterin by a gene transfer of GTP cyclohydrolase IcDNA improves vascular dysfunction in insulin-resistant rats.

通过 GTP 环化水解酶 IcDNA 基因转移补充四氢生物蝶呤可改善胰岛素抵抗大鼠的血管功能障碍。

• 发表时间: 2005
• 期刊: J Cardiovasc Pharmacol 46
• 作者: Shinozaki K;Nishio Y;Yoshida Y;Koya D;Ayajiki K;Masada M;Kashiwagi A;Okamura T
• 通讯作者: Okamura T

Regulation of ATP-sensitive potassium channel subunit Kir6.2 expression in rat intestinal insulin-producing progenitor cells

• DOI: 10.1074/jbc.m410759200
• 发表时间: 2005-01-21
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Hashimoto, T;Nakamura, T;Kashiwagi, A
• 通讯作者: Kashiwagi, A