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Molecular biological study on biosynthesis of prostglandins and thromboxane

Research Project

Project/Area Number 08457042
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

TANABE Tadashi  National Cardiovascular Center Research Institute Department of Pharmacology, Director, 薬理部, 部長 (60025624)

Co-Investigator(Kenkyū-buntansha) SHIMONISHI Manabu  National Cardiovascular Center Research Institute Department of Pharmacology, Re, 薬理部, 室員 (70300978)
HATAE Toshihisa  National Cardiovascular Center Research Institute Department of Pharmacology, Re, 薬理部, 室員 (10251026)
INOUE Hiroyasu  National Cardiovascular Center Research Institute Department of Pharmacology, Se, 薬理部, 室長 (40183743)
YOKOYAMA Chieko  National Cardiovascular Center Research Institute Department of Pharmacology, Se, 薬理部, 室長 (90200914)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1996: ¥2,800,000 (Direct Cost: ¥2,800,000)
Keywordsprostaglandin / cyclooxygenase / glucocorticoid / prostacyclin / biosynthesis / transcription / atherosclerosis / シクロオキシゲナーゼ-2 / プロスタサイクリン合成酵素 / トロンボキサン / トロンボキサン合成酵素 / シクロオキシゲナーゼ / 発現 / 構造 / 分子生物学
Research Abstract

The present study have been carried out with vascular endothelial cells, smooth muscle cells and macrophages or with gene-targgetting mice to investigate the mechanism of gene expression of the enzymes involved in the biosynthesis of prostacyclin (PGI_2) and thromboxane, which are cyclooxygenase (COX) synthesizing prostglandin H_2 (PGH_2), and PGI_2 and TX synthases isomerizing PGH_2 to PGI_2 and TX, respectively. The results obtained under this study are as follows. (1) the expression of COX-2, a key enzyme for the synthesis for inflammatory PGs is inhibited by anti-inflammatcry steroid, glucocorticoid. We studied the suppression mechanism of COX--2 gene in endothelial cells by glucocortocoid and charcterizethe role of its receptor. A polyphenol compond, resveratrol was found to inhibit the expression and enzyme activity of COX-2. (2) The gene expression of COX-1 and -2, and PGI_2 synthase in blood vessels was examined by in situ hybridization with anti-seuse RNAs. The expression levels of these enzymes in aorta were higher than those in vein. Especially, the level of COX-2 in vein was quite low. (3) High level of expression of PGI_2 synthase was gained with a baculovirus system. The overexpression of PGI_2 synthase in kidney 293 cells was found to induce apoptosis. (4) The expression of PGI_2 synthase in rat peritoneal macrphages was decreasedby activation using casein or BCG with concomitant increase of TX synthase level. (5) PGI_2 synthase-deficieint mice exhibited a morphological change in kidney, and pathological analysis of the mice showed the thickning of arteries, atherosclerosis or fibrosis.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (62 results)

All Other

All Publications (62 results)

  • [Publications] Hatae, T.: "Site-directed mutagenesis of human prostacyclin synthase : alteration of Cys441 of the Cys-poket, and Glu347 and Arg350 of the EXXR motif" FEBS Lett.389. 268-272 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokoyama, C.: "Human gene encoding prostacyclin synthase(PTGIS) : genomic organization ,chromosomal localization ,and promoter activity" Genomics. 36. 296-304 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tone, Y.: "The ragional distriboution and cellular localization of mRNA encoding rat prostacyclin synthase" Eur.J.Cell Biol.72. 268-277 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Segrola, R.J.: "Cyclic strain is a weak inducer of prostacyclin synthase expression in povine aortic endothelial cells" J.Surg.Res.69. 135-138 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kelly, D.J.: "Benzo[a]pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells" Carcinogenesis. 18. 795-799 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Master, J.R.: "Retionoids suppress epidermal qrowth-factor induced transcription of cyclooxyese-2 in human oral epithelial cells" Cancer. 57. 1081-1085 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Niiro, H.et al.: "Regulation by interleukin-10and interleukin-4 of cyclooxygenase-2 expression in human neutrophils" Blood. 89. 1621-1628 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuwamoto, S.et al.: "Inverese gene expression of prostasyclin and thromboxane synthases in resident and activated macrophaqes" FEBS Lett.409. 242-246 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mestre, J.R.et al.: "Retinoids suppress phorbol ester-ester induced induction of cyclooxygenase-2" Cancer Res.57. 1081-1085 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kito, H.et al.: "Cyclooxygenase expression in bovine aortic endothelial cells exposed to cyclic strain" Endothelium. 6. 107-112 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takahashi, S.et al.: "Localization of cyclooxygenase-2 and regulation of its expression gastric ulcers" Am.J.Physiol.275. G1137-G1145 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Subbaramaiah, K.et al.: "Resveratrol inhibits cyclooxgenase transcription and activity in phorbol ester-treated human mammary epithelial cells" J.Biol.Chem.273. 21875-21882 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Todaka, T.et al.: "Gene transfer of human prostacyclin synthase prevents intimal hyperplasia following carotid balloon injury in rats" Stroke. 30. 419-426 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue, H.et al.: "Glucocorticoid-mediated suppression of the promoter activity ofthe expression of the receptor in vascular endothelial cells" Biochem.Biopys.Res.Commun.254. 292-298 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Toh, H.: "Cyclooxygenases ; Structure and evolutional aspects “Eicosanids and related componds in plants and animals"" Portland press, 22(228) (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokoyama, C.et al.: "Human gene for prostacyclin synthase (PTGIS) : isolation, structure and chromosomal localization." Genomics. 36. 296-304 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hatae, T., et al.: "Site-directed mutagenesis of human prostacyclin synthase : Alteration of Cys441, of the Cys-pocket, and Glu347 and Arg350 of the EXXR motif." FEBS Lett.389. 268-272 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tone, Y.et al.: "The regional distribution and cellular localization of mRNA encoding rat prostacyclin synthase." Eur.J.Cell Biol.72. 268-277 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Niiro, H.et al.: "Regulation by interleukin-10 and interleukin-4 of cyclo-oxygenase-2 expression in human neutrophils." Blood. 89. 1621-1628 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuwamoto, S.et al: "Inverse gene expression of prostacyclin and thromboxane synthases in resident and activated macrophages." FEBS Lett.409. 242-246 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kelly, D.J.et al.: "Benzo(a)pyrene up-regulates cyclooxygenase-2 gene expression in oral epitherial cells." Carcinogenesis. 18. 795-799 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mestre, J.R.et al.: "Retinoids suppress phorbol ester-mediated induction of cyclooxygenase-2." Cancer Res.57. 1081-1085 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mestre, J.R.et al.: "Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells." Cancer Res.57. 2890-2895 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Segurola, R.J.et al.: "Cyclic strain is a weak inducer of prostacyclin synthase expression in bovine aortic endothelial cells." J.Surg.Res.69. 135-138 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue H.et al.: "Transcriptional role of the nuclear factor kB site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in monocytic differentiated U937 cells." Biochem.Biophys.Res.Commun.244. 143-148 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Subbaramaiah, K.et al.: "Resveratrol inhibits cyclooxygenase-2 transcriptionand activity in phorbol ester-treated human mammary epitherial cells." J.Biol.Chem.273. 21875-21882 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takahashi, S.et al.: "Localization of cyclooxygenase-2 and regulation of its expression in gastric ulcers in rat." Am.J.Phisiol.275. G1137-G1145 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kito, H.et al.: "Cyclooxygenase expression in bovine arortic endothelial cells exposed to cyclic strain." Endothelium. 6. 107-112 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Todaka, T.et al.: "Gene transfer of human prostacyclin synthase (PGIS) prevents intimal hyperplasia following arotid balloon injury in rats." Stroke. 30. 419-426 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue, H.et al: "Glucocorticoid-mediared suppression of the promoter activity of the cyclooxygenase-2 geneis modulated by the expression of the receptor in vascular endothelial cell" Biochem.Biophys.Res.Commun.254. 292-298 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Subbaramaiah, K.et al.: "Increased expression of cyclooxygenase-2 in human mammary epithelial cells transformed by the HER-2/Neu Oncogene." Cancer Res.( in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kito,H.: "Cyclooxygenase expression in bovine aortic endothelial cells exposed to cyclic strain" Endothelium. 6. 107-112 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takahashi,S.: "Localization of cyclooxygenase-2 and regulation of its express-ion in gastric ulcers" Am.J.Physiol.275. G1137-G1145 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Subbaramaiah,K.: "Resveratrol inhibits cyclooxygenase transcription and activity in phorbol ester-treated human mammary epithelial cells" J.Biol.Chem.273. 21875-21882 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Todaka,T.: "Gene transfer of human prostacyclin synthase prevents intimal hyperplasia following carotid balloon injury in rats" Stroke. 30. 419-426 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inoue,H.: "Glucocorticoid-mediated suppression of the promoter activity of the expression of the receptor in vascular endothelial cells" Biochem.Biophys.Res.Commun.254. 292-298 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 籐 博幸: "COX-1およびCOX-2の立体構造について" 現代医療. 30. 65-87 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 波多江 利久: "イソメラーゼ活性を示すP450" 化学と生物. 36. 534-539 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 横山 知永子: "プロスタサイクリン合成酵素と受容体" Bio Clinica. 13. 45-49 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 井上 裕康: "COX-2の転写調節" 現代医療. 31. 121-129 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 田辺 忠: "オーバービュー" 血管と内皮. 9. 5-6 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 横山 知永子: "プロスタサイクリン合成酵素の構造と遺伝子発現" 血管と内皮. 9. 33-38 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 井上 裕康: "血管におけるシクロオキシゲナーゼの発現" 血管と内皮. 9. 25-32 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Toh,H.: "Cyclooxygenases: Structure and evolutionary aspects “Eicosanoids and related compounds in plants and animals"" Portland Press, 22(228) (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Niiro: "Regulation by interleukin-10 and interleuikn-4 of cyclooxygenase-2 expression in human neutrophils" Blood. 89. 1621-1628 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Kuwamoto: "Inverese gene expression of prostasyclin and thromboxane synthases in resident and activated macrophages" FEBS Lett.409. 242-246 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] D.J.Kelly: "Benzo(a)pyrene up-regulates cyclooxygenase-2 gene expression in oral epitherial cells" Carcinogenesis. 18. 795-799 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] J.R.Mestre: "Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells" Cancer Res.57. 2890-2895 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] J.R.Mestre: "Retinoids suppress phorbol ester-ester induced induction of cyclooxygenase-2" Cancer Res.57. 1081-1085 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] R.J.Segrola: "Cyclic strain is a weak inducer of prostacyclin synthase expression in bovine aortic endotherial cells" J.Surg.Res.69. 135-138 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Inoue: "Transcriptional role of the nuclear factor kB site in the induction by lipopolysaccharide and suppression of cyclooxygenase" Biochem.Biophys.Res.Commun.(in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] 田辺忠: "誘導型シクロオキシゲナーゼ" ファルマシア. 32・8. 938-942 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 井上裕康: "COX-1とCOX-2の生化学と分子生物学2 誘導と転写調節機構" 治療学. 30・12. 1347-1351 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 波多江利久: "プロスタサイクリン生合成-プロスタサイクリン合成酵素の蛋白構造と遺伝子発現" 動脈硬化. 24・9. 449-455 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hatae,T.: "Site-directed mutagenasis of human prostacyclin synthase : alteration of Cys^<441> of the Cys-poket,and Glu^<347> and Arg^<350> of the EXXR mofit" FEBS Lett.389. 268-272 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yokoyama,C.: "Human gene encoding prostacyclin synthase (PTGIS) : genomic organization chromosomal localization,and promoter activity" Genomics. 36. 296-304 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tone,Y.: "The ragional distribution and cellular localization of mRNA encoding rat prostacyclin synthase" Eur.J.Cell Biol.72. 268-277 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Segrola,R.J.: "Cyclic strain is a weak inducer of prostacyclin synthase expression in povine aortic endothelial cells" J.Surg.Res.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kelley,D.J.: "Benzo 〔a〕 pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells" Carcinogenesis. (in Press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Mestre,J.R.: "Retinolds suppress epidermal growth-factor induced transcription of cyclooxyse-2 in human oral epithelial cells" Cacer Res.(in Press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 井上裕康: "NOSとCOX" メディカルレビュー社, 193 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 田辺忠: "分子細胞生物学辞典" 東京化学同人, 1025 (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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