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Molecular mechanisms of vascular aging : analysis of a newly developed aging mouse

Research Project

Project/Area Number09044256
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field Circulatory organs internal medicine
Research InstitutionGunma University School of Medicine

Principal Investigator

NAGAI Ryozo  Gunma University School of Medicine, 2nd Dept of Int Med.Professpr, 医学部, 教授 (60207975)

Co-Investigator(Kenkyū-buntansha) KURABAYASHI Masahiko  Gunma University School of Medicine, 2nd Dept of Int Med.Associate professor, 医学部, 助教授 (00215047)
WILCOX Josiah N.  Emory University Dept of Medicine, Associate Professor, 医学部, 准教授
WILIOX Josia  エモリー大学, 医学部, 准教授
Project Period (FY) 1997 – 1998
Project Status Completed(Fiscal Year 1998)
Budget Amount *help
¥5,600,000 (Direct Cost : ¥5,600,000)
Fiscal Year 1998 : ¥2,300,000 (Direct Cost : ¥2,300,000)
Fiscal Year 1997 : ¥3,300,000 (Direct Cost : ¥3,300,000)
Keywordsaging / klotho / in situ hybridization / transcription factor / BTEB2 / HEX / smooth muscle / phenotypic modulation / plotho / in situ hydridization / 転写因子 / BTEB2 / HEX / 形質変換 / 血管内皮 / 一酸化窒素 / parabiosis / リング標本 / 液性因子 / 血管保護
Research Abstract

Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse that revelas age-related disorders including arteriosclerosis. The Klotho gene encodes a novel cell surface protein of 1014 amino acids. The extracellular domain consists of two intenal repeats, which exhibit 20-40 % sequence identity to bglucosidases of bacteria and plants as well as to mammalian lactase glycosylceramidase. In situ hybridization analysis shows Klotho mRNA expression in the distal convoluted tubules in kidney as well as cholid plexus in brain. There is an intense immunoreactivity of Klotho in the convoluted tubules of the normal kidney, while no reactivity detected in an atrophic kidney.
We demonstrate that the vasodilator response of aorta to acetylcholine is significantly attenuated in and homozygous Klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous Klotho mice resulted in restoration of endothelial function in heterozygous Klotho mice. ACE inhibitor and angiotensin II type I receptor antagonist partially improves endothelium-dependent relaxation of aorta in heterozygous Klotho mice. These results suggest that the Klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.
Transcription factors in smooth muscle cell, like BTEB2 and Hex, are involved in regulation of genes induced during vascular remodeling, such as SMemb or tissue factor genes.
Immunohistochemistry at two weeks after balloon-injured rat aorta showed that both Hex and BTEB2 are induced in adventitia followed by expression in neointima. In situ hybridization using riboprobes for BTEB2 and Hex also demonstrated that these transcription factors are excellent molecular markers for phenotypically modulated adventitial and smooth muscle cell.

Report

(3results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report

Research Products

(24results)

All Other

All Publications

  • [Publications] Kuro-o M.et al: "Mutation of the mouse Klotho gene leads to a syndrome resembling aging" Nature. 390・6655. 45-51 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsumura Y.et al: "Identification of the human Klotho gene and its two transcripts encoding membrane and secreted Klotho protein." Biochem. Byophys. Res. Commun.243・3. 626-630 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraki-Iida T.et al: "Structure of the mouse Klotho gene and its two transcripts encoding membrane and secreted protein." FEBS Lett.424・1-2. 6-10 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y.et al: "Klotho protein protects against endothelial dysfunction." Biochem. Biophys. Res. Commun.248・2. 324-329 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa H.et al: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem. Biophys. Res. Commun.249・3. 865-871 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohyama Y.et al: "Molecular cloning of rat Klotho cDNA : markedly decreased expression of Klotho by acute inflammatory stress." Biochem. Biophys. Res. Commun.253・3. 920-925 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H., Suga T., Utsugi T., Ohyama Y., Kurabayashi M., Kaname T., Kume E., Iwasaki H., Iida A., Shiraki-Iida T., Nishikawa S., Nagai R., Nabeshima Y.: "Mutation of the mouse Klotho gene leads to a syndrome resembling ageing" Nature. 390 (6655). 45-51 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsumura Y., Aizawa H., Shiraki-Iida T., Nagai R., Kuro-o M., Nabeshima Y.: "Identfication of the human Klotho gene and its two transcripts encoding membrane and secreted Klotho protein" Biochem Biophys Res Commun.243 (3). 626-630 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraki-Iida T., Aizawa H., Matsumura Y., Sekine S., Iida A., Anazawa H., Nagai R., Kuro-o M., Nabeshima Y.: "Structure of the mouse Klotho gene and its two transcripts encoding membrane and secreted protein" FEBS Lett.424 (1-2). 6-10 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y., Yamagishi T., Nakamura T., Ohyama Y., Aizawa H., Suga T., Matsumura Y., Masuda H., Kurabayashi M., Kuro-o M., Nabeshima Y., Nagai R.: "Klotho protein protect against endothelial dysfunction" Biochem Biophys Res Commun.248 (2). 324-329 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa H., Saito Y., Nakamura T., Inoue M., Imanari T., Ohyama Y., Matsumura Y., Masuda H., Oba S., Mise N., Kimura K., Hasegawa A., Kurabayashi M., Kuro-o M,Nabeshima Y., Nagai R.: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem Biophys Res Commun.249 (3). 865-871 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohyama Y., Kurabayashi M., Masuda H., Nakamura T., Aihara Y., Kaname T., Suga T., Arai M., Aizawa H., Matsumura Y., Kuro-o M., Nabeshima Y., Nagai R.: "Molecular cloning of rat klotho cDNA : markedly decreased expressin of klotho by acute inflammatory stress." Biochem Biophys res Commun.251 (3). 920-925 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y et al: "Klotho protein prorects against endothelial dysfunction" Biochem.Biophys.Res.Commun.248. 324-329 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Aizawa H et al: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem.Biophys.Res.Commun.249. 865-871 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Oyama Y et al: "Molecular Cloning of Rat klotho cDNA:Markedly Decreased Expression of klotho by Acute inflammatory Stress." Biochem.Biophys.Res.Commun.251. 920-92* (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Suzuki T et al: "Mechanisms of transcriptional regulation of gene expression in smooth muscle cells." Circ Res. 82. 1238-1242 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Aikawa M et al: "Lipid lowering promotes accumulation of mature smooth muscle cells in atheroma of hypercholesterolemic rabbits." Circ Res. 83. 1015-1026 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Manabe I et al: "Isolation of the embryonic form of smooth muscle myosin heavy chain (SMemb/NMHC-B)gene and characterization of its 5'-flanking region." Biochem Biophys Res Comm. 239. 598-605 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Manabe I. et al.: "Isolation of the embryonic form smooth muscle myosin heaychain gene and characterization of its 5'-flanking region" Biochem. Biophys. Res. Commun.239. 598-605 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kuro-o et al.: "Mutation of the mouse Klotho gene leads to a syndrome resembling ageing" Nature. 390. 45-51 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suzuki T. st al.: "A novel biochemical method for aortic dissection" Circulation. 93. 1244-1249 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suzuki T. st al.: "Preferential differentiation of P19 mouse embryonal carcinoma cells into smooth muscle cells" Circ. Res.78. 395-404 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kanda T. et al.: "Modification of viral myocarditis in mice by interleukin-6" Circ. Res.78. 848-856 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe M. et al.: "Structure and characterization of the 5'-flanking region of the mouse smooth muscle myosin heavy chain SM'yz gene" Circ. Res.78. 978-989 (1996)

    • Related Report
      1997 Annual Research Report

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Published : 1997-04-01   Modified : 2016-04-21  

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