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The Ca-activated K channel as a new therapeutic target for vascular remodeling, and its expressional control mechanism

Research Project

Project/Area Number 16590656
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionAkita University

Principal Investigator

HASEGAWA Hitoshi  Akita University, Division of cardiovascular and respiratory medicine, Assistant professor, 医学部, 講師 (70301059)

Co-Investigator(Kenkyū-buntansha) WATANABE Hiroyuki  Akita University, Division of cardiovascular and respiratory medicine, Assistant professor, 医学部, 講師 (80323145)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsL-NAME / vascular remodeling / TRAM34 / NFκ-B / imidazole / pyrazole系 / clotrimazole / SOCE / SOCE / NFk-B / 血管モデリング
Research Abstract

1.In the present study, the inhibition of expression and function of the Ca-activated K channel (IKca) in its involvement in vascular inflammation and subsequent vascular remodeling formation such as cell multiplication and dedifferentiation were investigated as therapeutic targets for vascular lesion formation.
2.Analysis of the molecular mechanism of IKca expression control in vascular smooth muscle cells and immune system cells. In order to determine the association between vascular lesion formation in states of cardiovascular disease characterized mainly by hypertension and arteriosclerosis, and IKca expression modification in vascular and immune cells, while also analyzing the possibility of IKca as a new therapeutic target, the following additional investigations were conducted in succession: a) analysis of the molecular mechanism of IKca expression control in vascular smooth muscle cells and immune cells, b) the search for a therapeutic drug that targeted IKca expression in the b … More ase clinical state model of vascular disease.
3.Cultured vascular smooth muscle cells from the rat aorta, obtained using the explant method, were cultured under stimulation by angiotensin II and PDGF, for analyses of the association between the expression of BTEB2 and of IKca occurring with phenotype transformation into the proliferative form, and the effects of NO donors and superoxide anions on IKca expression. Increases in BTEB2 and IKca expression were decreased by NO donors and intensified by superoxide anions. The search for a therapeutic drug that targets IKca expression in the base clinical state model of vascular disease
4.The relationship between the NFk-B activator, which is a transcription factor sensitive to redox as well as increased superoxide anion production resulting from NO decrease and has a corresponding site on IKca promoters, and IKca expression in smooth muscle and T-lymphocytes was discussed with respect to rats receiving prolonged L-NAME administration. In addition, as indicators for the inhibition of IKca expression and NFkB activation, the efficacies of the following were analyzed: (1) imidazole/pyrazole-type drugs, clotrimazole, TRAM34 (all are selective IKca inhibitors), (2) statin-type drugs, and (3) NS1619. Although all drugs tended to inhibit IKca expression and NFkB activation, no significant differences were observed. (4) The effect of low-molecular-weight heparin, which possesses antiplatelet and anti-inflammatory properties, was investigated using rats that received prolonged L-NAME administration. Low-molecular-weight heparin inhibited the cardiovascular remodeling that occurs with prolonged L-NAME administration, such as pericoronary fibrosis and increased medial smooth muscle hypertrophy. Less

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (5 results)

All 2007 2005 2004

All Journal Article (5 results)

  • [Journal Article] Essential role of the N-terminus of murine Orail in store-operated Ca2+ entry.2007

    • Author(s)
      Yoichirou Takahashi, Manabu Murakami, Hiroyuki Watanabe, Hitoshi Hasegawa, Takayoshi Ohba, Yoshiko Munehisa, Kiyoshi Nobori, Kyoichi Ono, Toshihiko Iijima, Hiroshi Ito.
    • Journal Title

      Biochemical and Biophysical Research Communications 356

      Pages: 45-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Essential role of the N-terminus of murine orail in store-operated Ca2+entry.2007

    • Author(s)
      Yoichirou Takahashi, Manabu Mu urakami, Hiroyuki Watanabe, Hitoshi Hasegawa, Takayoshi ohba, Yoshiko Munehisa, Kiyoshi Nobor, Kyoichi ono, Toshihiko Iijima, Hiroshi Ito
    • Journal Title

      Biochemical and Biophysical Research Communications 356

      Pages: 45-52

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The effect of Unoprostone on store operated Ca entry in human aortic smooth muscle cells.2005

    • Author(s)
      Akiko Watanabe, Hiroyuki Watanabe, Kyoichi Ono, Tkayoshi Ohba, Manabu Murakami, Hitoshi Hasegawa, Masahiro Sasaki, Toshihiko Iijima, Yoshitomi T, Ito H.
    • Journal Title

      Akita J Med 32

      Pages: 7-15

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Low molecular weight heparin prevents cardiovascular remodeling induced by the long-term inhibition of nitric oxide synthase with N-nitro-L-arginine methyl ester in rat hearts2004

    • Author(s)
      Hitoshi Hasegawa, Takashi Saito, Yoshimasa Fujiwara, Fukiko Kurokawa, Toshimitu Kosaka, Hiroyuki Watanabe, Kenji Iino, Masaru Ishida, Takashi Koyama, Kouichi Kawamura, Hirotake Masuda, Mamoru Miura, Hiroshi Ito
    • Journal Title

      Akita J Med 31

      Pages: 221-230

    • NAID

      110001052883

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Low molecular weight heparin prevents cardiovascular remodeling induced by the long-term inhibition of nitric oxide synthase with N-nitro-L-arginine methyl ester in rat hearts.2004

    • Author(s)
      Hitoshi Hasegawa, Takashi Saito, Yoshimasa Fujiwara, Fukiko Kurokawa, Toshimitu Kosaka, Hiroyuki Watanabe, Kenji Iino, Masaru Ishida, Takashi Koyama, Kouichi Kawamura, Hirotake Masuda, Mamoru Miura, Hiroshi Ito
    • Journal Title

      Akita J Med 31

      Pages: 221-230

    • NAID

      110001052883

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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