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2001 Fiscal Year Final Research Report Summary

Mechanism of tumor necrosis factor gene expression in the development of heart failure and cardiac hypertrophy

Research Project

Project/Area Number 12835001
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research InstitutionGunma University School of Medicine

Principal Investigator

YOKOYAMA Tomoyuki  Gunma university, Second department of Internal medicine, lectuer, 医学部, 講師 (70312890)

Project Period (FY) 2000 – 2001
Keywordstumor necrosis factor / cardiac fibroblasts / cardiac myocytes / promoter / proteinkinase G
Research Abstract

Clinical observations indicate that the concentration of tumor necrosis factor (TNF) is elevated in patients with advanced heart failure or hypertrophic cardiomyopathy. However, the mechanisms for TNF production in the setting of these diseases are poorly understood. We recently showed that angiotensin II (ANGII) as well as mechanical stretch stimulate the production of TNF in cardiac fibroblasts. To extend these observations, we have examined the moleculer mechanisms by which ANGII up regulates TNFα gene expression. Using neonatal rat cardiac fibroblasts. Northern blot analysis showed that treatment with ANGII, endothelin-1 (ET1) or lipopolysaccharide (LPS) induced TNFαmRNA expression. These increase in TNFαmRNA level were regulated at transcriptional level as determined by luciferase activity of TNFα promoter gene. Progressive deletion analysis of TNFα promoter gene showed that the ANGII-responsive region lies between -100 to -70bp from the transcription start site. On the other hand, LPS-responsive region lies between -200 to -100bp. Further, mutation analysis indicated that the ANGII-responsive element could interact with Bs and NF-_KB, but the LPS-responsive element could interact with Sp1 . Additional studies were performed to evaluate the intracelluler signaling pathway associated LPS-induced TNFα gene expression. The increase of TNFαmRNA expression was attenuated by KT5823 which is a PKG specific inhibitor, whereas MAP kinase, PKA or PKC inhibitors had no effect on this response. Moreover, 8 bromo-cyclic GMP induced TNFαmRNA expression. We conclude that TNFα gene expression is transcriptionaly activated by ANGII, ET1 and LPS in cardiac fibroblasts. However, this response is mediated through different transcriptional factors by ANGII and LPS. Thus, the mechanisms for TNF production in heart failure or cardiac hypertrophy should differ from those in infectious disease. Further, PKGdependent signaling pathway may be important for this response.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] T.Hatori, et al.: "Stress Thatllium-201 myocardial scintigraphy in patients with"Chest. 120. 1409-1412

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Tanaka, et al.: "Overexpression of interleukin-6 aggravates viral myocarditis"J Mol Cell Cardiol. 33. 1627-1635

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      「研究成果報告書概要(和文)」より
  • [Publications] K.Sekiguchi, et al.: "Homeobox protein Hex induces SMemb/nonmuscle myosin 〜"Circulation Res. 88. 52-58

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Tanaka, et al.: "Induction of VEGF gene transcription by IL-1 β is mediated 〜"J Mol Cell Cardiol. 12. 1955-1967

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      「研究成果報告書概要(和文)」より
  • [Publications] M.Arai, et al.: "Mechanism of doxorubicin-induced inhibition of sarcoplasmic 〜"Circulation Res. 86. 8-14

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      「研究成果報告書概要(和文)」より
  • [Publications] Hatori T, Toyama T, Yokoyama T, Arai M, Kurabayashi M, Kanda T: "Stress Thallium-201 myocardial scintigraphy in patients with complete occlusion of the left main coronary artery"Chest. 120. 1409-1412 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, Yokoyama T, Kurabayashi M: "Overexpression of interluekin-6 aggravates viral myocarditis: Impaired increase in tumor necrosis factor-α"J Mol Cell Cardiol. 33. 1627-1635 (2001)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Sekiguchi K, Kurabayashi M, Oyama Y, Tanaka T, Sakamoto H, Hoshino Y, Kanda T,_Yokoyama T, Shimomura Y, Iijima H, Ohyama Y, Nagai R: "Homeobox protein Hex induces Smemb/nonrnuscle myosin heavy chain- β gene expression through the cAMP-responsive element"Circ Res. 88. 52-58 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] SetaY, Kanda T, Tanaka T, Arai M, Sekiguchi K, Yokoyama T, Kurimoto M, Taruma J, Kurabayashi M: "Interleukin 18 in acute myocardial infarction."Heart. 84. 668 (2000)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka T, Kurabayashi M, Kanai H, Sekigichi K, Aihara Y, Yokoyama T, Arai M, Kanda T, Nagai R: "Induction of VEGF gene transcription by IL-1 β is mediated through stress-activated MAP kinases and Sp 1 sites in cardiac myocytes"J Mol Cell Cardiol. 32. 1955-1967 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai M, Yoguchi A, Takizawa T, Yokoyama T, Kanda T, Kurabayashi M, Nagai R: "Mechanism of doxorubicin-induced inhibition of sarcoplasmic reticulum Ca2+-ATPase gene transcription"Circ Res. 86. 8-14 (2000)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Seta Y, Kanda T, Yokoyama T, Arai M, Sekiguchi K, Tanaka T, Kobayashi I, Kurabayashi M, Nagai R: "Therapy with the nonpeptide endothlin receptor antagonist 97-139 in a murine model of congestive heart failure : reduction of cardiac mass and myofiber hypertrophy"Jpn Heart J. 41. 79-85 (2000)

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      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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