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Adipocytokine-related genes and insulin resistance

Research Project

Project/Area Number 14570090
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionHoshi University

Principal Investigator

KAMATA Katsuo  Hoshi University, Inst. Med. Chem., Professor, 医薬品化学研究所, 教授 (40121496)

Co-Investigator(Kenkyū-buntansha) MATSUMOTO Takayuki  Hoshi University, Inst. Med. Chem., Research Assistant, 医薬品化学研究所, 助手 (30366835)
KOBAYASHI Tsuneo  Hoshi University, Inst. Med. Chem., Research Assistant, 医薬品化学研究所, 助手 (90339523)
末永 浩  星薬科大学, 医薬品化学研究所, 助手 (70277698)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsadipocytokine / diabetes mellitus / endothelium / endothelin-1 / NAD / Hoxidase / PPARα / EDHF / cyclic AMP / インスリン / 活性酸素
Research Abstract

1) We tested J-104132, a potent orally active mixed antagonist of endothelin A and B (ET_A/ET_B) receptors in streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. The acetyicholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was significantly attenuated following chronic administration of J-104132. The amount of superoxide anion was significantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment significantly decreased the level of superoxide anion in diabetic rats. The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was significantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.
2) The decreased rela … More xation in diabetes was improved by the chronic administration of bezafibrate. The expressions of the mRNAs for PPARx and PPARγ were significantly decreased in STZ-induced diabetic ratsand this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate-treated diabetic rats than in non-treated diabetic rats. Although the expression of the mRNA for preproET-1 (ppET-1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate. These results suggest that downregulations of PPARct and y may lead to an increased expression of prepro ET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.
3) In isolated superior mesenteric artery rings from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats, and enhanced by 3-isobutyl-1-methylxanthine, a cAMP-phosphodiesterase inhibitor. These enhanced EDKF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHE-type relaxation was enhanced by cilostamide, a phosphodiesterase 3 (PDE3)-selective inhibitor, but not by Ro 20-1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP phosphodiesterases (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but that for PDE4D was not We conclude that the impairment of EDHE-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.
4) In adiponectin knockout mice, acetylcholine-induced relaxation was not changed as compared with controls, indicating that the reduced adiponectin itself induces the vascular complications. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Kanie, Kamata: "Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat"Br.J.Pharmacol.. 135. 1935-1942 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanie et al.: "Relationship between peroxisome proliferator-activated receptors (PPARalpha and PPARgamma) and endothelium-dependent relaxation in streptozotocin-induced diabetic rats"Br.J.Pharmacol.. 140. 23-32 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Makino et al.: "Mechanisms underlying increased release of endothelin-1 from aorta in diabetic rats"PEPIDES. 22. 639-645 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Makino, Kamata: "Effects of chronic administration of L-arginine on vasoactive responses induced by endothelin-1 and its plasma level in streptozotocin-induced diabetic rats."J.Smooth Muscle Res.. 38. 101-115 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi, Kamata: "Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats"Am.J.Physiol.Heart Circ.Physiol.. 283. H1761-H1768 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi, Kamata: "Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortic from established STZ-induced diabetic rats"Atherosclerosis. 155. 313-321 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K Matsumoto et al.: "Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats"Am.J.Physiol.Heart Circ.Physiol.. 285. H283-H291 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi et al.: "Possible involvement of IGF-1 receptor and IGF-binding protein in insulin-induced enhancement of noradrenaline response in diabetic rat aorta"Br.J.Pharmacol.. 140. 285-294 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suenaga, Kamata: "Lysophosphatidylcholine potentiates vascular contractile responses in rat aorta via activation of tyrosine kinase"Br.J.Pharmacol.. 135. 789-799 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suenaga, Kamata: "Lysophosphatidylcholine activates extracellular-signal-regulated protein kinase and potentiates vascular contractile responses in rat aorta"J.Pharmacol.Sci.. 92. 348-358 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi, Kamata: "Modulation by hydrogen peroxide of noradrenaline-induced contraction in aorta from streptozotocin-induced diabetic rat"Eur.J.Pharmacol.. 441. 83-89 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kamata et al.: "Mechanisms underlying attenuated contractile response of aortic rings to noradrenaline in fructose-fed mice"Eur.J.Pharmacol.. 428. 241-249 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanie, Kamata: "Contractile responses in spontaneously diabetic mice I. Involvement of superoxide anion in enhanced contractile response to aorta to norepinephrine in C57/BI/Ksj(db/db) mice"Gen.Pharmacol.. 35. 311-318 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanie, Kamata: "Contractile responses in spontaneously diabetic mice II. Effect of cholestyramine on enhanced contractile response of aorta to norepinephrine in C57/BI/Ksj(db/db) mice"Gen.Pharmacol.. 35. 319-323 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suenaga et al.: "Effects of calmodulin antagonist (W-7) on phorbol ester (PMA)-induced contractile response in isolated rat aorta"J.Smooth Muscle Res.. 37. 1-7 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Kobayashi, et al.: "J Possible involvement of IGF-1 receptor and IGF-binding protein in insulin-induced enhancement -----"Br.J.Pharmacol.. 140. 285-294 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanie, Kamata: "Relationship between proliferator-activated recptors (PPARα and PPARγ)and endothelium-dependent ---------"Br.J.Pharmacol.. 140. 23-32 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Suenaga, K.Kamata: "Lysophosphatidylcholine activates extracellular-signal-regulated protein kianse and proteintiates-----"J.Pharmacol.Sci.. 92. 348-358 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Matsumoto et al.: "Alterations in EDHF-type relaxation and phosphodi-esterase activity in mesenteric arteries from--------"Am.J.Physiol.Heart Circ.Physiol.. 285. H283-H291 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Matsumoto et al.: "Characterization of arterial reactivity in a new rat model of tipe II diabetes"Can.J.Physiol.. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Matsumoto et al.: "Alteration of shear-stress induced contractile response and agonist induced vasodilation"Atherosclerosis. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi, T., Kamata, K.: "IGF-1 receptor or VEGE mRNA expression by chronic high dose insulin-treatment in aorta from control or established diabetic rats"Am. J. Physiol. Heart Circ. Physiol.. 283. H1761-H1768 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suenaga, H., Kamata, K.: "Lysophosphatidylcholine potentiates vascular contractile responses via tyrosine kinase in rat aorta"Br. J. Pharmacol.. 135. 789-799 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanie, K., Kamata, K.: "Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction streptozotocin-induced diabetic rat"Br. J. Pharmacol.. 135. 1395-1942 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kobayashi, T., Kamata, K.: "Regulation of hydrogen peroxide on noradrenaline-induced contractile response in aorta from streptozotocin-induced diabetic rats"Eur. J. Pharmacol.. 441. 83-89 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hayakawa, K., Kimura, M., Kamata, K.: "Mechanisms underlying GABA-induced antihypertensive effect in spontaneously hypertensive rats"Eur. J. Pharmacol.. 438. 107-113 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Makino, A., Kamata, K.: "Effects of chronic administration of L-arginine on vasoactive responses induced by endothelin-1 and its plasma level in streptozotocin-induced diabetic rats"J. Smooth Muscle Res.. 38. 101-115 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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