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1999 Fiscal Year Final Research Report Summary

Role of Hepatocyte Growth Factor in the Pathogeresis of Cardioucscalon Disease

Research Project

Project/Area Number 09557060
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Circulatory organs internal medicine
Research InstitutionOsaka University

Principal Investigator

MOCISHITE Rynichi  Division of Gene Therapy Science, Osaka University, 医学系研究科, 助教授 (40291439)

Co-Investigator(Kenkyū-buntansha) MATSUMOTO Kunio  Department of Biochemstry, Osaka University, Associat Prof., 医学系研究科, 助教授 (90201780)
MORIGACH Atsvsh  Department of Genatric Med. Osaka University, Associat Prof., 医学系研究科, 助手 (10273666)
HIGAKI Jitsuo  Department of Genatric Med. Osaka University, Associat Professor, 医学系研究科, 助教授 (70189744)
TAIGI Mutsuo  Sumitoro Pharmocoutul., 主任研究員
Project Period (FY) 1997 – 1999
KeywordsHGF / gene therapy / angiogenesis / hynes tersion / emdothetial calls / 遺伝子治療 / 血管新生
Research Abstract

In this study, we investigated the role of hepatocyte growth factor (HGF) in the pathogenesis of cardiovascular disease. Initially, we focused on the application of therapeutic angiogenesis using HGF. The feasibility of a novel therapeutic strategy using angiogenic growth factors by expediting and /or augmenting collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of angiogenic growth factors whose mitogenic activity on endothelial cells is very potent. In this study, we hypothesized that transfection of HGF gene into ischemic hindlimb model could induce therapeutic angiogenesis in resonse to hypoxia.
At 3, 5 and 7 weeks after transfection, blood flow was significantly increased in hindlimb transfected with human HGF vector compared to control vector, accompanied by a significant increase in human HGF. The number of vessels around the injection sites of hindlimb transfected with HGF gene was sign … More ificantly increased as compared to control vector or vehicle. Interestingly, endogenous HGF concentration in ischemic hindlimb was significantly decreased as compared to non-ischemic hindlimb. Therefor, we reasoned that transfection of HGF gene into ischemic hindlimb could induce a beneficial response in response to the decreased endogenous HGF. Indeed, vascular HGF concentration in the diseased segments of vessels from patents with peripheral arterial disease was also significantly decreased as compared to disease-free segments from the same patients, accompanied by a marked reduction in HGF mRNA. Importantly, angiogenic property of HGF was also observed in diabetic rats. Here, we provide direct in vivo evidence for angiogenesis induced by transfection of human HGF gene in rat and rabbit ischemia hindlimb model, as potential "cytokine supplement therapy" for peripheral arterial disease. Currently, we submitted human gene therapy trail using HGF to treat peripheral arterial disease.
We also studied the possibility of serum HGF concentration as potential index of atherosclerosis. HGF might contribute to protection and/or repair of vascular endothelial cells injured by high blood pressure. Interestingly, serum HGF concentration in hypertensive paients with complications was significantly higher than that in hypertensive patients without complications and normotensive subjects. Moreover, serum HGF concentration in diabetic. patients with hypertensive complications was even higher than that in diabetics without complications. These data suggest that HGF may be considered as a new index of the severity of hypertension. Less

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Takahashi H, Okamoto, E. Fujimoto: "Curative gene therapy of liver cirrhosis by hepatocyte growth factor in rats"5. 226-230 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Morishita R, Nakamura S, Tanlyans S, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higuchi J, Ogihara T: "Thernpeutla anglogenesis induced by human recomblant hepatocyte growth factor in rabbit bind limb ischemia model as "cytokino supplement therapy""33. 1379-1384 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto K, Morishita R, Moriguchi A, Tomita N, Yo Y, Nishii T, Matsumoto K, Nakamura T, Higeki I, Ogihara T: "Prevention of renal damage by anglotenain IL blockode, accompanied by hicressed renal heputocyte growth factor in experimental hypertensive rats"34. 279-284 (1999)

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  • [Publications] Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taizi M, Noguchi H, Matsumoto K, Nakamura T, Higeki I, Ogihara T: "Potential role of hepatocyte growth factor, a novel anglogenic growth factor, in periphetal arterial disease : down regulation of HGP in response to hypoxla in vascular cells"100. II301-II308 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Taniyama Y, Morishita R, Nakagami H, Moriguchi A, Sakonjo H, Kim S, Matsumoto K, Nakamura T, Higeki I, Ogihara T: "Potential contribution of a novel anti-Ilbrotio foctor, hepalocyte growth factor, to prevention of myocordial fibrosis by anglotensin Il blocade in cordlornyopathic harnster"(in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Morishita R, Moriguchi A, Higeki I, Ogihara T: "Hepatocyte growth factor as potential index of severity of hyper tension"22. 161-167 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higaki J, Ogihara T.: "Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium : up-regulation of essential transcription factor for angiogenesis, ets."Gene Therapy. (in press).

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      「研究成果報告書概要(欧文)」より
  • [Publications] Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taizi M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T: "Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease : down-regulation of HGF in response to hypoxia in vascular cells."Circulation. 100. II301-II308 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T: "Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as "cytokine supplement therapy""Hypertension. 33. 1379-1384 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Takahashi H, Oakamoto E, Fujimoto J.: "Curative gene therapy of liver cirrhosis by hepatocyte growth factor in rats."Nature Medicine. 5. 226-230 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yo Y, Morishita R, Nakamura S, Tomita N, Yamamoto K, Moriguchi A, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "Potential role of hepatocyte growth factor in the maintenance of renal structure : anti-apoptotic action of HGF on epithelial cells."Kidney International. 54. 1128-1138 (1998)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Nakano N, Morishita R, Moriguchi A, Nakamura Y, Hayashi S, Aoki M, Kida I, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "Negative regulation of local hepatocyte growth factor (HGF) expression by angiotensin II and transforming growth factor-β in blood vessels :potential role of HGF in cardiovascular disease."Hypertension. 32. 444-451 (1998)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Nakano N, Moriguchi A, Morishita R, Kida I, Tomita N, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor, in experimental hypertensive rats."Hypertension. 30. 1448-1454 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Morishita R, Nakamura S, Nakamura Y, Aoki M, Moriguchi A, Kida I, Yo Y, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "Potential role of endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes mellitus."Diabetes. 46. 138-142 (1997)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Morishita R, Higaki J, Hayashi S, Yo Y, Aoki M, Nakamura S, Moriguchi A, Matsushita H, Matsumoto K, Nakamura T, Ogihara T.: "Role of hepatocyte growth factor in endothelial regulation : Prevention of high D-glucose-induced endothelial cell death by prostaglandins and phosphodiesterase type 3 inhibitor."Diabetologia. 40. 1053-1061 (1997)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura Y, Morishita R, Higaki J, Kida I, Aoki M, Moriguchi A, Yamada K, Hayashi S, Yo Y, Nakano H, Matsumoto K, Nakamura T, Ogihara T.: "Hepatocyte growth factor (HGF) ia a novel member of endothlium-specific growth factors : additive stimulatory effect of HGF with basic fibroblast growth factor, but not vascular endothelial growth factor."Journal of Hypertension. 14. 1067-1072 (1996)

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  • [Publications] Nakamura Y, Morishita R, Nakamura S, Aoki M, Moriguchi A, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "A vascular modulator, hepatocyte growth factor, is associated with systolic pressure."hypertension. 28. 409-413 (1996)

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Published: 2001-10-23  

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