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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
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1997: ¥6,200,000 (Direct Cost: ¥6,200,000)
KeywordsHGF / gene therapy / angiogenesis / hynes tersion / emdothetial calls / 遺伝子治療 / 血管新生 / 閉塞性動脈硬化症 / 糖尿病 / 内皮 / 虚血 / VEGF / アポトーシス / 再狭管 / 血管新迷
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

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

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

    • Related Report
      1999 Annual Research Report
  • [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 indeced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as"cytokino supplement therapy""Hypertension. 33. 1379-1384 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsumoto K, Morishita R, Moriguchi A, Tomita N, Yo Y, Nishii T, Matsumoto K, Nakamura T, Higaki J, Ogihara T.: "Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats"Hypertension. 34. 279-284 (1999)

    • Related Report
      1999 Annual Research Report
  • [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 decade: down-regulation of HGF in response to hypoxia in vascular cells"Circulation. 100. II301-II308 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Taniyama Y, Morishita R,Nakagami H,Moriguchi A,Sakonjo H,Kim S,Matsumoto K, Nakamura T, Higaki J,Ogihara T.: "Potential contribution of a novel anti-fibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotension II blockade in cardiomyopathic hamster"Circulation. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Morishita R, Moriguchi A, Higaki J, Ogihara T.: "Hepatocyte growth factor as potential index of severity of hypertension"Hypertension Research. 22. 161-167 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakano N,Morishita R,: "Negative regulation of local hepatocyte growth factor(HGF)expression by angiotensin II and transforing growth factor-β in bloob vessels:potential role of HGF in cardiovascular disease." Hypertension. 32. 444-451 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yo Y,Morishita R,: "Actions of hepatocyte growth factor as a local modulator in the kidny:potential role in pathogenesis of renal disease." Kidney International. 53. 50-58 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] nakamura S,Morishita R,: "A novel vascular modulator,hepatocyte growth factor(HGF),as a potential index of the severity of hypertension." Biochemical Biophysics Research Communication. 242. 238-243 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yo Y,Morishita R,: "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)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ueki T,Kaneda Y,: "Curative gene therapy of liver cirrhosis by hepatocyte growth factor in rats." Nature Medicine. 5. 226-230 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Morishita R,Nakamura S: "Therapeutic angiogenesis induced by human recemoinant hepatocyte groeth factor in rabbit hind limb ischemia model as“cytokine supplement therapy."" Hypertensin. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Morishita R,Aoki M,: "Gene therapy for myocardial infarction." Kluwer Academic Publishers, 531-550 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Morishita R,Aoki M,: "Functional analysis of tissue renin-angiotensin Systemusing“Gain and Loss of Function"Approaches;In vivo test of in vitoro hypothesis.in“Angiotensin II receptor blockade;physiological and chinical implications."" Kluwer Academic Publishers(in press), (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Morishita R: "Potential role of endothelium-specific growth factor,hepatocyte growth factor,on endothelial damage in diabetes mellitus." Diabetes. 46. 138-142 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Morishita R: "Potential role of novel vascular modulator ,hepatocyte growth factor(HGF),in cardiovascular disease ; characterization and regulation of lacal HGF system." Journal of Atherosclerosis and Thrombosis. 4. 12-19 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Morishita R: "Role of hepatocyte growth factor in edothelial regulation : Prevention of higt D-glucose-induced endothelial cell death by prostaglandins and phospho-" Diabetologia. 40. 1053-1061 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakano N: "Role of angiotensin II in the regulation of a novel vascular modulator,hepatocyte growth factor,in experimental hypertensive rots." Hypertension. 30. 1448-1454 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yo Y: "Actions of Hepatocyte Growth Facor as a Local Modulator in the kidney : Potential Role in Pathogenesis of Renal Disease." Kidney International. 53. 50-58 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamura S: "A novel vascular modulator,hepatocyte growth factor(HGF),as a potential index of the severity of hypertension." Biochemical Biophysics Research Communication. 242. 238-243 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Morishita R: "Ischemic Heart" Kluwer Academic Publishers.(in press),

    • Related Report
      1997 Annual Research Report
  • [Publications] Morishita R: "Angiotensin II receptor blocka : physiological and clinical implications" Kluwer Academic Publishers.(in press), (1997)

    • Related Report
      1997 Annual Research Report

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

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