• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Establishment of a new antiatherosclerotic drug and its screening methods using an animal model.

Research Project

Project/Area Number 03557116
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 内分泌・代謝学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

KITA Toru  Dept. of Geriatric Medicine, Faculty of Medicine, Kyoto University, Professor., 医学部, 教授 (60161460)

Co-Investigator(Kenkyū-buntansha) NARISADA Masayuki  Shionogi Research Laboratories, Shionogi & Co., Ltd., Director., 常務取締役研究所所長
YOSHIOKA Hideyuki  Dept. of Geriatric Medicine, Faculty of Medicine, Kyoto University, Instructor., 医学部, 助手 (30231690)
NAGANO Yutaka  Dept. of Geriatric Medicine, Faculty of Medicine, Kyoto University, Instructor., 医学部, 助手 (80228048)
松本 光弘  京都大学, 医学部, 助手 (20229579)
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥16,600,000 (Direct Cost: ¥16,600,000)
Fiscal Year 1992: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1991: ¥11,600,000 (Direct Cost: ¥11,600,000)
KeywordsWHHL-rabbit / HMG-CoA Reductase / Hepatocyte / Probucol / LDL receptor / HMG-CoA還元酵素 / プロブコ-ル
Research Abstract

In order to establish the screening methods for anti-atherosclerotic drug, we could develop the primary culture system for rabbit hepatic cells as reported last year. In addition when we added collagens in the culture medium, we found that rabbit hepatic cells could easily attach to the dish. This finding makes our experiments to be done easily.
As reported last year, pravastatin, an inhibitor of HMG-CoA reductase inhibitor, induced the expression of LDL receptor in hepatic cells. Moreover, we found that pravastatin decreased apo B secretion significantly from the liver. On the other hand, when we incubated hepatic cells with LDL, 'hepatic cells secreted apo B more than that of control cells. When we added pravastatin to the cells, cellular cholesteryl ester was decreased. Therefore these results indicated that the change of apo B secretion was in parallel with the change of cellular cholesteryl ester contents. Furthermore we investigated intracellular degradation of apo B prior to secretion and found that the addition of pravastatin accelerated intracellular degradation of apo B, while LDL slowed apo B intracellular degradation rate. However the change of cellular cholesteryl ester could not affect apo B mRNA levels, examined by northen blot analysis.
We conclude that intracellular cholesteryl ester contents play a critical role for apo B secretion and intracellular apo B degradation rate could be the main mechanism that regulated apo B secretion in response to the change of intracellular cholesteryl ester level. We are investigating the detail mechanism of these findings.
Finally it is still very difficult to make new compounds which have at least two activities, such as an inhibitor of HMG-CoA reductase and an antioxidant action. This experiment is undergoing.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] TANAKA,M.,JINGAMI,H.,OTANI,H.,Cho,M.,UEDA,Y.,ARAI,H.,NAGANO,Y.,DOI,T.& KITA,T.: "Regulation of apolipoprotein B production and secretion in response to the change ofintracellular cholesteryl ester contents in rabbit hepatocytes." J.Biol.Chem.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] UEDA,Y.,ARAI,H.,KAWASHIMA,A.,NAGANO,Y.Cho,M.,TANAKA,M.& KITA,T.: "Different expression of modified low density lipoprotein receptors in rabbit peritoneal macrophages and kupffer cells." Atherosclerosis.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KITA,T.,Yokdoe,M.,ARAI,H.,IIYAMA,M.,UEDA,Y.,UEYAMA,K.& NARUMIYA,S.: "Cigarette smoke,LDL and cholesteryl ester accumulation in macrophages." Ann.N.Y.Acad.Sci.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] ARAI,H.,NAGANO,Y.,NARUMIYA,S.& KITA,T.: "Decreased arachidonate metabolism in mouse peritoneal macrophages after foam cell transformation with oxidized low-density lipoproteins." J.Biochem.112. 482-487 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] HARA,S.,NAGANO,Y.,SASADA,M.& KITA,T.: "Probucol pre-treatment enhances the chemotaxis of mouse peritoneal macrophages." Arteriosclerosis and Thrombosis. 12. 593-600 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] NAGANO,Y.,NAKAMURA,T.,MATSUZAWA,Y.,Cho.,M.,UEDA,Y.& KITA,T.: "probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit--long-term antiatherogenic effect and effects on established plaques." Atherosclerosis. 92. 131-140 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tanaka, M., Jingami, H., Otani, H., Cho, M., Ueda, Y., Arai, H., Nagano, Y., Doi, T.& Kita, T.: "Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes." J.Biol.Chem.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ueda, Y., Arai, H., Kawashima, A., Nagano, Y.Cho, M., Tanaka, M. & Kita, T.: "Different expression of modified low density lipoprotein receptors in rabbit peritoneal macrophages and kupffer cells." Atherosclerosis, Press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kita, T., Yokode, M., Arai, H., Iiyama, M., Ueda, Y., Ueyama, K. & Narumiya, S.: "Cigarette smoke, LDL and cholesteryl ester accumulation in macrophages." Ann.N.Y.Acad. Sci.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Arai, H., Nagano, Y., Narumiya, S. & Kita, T.: "Decreased arachidonate metabolism in mouse peritoneal macrophages after form cell transformation with oxidized low-density lipoproteins." J.Biochem.112. 482-487 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hara, S., Nagano, Y., Sasada, M. & Kita, T.: "Probucol pre-treatment enhances the chemotaxis of mouse peritoneal macrophages." Arteriosclerosis and Thrombosis. 12. 593-600 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nagano, Y., Nakamura, T., Matsuzawa, Y., Cho., M., Ueda, Y.& Kita, T.: "Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit -- long-term antiatherogenic effect and effects on established plaques." Atherosclerosis. 92. 131-140 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tanaka,M.,Jingami,H.,Otani,H.,Cho,M.,Ueda,Y.,Arai,H.,Nagano,Y.,Doi,T.&Kita,T.: "Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes." J.Biol.Chem.

    • Related Report
      1992 Annual Research Report
  • [Publications] Ueda,Y.,Arai,H.,Kawashima,A.,Nagano,Y.Cho,M.,Tanaka,M&Kita,T.: "Different expression of modified low density lipopeotein receptorsin rabbit peritoneal macrophages and kupffer cells." Atherosclerosis.

    • Related Report
      1992 Annual Research Report
  • [Publications] Kita,T.,Yokdoe,M.,Arai,H.,Iiyama,M.,Ueda,Y.,Ueyama,K&Narumiya,S.: "Cigarette smoke,LDL and cholestery ester accumulation in macrophages." Ann.N.Y.Acad.Sci.

    • Related Report
      1992 Annual Research Report
  • [Publications] Arai,H.,Nagano,Y.,Narumiya,S.&Kita,T.: "Decreased arachidonate metabolism in mouse peritoneal macrophages after foam cell transformation with oxidized low-density lipoproteins." J.Biochem.112. 482-487 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hara,S.,Nagano,Y.,Sasada,M&Kita,T.: "Probucol pre-treatment enhances the chemotaxis of mouse peritoneal macrophages." Arterioselerosis and Thrombosis. 12. 593-600 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nagano,Y.,Nakamura,T.,Matsuzawa,Y.,Cho.,M.,Ueda,Y.&Kita,T.: "Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit--long-term antiatherogenic effect and effect one established plaques." Atherosclerosis. 92. 131-140 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hara,S.,Nagano,Y.,Sasada,M. & Kita,T.: "Probucol pre-treatment enhances the chemotaxis of mouse peritoneal macrophages." Arteriosclerosis and Thrombosis.

    • Related Report
      1991 Annual Research Report
  • [Publications] Nagano,Y.,Nakamura,T.,Matsuzawa,Y.,Cho,M.,Ueda,Y.& Kita,T.: "Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit -- long-term antiatherogenic effect and effects on established plaques." Atherosclerosis.

    • Related Report
      1991 Annual Research Report
  • [Publications] Nagano,Y.,Arai,H.& Kita,T.: "High density lipoprotein loses its effect to stimulate efflus of cholesterol from foam cells after oxidative modification." Proc.Natl.Acad.Sci.U.S.A.88. 6457-6461 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kita,T.: "Oxidized lipoproteins and probucol." Current Opinion in Lipidology. 2. 35-38 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] O′Brien,K.,Nagano,Y.,Gown,A.,Kita,T.& Chait,A.: "Probucol treatment affects the cellular composition but not anti-oxidized LDL immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits." Arteriosclerosis and Thrombosis. 11. 751-759 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kume,N.,Arai,H.,Kawai,C.& Kita,T.: "Receptors for modified low-density lipoproteins on human endothelial cells: different recognition for acetylated low-density lipoprotein and oxidized low-density lipoprotein." Biochim.Biophys.Acta. 1091. 63-67 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kita,T.,Ishii,K.,Yokode,M.,Kume,N.,Nagano,Y.,Otani,H.,Arai,H.,Ueda,Y.& Kawai,C.: "Lipoproteins and Atherosclerosis." Jpn.Circ.J.54. 1226-1232 (1990)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kita,T.,Ishii,K.,Yokode,M.,Kume,N.,Nagano,Y.,Arai,H.& Kawai,C.: "The role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis." European Heart Journal. 11. 122-127 (1990)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kita,T.,Yokode,M.,Ishii,K.,Arai,H.& Nagano,Y.: "The role of atherogenic low density lipoproteins (LDL) in the pathogenesis of atherosclerosis." Ann.New York Acad.Sci.598. 188-193 (1990)

    • Related Report
      1991 Annual Research Report

URL: 

Published: 1991-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi