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Study for the mechanism of LDL modification search for its inhibitor.

Research Project

Project/Area Number 63870014
Research Category

Grant-in-Aid for Developmental Scientific Research

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) OGO Toshiharu  Eisai Co., Ltd., The 1st Exploratory Drug Division, Director, 研究開発本部, 探索第一研究部長
HORIUCHI Seiko  Kumamoto University, Faculty of Medicine, Instructor, 医学部, 講師
NARUMIYA Shu  Kyoto University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (70144350)
Project Period (FY) 1988 – 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 1989: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1988: ¥8,000,000 (Direct Cost: ¥8,000,000)
KeywordsOxidized LDL / Antioxidant / Atherosclerosis / Foam cell / Oxidized LDL receptor / 酸化LDL受容体 / 泡洙細胞 / マクロファージ / 修飾LDL / 受容体 / スーパーオキサイド
Research Abstract

One of the characteristic events in the early lesions of atherosclerosis is the accumulation of lipid-laden foam cells. Recent studies have demonstrated that most of the foam cells are derived from monocute-macrophages. These macrophages accumulate lipids in their cytoplasms, most of which are derived from low density lipoproteins (LDL). Because these cells express very few number of classical LDL receptor, the mechanism of LDL incorporation into macrophages has been a focus of extensive investigation.
Goldstein et al. reported that LDL modified chemically by acetylation can be recognized and incorporated by a receptor on macrophages and they named it acetyl-LDL receptor. However, it seems unlikely that such acetylation of LDL would occur in vivo. Therefore, several investigators have been studying what are modified forms of LDL in vivo. Endothelial cell modified LDL, oxidized LDL and cigarette smoke modified LDL are now proposed as a candidate for naturally occurring modified LDL. And … More recently there are lots of evidences that endothelial cell modified LDL is as same as oxidized LDL. Parthasarathy have observed in vitro that LDL converted by chemical oxidation with Cu^<++> or Fe^<++> into a negatively-charged form transforms macrophages into foam cells and suggested that the uptake mechanism of this oxidized LDL by macrophages is mediated by the acetyl-LDL receptor. However in our previous study, we found that acetyl-LDL inhibited the degradation of [^<125>I]oxidized LDL by macrophages only by 55 %. This result has led us to postulate that the uptake mechanisms of the two lipoproteins may be different. 0ur current study was undertaken to examine the above hypothesis by comparing the binding properties of oxidized LDL, cigarette-smoke modified LDL and acetyl-LDL to macrophages. To this, we have performed competition and cross-competition in binding and degradation in macrophages. The results clearly showed that the macrophage receptors for modified LDL are composed of at least three distinct receptors with different specificities. Two of them are specific for those three LDL and the rest is a common receptor for both oxidized and cigarette smoke modified LDL, and acetyl-LDL. In the process of modifying LDL by Cu^<++>, Fe^<++> or cigarette extract, we found that superoxide anion (O_2) played an important role for modification and super-oxide dismutase (SOD) inhibited those reactions. However catalase could not prevent the modification of LDL. Therefore, in stead of S.O.D., we screened out several agents as an antioxidant, such as probucol, vitamin E or vitamin C derivatives.
Probucol, so far, is an only agents which could prevent the modification of LDL. Other agents could not prevent those reaction because those could not be included into LDL particles. We next performed in vivo experiment to ask antiatherogenic activity of probucol as an antioxidant using WHHL-rabbits. When rabbits were fed 1 % probucol diet for 17 months since they were 2 month of age, the surface area of atheromatous lesion in aorta was 23 % in comparison with that of 93 % in control WHHL-rabbit. Even when rabbits were fed 1 % probucol diet at 8 month of age when their surface area of lesion was 54 %, 6 month later their lesion became about 38 % on an average. Those date indicated that oxidized LDL is one of the candidate modified LDL in vivo and probucol has a strong antiatherogenic effect. Less

Report

(3 results)
  • 1989 Annual Research Report   Final Research Report Summary
  • 1988 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [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." Eur.Heart J.in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [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.N.Y.Acad.Sci.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Arai,H.,Kita,T.,Yokode,M.,Narumiya,S.& Kawai,C.: "Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages;different uptake mechanisms for acetylated and oxidized low density lipoproteins." Biochem.Biophys.Res.Commun.159. 1375-1382 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Nagano,Y.,Kita,T.,Yokode,M.,Ishii,K.,Kume,N.,Otani,H.,Arai,H.& Kawai,C.: "Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits." Arteriosclerosis. 9. 453-461 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.& Narumiya,S.: "Purification of the thromboxane A_2/prostaglandin H_2 receptor from human biood platelets." J.Biol.Chem.264. 16496-16501 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Sekine,A.,Fujiwara,M.& Narumiya,S.: "Asparagine residue in the rho gen product is the modification site for botulinum ADP-ribosyltransferase." J.Biol.Chem.264. 8602-8605 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Horiuchi,S.,Takata,K.,Araki,N.& Morino,Y.: "Regional ligand domain is involved in scavenger receptor-mediated recognition of maleyl-albumin by rat sinusoidal liver cells." J.Molec.Recognition. 2. 56-62 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takata,K.,Horiuchi,S.,Araki,N.,Shiga,M.,Saitoh,M.& Morino,Y.: "Scavenger receptor of human monocytic leukemia cell line(THP-1)and murine macrophages for non-enzymatically." Biochim.Biophys.Acta. 986. 18-26 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takata,K.,Horiuchi,S.& Morino,Y.: "Scavenger receptor-mediated recognition of maleylated albumin and its relation to subsequent endocytic degradation." Biochim.Biophys.Acta. 984. 273-280 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [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." Eur. Heart J., in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [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. N.Y. Acad. Sci., in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Arai, H., Kita, T., Yokode, M., Narumiya, S. & Kawai, C.: "Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages; different uptake mechanisms for acetylated and oxidized low density lipoproteins." Biochem. Biophys. Res. Commun., 159: 1375-1382, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Nagano, Y., Kita, T., Yokode, M., Ishii, K., Kume, N., Otani, H., Arai, H. & Kawai, C.: "Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits." Arteriosclerosis, 9: 453-461, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Ushikubi, F., Nakajima, M., Okuma, M., Fujiwara, M., & Narumiya, S.: "Purification of the thromboxane A_2/prostaglandin H_2 receptor from human blood platelets." J. Biol. Chem., 264: 16496-16501, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Sekine, A., Fujiwara, M. & Narumiya, S.: "Asparagine residue in the rho gen product is the modification site for botulinum ADP-ribosyltransferase." J. Biol. Chem., 264: 8602-8605, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Horiuchi, S., Takata, K., Araki, N. & Morino, Y.: "Regional ligand domain is involved in scavenger receptor-mediated recognition of maleyl-albumin by rat sinusoidal liver cells." J. Molec. Recognition, 2: 56-62, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takata, K., Horiuchi, S., Araki, N., Shiga, M., Saitoh, M. & Morino, Y.: "Scavenger receptor of human monocytic leukemia cell line (THP-1) and murine macrophages for nonenzymatically." Biochim. Biophys. Acta, 986: 18-26, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takata, K., Horiuchi, S. & Morino, Y.: "Scavenger receptor-mediated recognition of maleylated albumin and its relation to subsequent endocytic degradation." Biochim. Biophys. Acta, 984: 273-280, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [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." Eur.Heart J.

    • Related Report
      1989 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.N.Y.Acad.Sci.

    • Related Report
      1989 Annual Research Report
  • [Publications] Arai,H.,Kita,T.,Yokode,M.,Narumiya,S.&Kawai,O.: "Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages;different uptake mechanisms for acetylated and oxidized low density lipoproteins." Biochem.Biophys.Res.Commun.159. 1375-1382 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Nagano,Y.,Kita,T.,Yokode,M.,Ishii,K.,Kume,N.,Otani,H.,Arai,H.&Kawai,C.: "Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits." Arteriosclerosis. 9. 453-461 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.&Narumiya,S.: "Purification of the thromboxane A_2/prostaglandin H_2 receptor from human blood platelets." J.Biol.Chem.264. 16496-16501 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Sekine,A.,Fujiwara,M.&Narumiya,S.: "Asparagine residue in the rho gen product is the modification site for botulinum ADPーribosyltransferase." J.Biol.Chem.264. 8602-8605 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Horiuchi,S.,Takata,K.,Araki,N.&Morino,Y.: "Regional ligand domain is involved in scavenger receptorーmediated recognition of maleylーalbumin by rat sinusoidal liver cells." J.Molec.Recognition. 2. 56-62 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Takata,K.,Horiuchi,S.,Araki,N.,Shiga,M.,Saitoh,M.&Morino,Y.: "Scavenger receptor of human monocytic leukemia cell line(THPー1)and murine macrophages for nonーenzymatically." Biochim.Biophys.ACTA. 986. 18-26 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Takata,K.,Horiuchi,S.&Morino,Y.: "Scavenger receptorーmediated recognition of maleylated albumin and its relation to subsequent endocytic degradation." Biochim.Biophys.Acta. 984. 273-280 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Nagano,Y.,;Kita,T.,;Yokode,M.;Ishii,K.;Kume,N.;Ootani,H.;Arai,H.;Kawai,C.: Arteriosclerosis.

    • Related Report
      1988 Annual Research Report
  • [Publications] Arai,H.;Kita,T.;Yokode,M.;Narumiya,S.;Kawai,C.: Biochem.Biophys.Res.Commun.

    • Related Report
      1988 Annual Research Report
  • [Publications] Sekine,A.;Fujiwara,M.;Narumiya,S.: J.Biol.Chem.in press.

    • Related Report
      1988 Annual Research Report
  • [Publications] Narumiya,S.;Morii,N.;Sekine,A.;Fujiwara,M.: J.Biol.Chem.263. 17255-17258 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Takata,K.;Horiuchi,S.;Araki,N.;Shiga,M.;Saitoh,M.;Morino,Y.: Biochim.Biophys.Acta.

    • Related Report
      1988 Annual Research Report
  • [Publications] Horiuch,S.;Takata,K.;Araki,N.;Morino,Y.: Journal of Molecular Recognition.

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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