1998 Fiscal Year Annual Research Report

メイラード反応後期生成物(AGE)の構造と生物医学的意義に関する研究

Research Project

Project/Area Number	10044305
Research Category	Grant-in-Aid for international Scientific Research
Section	Joint Research .
Research Institution	Kumamoto University
Principal Investigator	堀内正公熊本大学, 医学部, 教授 (10117377)
Co-Investigator(Kenkyū-buntansha)	PAUL J.Thorn エセックス大学, 生物化学部, 教授 BARD Smedsro トロムソ大学, 医学部, 教授 JOHN W.Bayne サウスカロライナ大学, 理学部, 教授 VINCENT M. M ケイスウェスタンリザーブ大学, 医学部, 教授宮崎章熊本大学, 医学部, 講師 (70253721)
Keywords	糖尿病合併症 / メイラード反応 / AGE / AGE受容体 / 老化
Research Abstract	本年度はAGEの主要構造体の生体内局在、並びにAGE受容体の構造と機能の2つの角度から解析し、下記の結果が得られた。 1.AGEの主要構造体の解析及びその生体内局在これまで我々はNε-(carboxymethyl)lysine(CML)が主要なAGE構造体であり、糖尿病合併症、動脈硬化症、アルツハイマー病などの病変部に蓄積することを明確にして来た。本年度はベインズ博士及びモニアー博士との共同研究によって合成したpyrralineとpentosidine、さらにソナリー博士が合成したNε-(carboxyethyl)lysine(CEL)及びimdazoloneなど、4つのAGE構造体に対する特異的なモノクローナル及びポリクローナル抗体の作製に成功した。又、これらの抗体を用いたinvitro の研究から、pyrraline及びimidazoloneは3-deoxyglucosoneに由来する構造体であること、又、メイラード反応の進行に伴ってmethylglyoxalが発生し、このアルデヒドを経由してCELが形成されることが明らかとなった。さらに、組織免疫学的研究から、pyrralineがヒト動脈硬化病変の細胞外マトリックス、また、家族性筋萎縮性側索硬化症患者の神経細胞体にpentosidineの蓄積を同定した。 2.AGE受容体の構造と機能解明我々はMSR-A(macrophage scavengerreceptor,Class A)がマクロファージ系細胞の主要AGS受容体であることを明確にして来たが、本年度はスメストロ教授との共同研究によって、肝臓の類洞内皮細胞に発現するAGE受容体の解析を行い、MSR-Aとは異なる新規AGE受容体が肝類洞内皮細胞に発現し、ホルムアルデヒド修飾蛋白をリガンドとすることが明らかとなった。さらに、AGE受容体ファミリーとして報告されているGalectin-3をCHO細胞に過剰発現させると、AGE蛋白のみならず、酸化LDLおよびアセチルLDLをもリガンドとして認識し、泡沫化することが明らかとなり、動脈硬化症の発症、特に新たな泡沫化機構の可能性が示唆された。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Jing Meng et al.: "Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage" Atherosclerosis. 136. 355-365 (1998)
[Publications] Kazuyoshi Ikeda et al.: "Determination of glycated albumin by enzyme-linked boronate-immunoassay(ELBIA)" Clin.Chem.442. 256-263 (1998)
[Publications] Hideki Hakamata et al.: "Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of oxidized low density lipoprotein" J.Lipid Res.39. 482-494 (1998)
[Publications] Hirofumi Matsuda et al.: "Molecular cloning,functional expression,tissue distribution and activation by acetylated LDL in macrophages of rat acyl-coenzyme A:cholesterol acyltransferase" Biochem.Biophys.Acta.1391. 193-203 (1998)
[Publications] Yi Ding et al.: "Reduced expression of the macrophage scavenger receptors in macrophage-like cell mutants resistant to Brefeldin A." Biochem.Biophys.Res.Commun.243. 277-283 (1998)
[Publications] Hisashi Sakaguchi et al.: "Role of macrophage scanvenger receptors in fat-induced atherosclerosis in mice" Lab.Invest.78. 423-434 (1998)
[Publications] Ryoji Nagai et al.: "Conversion of Amadori product of Maillard reaction to N ε-(carboxymethyl)lysine in alkaline conditions" FEBS Letts.425. 355-360 (1998)
[Publications] Kazuyoshi Ikeda et al.: "Immunochemical approaches to AGE-structures:characterization of anti-AGE antibodies" J.Immunol.Methods. 215. 95-104 (1998)
[Publications] Hiroyuki Sano et al.: "Insulin enhances macrophage scavenger receptor-mediated endocytic uptake of advanced glycation end products" J.Biol.Chem.273. 8630-8637 (1998)
[Publications] Noriyuki Sakata et al.: "Increased advanced glycation end products in atheroscleroric lesions of patients with end-stage renal disease" Atherosclerosis. 142. 67-77 (1999)
[Publications] Yoshiteru Jinnouchi et al.: "Glycolaldehyde-modified low density lipoprotein leads macrophages to foam cells via the macrophage scavenger receptor" J.Biochem.123. 1208-1217 (1998)
[Publications] Yoshida,S.et al.: "Immunohistochemical study of human advanced glycation end-products(AGE)and grewth factors in cardiac tissues of patients on maintenance dialysis and with kidney trasplantation" Clin.Nephrol.49. 273-280 (1998)
[Publications] Takemi Kimura et al.: "Localization of identified advanced glycation end product structures,N ε-(carboxymethyl)-lysine and pentosidine,in age-related inclusions in human brains" Pathol.Intenational.48. 575-579 (1998)
[Publications] Ken Matsuse et al.: "Immunohistochemical detection of advanced glycation end products in pulmonary fibrosis" J.Clin.Pathol.51. 515-519 (1998)
[Publications] Tatsuro Ishibashi et al.: "Nε-(Carboxymethyl)lysine accumulates in soft drusen and choroidal neovascular membranes" Arch.Opthalmol.116. 1629-1632 (1998)
[Publications] Noriyuki Sakata et al.: "Immunohistochemical localization of different epitopes of advanced glycation end products in human atherosclerotic lesions" Atherosclerosis. 141. 61-75 (1998)
[Publications] Ling,X.et al.: "Immunohistochemical distribution and subcellular localization of threee distinct specific molecular structures of advanced glycation end products in human tissues" Lab.Invest.78. 1591-1606 (1998)
[Publications] Masahiko Kushiro et al.: "Accumulation of N-episilon-(carboxymethyllysine)and changes in glomerular extracellular matrix components in Otsuka Long-Evans Tokushima fatty rat:a model of spontaneous NIDDM" Nehpron. 79. 458-468 (1998)

1998 Fiscal Year Annual Research Report

メイラード反応後期生成物(AGE)の構造と生物医学的意義に関する研究

Principal Investigator

堀内 正公 熊本大学, 医学部, 教授 (10117377)

Research Products

[Publications] Jing Meng et al.: "Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage" Atherosclerosis. 136. 355-365 (1998)

[Publications] Kazuyoshi Ikeda et al.: "Determination of glycated albumin by enzyme-linked boronate-immunoassay(ELBIA)" Clin.Chem.442. 256-263 (1998)

[Publications] Hideki Hakamata et al.: "Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of oxidized low density lipoprotein" J.Lipid Res.39. 482-494 (1998)

[Publications] Hirofumi Matsuda et al.: "Molecular cloning,functional expression,tissue distribution and activation by acetylated LDL in macrophages of rat acyl-coenzyme A:cholesterol acyltransferase" Biochem.Biophys.Acta.1391. 193-203 (1998)

[Publications] Yi Ding et al.: "Reduced expression of the macrophage scavenger receptors in macrophage-like cell mutants resistant to Brefeldin A." Biochem.Biophys.Res.Commun.243. 277-283 (1998)

[Publications] Hisashi Sakaguchi et al.: "Role of macrophage scanvenger receptors in fat-induced atherosclerosis in mice" Lab.Invest.78. 423-434 (1998)

[Publications] Ryoji Nagai et al.: "Conversion of Amadori product of Maillard reaction to N ε-(carboxymethyl)lysine in alkaline conditions" FEBS Letts.425. 355-360 (1998)

[Publications] Kazuyoshi Ikeda et al.: "Immunochemical approaches to AGE-structures:characterization of anti-AGE antibodies" J.Immunol.Methods. 215. 95-104 (1998)

[Publications] Hiroyuki Sano et al.: "Insulin enhances macrophage scavenger receptor-mediated endocytic uptake of advanced glycation end products" J.Biol.Chem.273. 8630-8637 (1998)

[Publications] Noriyuki Sakata et al.: "Increased advanced glycation end products in atheroscleroric lesions of patients with end-stage renal disease" Atherosclerosis. 142. 67-77 (1999)

[Publications] Yoshiteru Jinnouchi et al.: "Glycolaldehyde-modified low density lipoprotein leads macrophages to foam cells via the macrophage scavenger receptor" J.Biochem.123. 1208-1217 (1998)

[Publications] Yoshida,S.et al.: "Immunohistochemical study of human advanced glycation end-products(AGE)and grewth factors in cardiac tissues of patients on maintenance dialysis and with kidney trasplantation" Clin.Nephrol.49. 273-280 (1998)

[Publications] Takemi Kimura et al.: "Localization of identified advanced glycation end product structures,N ε-(carboxymethyl)-lysine and pentosidine,in age-related inclusions in human brains" Pathol.Intenational.48. 575-579 (1998)

[Publications] Ken Matsuse et al.: "Immunohistochemical detection of advanced glycation end products in pulmonary fibrosis" J.Clin.Pathol.51. 515-519 (1998)

[Publications] Tatsuro Ishibashi et al.: "Nε-(Carboxymethyl)lysine accumulates in soft drusen and choroidal neovascular membranes" Arch.Opthalmol.116. 1629-1632 (1998)

[Publications] Noriyuki Sakata et al.: "Immunohistochemical localization of different epitopes of advanced glycation end products in human atherosclerotic lesions" Atherosclerosis. 141. 61-75 (1998)

[Publications] Ling,X.et al.: "Immunohistochemical distribution and subcellular localization of threee distinct specific molecular structures of advanced glycation end products in human tissues" Lab.Invest.78. 1591-1606 (1998)

[Publications] Masahiko Kushiro et al.: "Accumulation of N-episilon-(carboxymethyllysine)and changes in glomerular extracellular matrix components in Otsuka Long-Evans Tokushima fatty rat:a model of spontaneous NIDDM" Nehpron. 79. 458-468 (1998)

堀内正公熊本大学, 医学部, 教授 (10117377)