アンギオスタチンを介したニックβ_2グリコプロテインIの血管新生に与える影響

• Project/Area Number: 17689031
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Hokkaido University
• Principal Investigator: 保田 晋助 Hokkaido University, 大学院・医学研究科, 助教 (00374231)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥21,060,000 (Direct Cost: ¥16,200,000、Indirect Cost: ¥4,860,000); Fiscal Year 2007: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2006: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: β_2グリコプロテインI / アンギオスタチン / 血管新生 / β_2グリコプロティンI

Research Abstract

β_2-glycoproteinI(β_2GPI)は血漿中に高濃度存在し、凝固・線溶系や脂質代謝に関する様々な生理活性を持つリン脂質結合蛋白である。β_2GPIは、プラスミンにより限定分解を受け、β_2GPIのリン脂質結合性が失われる(ニックβ_2GPI)。ニックβ_2GPIはプラスミノゲンに結合し、その活性を抑制することが明らかとなっている。我々はプラスミノゲンから生体内でプロセスをうけて生ずる血管新生抑制物質であるアンジオスタチン(AG)に注目し、ニックβ_2GPIがAGとの相互作用を通して血管新生に与える影響を明らかにすることを目的とした。
BIACOREによる両者の結合試験を行った結果、インタクトβ_2GPIはAGとの結合を示さなかったのに対し、ニックβ_2GPIは解離定数3.05×10^<-7>で比較的強固な結合を示した。次にMatrigel Invasion chamberを用い、AG1-5とニックβ_2GPIおよびβ_2GPIの添加時のHUVEC遊走を比較した結果、AGはHUVECの遊走を阻害するが、これにニックβ_2GPIを共に添加したものでは有為に遊走細胞の増加が見られた。細胞増殖における作用においても、AGはHUVECの増殖を阻害するが、ニックβ_2GPIを加えることでAGの作用が有為に抑制された。実際の血管形成を見るTube Formation Assayでは、AGを添加したものでは管腔形成の阻害が明らかであった。ニックβ_2GPIのみの添加ではコントロールとほぼ同程度の管腔形成が見られたが、AGとニックβ_2GPIを共に添加したものではニックβ_2GPI濃度依存的に管腔の面積の拡大が認められた。
血管新生抑制効果を持つAGにニックβ_2GPIが結合することによって、その血管新生抑制作用を阻害し、結果的にAGが存在する環境では血管新生に働くことが考えられた。つまり、血栓部位で線溶系が活性化したとき、側副血行路の形成を促す作用を持つと考えられた。

Research Products

• [Journal Article] Thrombotic microangiopathy in patients with phosphatidylserine dependent antiprothrombin antibodies and antiphospholipid syndrome. (2008)
  • Author(s): Kon Y, Atsumi T, Hagiwara H, Furusaki A, Kataoka H, Horita T, Yasuda S, Amengual O, Koike T.
  • Journal Title: Clinical & Experimental Rheumatology 26 Pages: 129-132
  • Peer Reviewed
• [Journal Article] Defective expression of ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus. (2007)
  • Author(s): Yasuda S, Stevens RL, Terada T, Takeda M, Hashimoto T, Fukae J, Horita T, Kataoka H, Atsumi T, and Koike T.
  • Journal Title: Journal of Immunology 179 Pages: 4890-4900
  • Peer Reviewed
• [Journal Article] Polymorphism in the Human Platelet Antigen 6b represents a risk factor for thrombocytopenia in patients with systemic lupus erythematosus. (2007)
  • Author(s): Amengual O, Atsumi T, Komano Y, Kataoka H, Horita T, Yasuda S, Koike T.
  • Journal Title: Arthritis and Rheumatism 56 Pages: 2803-2805
  • Peer Reviewed
• [Journal Article] Human monoclonal antibodies against the complex of phosphatidylserine and prothrombin from patients with antiphospholipid antibodies. (2007)
  • Author(s): Horita T, Ichikawa K, Kataoka H, Yasuda S, Atsumi T, Koike T.
  • Journal Title: Lupus 16 Pages: 509-516
  • Peer Reviewed
• [Journal Article] Polymyalgia rheumatica as the manifestation of unclassified aortitis. (2007)
  • Author(s): Kataoka H, Atsumi T, Hashimoto T, Horita T, Yasuda S, Koike T
  • Journal Title: Modern Rheumatology 18 Pages: 105-108
  • NAID: 10024149993
  • Peer Reviewed
• [Journal Article] ニックβ_2-グリコプロテインの構造と機能 (2007)
  • Author(s): 保田晋助
  • Journal Title: 分子リウマチ 4 Pages: 68-71
• [Journal Article] シェーグレン症候群のB細胞における転写因子E2A・Id3の発現異常 (2007)
  • Author(s): 中川靖子, 片岡浩, 保田晋助, 深江淳, 堀田哲也, 渥美達也, 柏崎晴彦, 小池隆夫, 井上農夫男
  • Journal Title: 北海道歯学雑誌 28 Pages: 27-35
  • NAID: 10019548529
  • Peer Reviewed
• [Journal Article] A Polymorphism in the Human Platelet Antigen 6b represents a risk factor for thrombocytopenia in patients with systemic lupus erythematosus. (2007)
  • Author(s): Amengual O, Atsumi T, Komano Y, Kataoka H, Horita T, Yasuda S, Koike T
  • Journal Title: Arthritis and rheumatism (In press)
• [Journal Article] Human monoclonal antibodies against the complex of phosphatidylserine and prothrombin from patients with antiphospholipid antibodies. (2007)
  • Author(s): Horita T, Ichikawa K, Kataoka H, Yasuda S, Atsumi T, Koike T
  • Journal Title: Lupus (In press)
• [Journal Article] ニックβ_2-グリコプロテインの構造と機能 (2007)
  • Author(s): 保田晋助
  • Journal Title: 分子リウマチ 4(1) Pages: 68-71
• [Journal Article] Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis : a pilot study. (2006)
  • Author(s): Furukawa S, Yasuda S, Amengual O, Horita T, Atsumi T, Koike T
  • Journal Title: Annals of Rheumatic Diseases 65(8) Pages: 1118-1120
• [Journal Article] 抗リン脂質抗体症候群における最近の進歩 (2006)
  • Author(s): 保田晋助, 小池隆夫
  • Journal Title: 分子リウマチ 3(1) Pages: 46-54
• [Journal Article] 抗リン脂質抗体の病原性解明へ (2006)
  • Author(s): 保田晋助, 小池隆夫
  • Journal Title: 日本臨床免疫学会雑誌 29(5) Pages: 311-318
  • NAID: 10019269275
• [Journal Article] Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis; a pilot study・ (2006)
  • Author(s): Furukawa S, Yasuda S, Amengual O, Horita T, Atsumi T, Koike T
  • Journal Title: Annals of Rheumatic Diseases (In press)
• [Journal Article] Urokinase-type plasminogen activator is a preferred substrate of the human epithelium serine protease tryptase ε/PRSS22. (2005)
  • Author(s): Yasuda S, Morokawa N, Wong GW, Rossi A, Madhusudhan MS, Sali A, Askew YS, Adachi R, Silverman GA, Krilis SA, Stevens RL.
  • Journal Title: Blood 105(10) Pages: 3893-3901
• [Journal Article] Butyrate suppresses tumor necrosis factor alpha production by regulating specific messenger RNA degradation mediated through a cis-acting AU-rich element. (2005)
  • Author(s): Fukae J, Amasaki Y, Yamashita Y, Bohgaki T, Yasuda S, Jodo S, Atsumi T, Koike T
  • Journal Title: Arthritis and Rheumatism 52・9 Pages: 2697-2707
• [Journal Article] Research around β_2-glycoprotein I: A major target for antiphospholipid antibodies. (2005)
  • Author(s): Atsumi T, Amengual O, Yasuda S, Masuura E, Koike T
  • Journal Title: Autoimmunity 38・5 Pages: 377-381
• [Journal Article] Antigenic structures recognized by anti-β_2-glycoprotein I auto-antibodies. (2005)
  • Author(s): Kasahara H, Matsuura E, Kaihara K, Yamamoto D, Kobayashi K, Inagaki J, Ichikawa K, Tsutsumi A, Yasuda S, Atsumi T, Yasuda T, Koike T
  • Journal Title: International Immunology 17・12 Pages: 1533-1542
• [Journal Article] Pathogenesis of antiphospholipid antibodies: impairment of fibrinolysis and monocyte activation via the p38 mitogen-activated protein kinase pathway. (2005)
  • Author(s): Yasuda S, Bohgaki M, Atsumi T, Koike T
  • Journal Title: Immunobiology 210・10 Pages: 775-780
  • NAID: 120000959527
• [Presentation] Defective expression of Ras Guanine Nucleotide Releasing Protein 1 in a subset of patients with systemic lupus erythematosus. (2007)
  • Author(s): Yasuda S, Stevens RL, Terada T, Horita T, Kataoka H, Fukae J, Hashimoto T, Atsumi T, Koike T
  • Organizer: American College of Rheumatology
  • Place of Presentation: Boston Convention Center, Boston, U.S.A.
• [Presentation] Altered expression of RasGRP4 in a Subset of Patients with Rheumatoid Arthritis. (2007)
  • Author(s): Hashimoto T, Yasuda S, Kataoka H, Horita T, Atsumi T, Stevens R, Koike T.
  • Organizer: The Annual European Congress of Rheumatology
  • Place of Presentation: CCIB, Barcelona, Spain
• [Presentation] Hemophagocytic syndrome in systemic lupus erythematosus. (2007)
  • Author(s): Fukaya S, Yasuda S, Kataoka H, Horita T, Atsumi T, Koike T.
  • Organizer: The 8th International Congress on SLE
  • Place of Presentation: Shanghai International Convention Center, Shanghai, China
• [Presentation] Phosphatidylserine dependent antiprothrombin antibody induces p38 mitogen-activated protein kinase (MAPK) phosphorylation leading to tissue fact or expression activated protein kinase (MAPK) phosphorylation leading to tissue factor expression. (2007)
  • Author(s): Oku K, Atsumi T, Amengual O, Sakai Y, Kataoka H, Horita T, Yasuda S, Koike T
  • Organizer: 12th International Congress on Antiphospholipid antibodies
  • Place of Presentation: Palazzo dei Congressi, Florence, Italy
• [Book] よくわかる関節リウマチのすべて (2008)
  • Author(s): 保田晋助, 小池隆夫
  • Publisher: 永井書店(In press)
• [Book] 「関節痛」、症候から迫る内科診療・典型例と非典型例によるアプローチ (2007)
  • Author(s): 深江 淳, 保田晋助, 小池隆夫
  • Total Pages: 10
  • Publisher: 中外医学社
• [Book] Hughes Syndrome (Khamashta MA, editor) (Antiphospholipid syndrome 2^<nd> edition) (2006)
  • Author(s): Yasuda S, Atsumi T, Koike T
  • Total Pages: 598
  • Publisher: Springer
• [Book] β_2-glycoprotein I and Anti-β_2-glycoprotein I antibodies In: Khamashta MA, editor. Hughes Syndrome. (2006)
  • Author(s): Yasuda S, Atsumi T, Koike T
  • Publisher: Springer
• [Remarks]
  • URL: http://www.med.hokudai.ac.jp/~med-2w/