Role of Macrophage Apoptosis in Atherosclerotic Plaque Rupture : Development of New Therapy

2008 Fiscal Year Final Research Report

• Project/Area Number: 19790532
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyushu University
• Principal Investigator: MATOBA Tetsuya Kyushu University, 大学病院・循環器内科, 循環器内科 (20448426)
• Project Period (FY): 2007 – 2008
• Keywords: 血管病態学 / 動脈硬化 / アポトーシス / ナノテクノロジー

Research Abstract

1.プラーク破綻モデルマウスの作成本研究において8週間の高脂肪食を負荷したApoE欠損マウスに4週間アンギオテンシンII持続負荷を行うことにより、腕頭動脈に高頻度の急性プラーク破綻(64%,n=11)およびburied fibrous cap(2.8±0.4/個体,n=11)生じるマウスモデルを作成した。
2.マクロファージ選択的ナノ粒子の作成マクロファージ選択的に治療因子を導入するため、径200nmのpoly(lactic-co-glycolicacid)(PLGA)ナノ粒子を作成した。FITCを封入したPLGAナノ粒子(FITC-NP)をマウスへ静脈注射したところ、1時間後の末梢血ではCD11b(+)Gr-1(-)の単球に選択的にFITCの取り込みを認めた。また、高脂肪食負荷を行ったApoE欠損マウスにFITC-NPを静脈注射したところ、腕頭動脈・動脈硬化巣内のマクロファージにFITC免疫染色を認め、PLGAナノ粒子が単球、マクロファージ選択的キャリアとなることが示された。
3.PPAR-γアゴニストであるピオグリタゾンは、マクロファージにおいてアポトーシスを誘導することが示されている(Thorp, Circulation 2007)。ピオグリタゾンをPLGAナノ粒子に封入し、上記プラーク破綻モデルマウスに対する静脈内投与を行ったところ、4週間後のプラーク破綻の減少を認めた。

Research Products

• [Journal Article] Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin into the Vascular Endothelium (2009)
  • Author(s): Kubo M, Egashira K, Inoue T, Koga J, Oda S, Chen L, Nakano K, Matoba T, Kawashima Y, Hara K, Tsujimoto H, Sueishi K, Tominaga R, Sunagawa K
  • Journal Title: Atheroscler Thromb Vasc Biol (in press)
  • Peer Reviewed
• [Journal Article] Formulation of nanoparticle-eluting stents by a cationic electrodeposit coating technology : Efficient and safe nano-drug delivery via bioabsorbable polymeric nanopartic e-eluting stents in porcine coronary arteries (2009)
  • Author(s): Nakano K, Egashira K, Masuda S, Funakoshi K, Zhao G, Kimura S, Matoba T, Sueishi K, Endo Y, Kawashima Y, Hara K, Tsujimoto H, Tominaga R, Sunagawa K
  • Journal Title: J Am Coll Cardiol : Cardiovascular Intervention 2(4) Pages: 277-283
  • Peer Reviewed
• [Journal Article] Essential Role of Angiotensin II Type 1a Receptors in the Host Vascular Wall, but Not the Bone Marrow, in the Pathogenesis of Angiotensin II-Induced (2009)
  • Author(s): Koga J, Egashira K, Matoba T, Kubo M, Ihara Y, Iwai M, Horiuchi M, Sunagawa K
  • Journal Title: Porcine Coronary Artery Model 31(9) Pages: 1791-1800
  • Peer Reviewed
• [Journal Article] ケモカインと動脈硬化 (2007)
  • Author(s): 的場哲哉、古賀純一郎、江頭健輔
  • Journal Title: 医学のあゆみ 223(13) Pages: 1205-1210
• [Journal Article] 海外文献紹介 (2007)
  • Author(s): 的場哲哉、江頭健輔
  • Journal Title: Angiology 7(1) Pages: 66-67
• [Presentation] Nanoparticle-Mediated Intracellular Delivery of Pitavastatin to Endothelial Progenitor Cells Ex Vivo Normalizes the Functional Activity for Therapeutic Neovascularization (2009)
  • Author(s): Kubo M, Egashira K, Oda S, Matoba T, Sunagawa K
  • Organizer: 第73回日本循環器学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-28
• [Presentation] Pitavastatin Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Stenosis, and Prevents Adverse Effects of Silorimus-Eluting Cypher Stent in Porcine Coronary Artery Model (2009)
  • Author(s): Tsukie N, Egashira K, Nakano K, Matoba T, Sunagawa K
  • Organizer: 第73回日本循環器学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-21
• [Presentation] Cholesterol-lowering therapy with the cholesterol absorption inhibitor ezetimibe inhibits plaque destabilization and rupture in the brachiocephalic arteries of ApoE-deficient mice (2009)
  • Author(s): Sato K, Egashira K, Katsuki S, Matoba T, Sunagawa K
  • Organizer: 第73回日本循環器学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-20
• [Presentation] Nanoparticle-mediated monocyte-selective transfection of dominant-negative monocyte chemoattractant protein-1 (MCP-1) mutant gene reduced plaque rupture in apoE-deficient mice (2008)
  • Author(s): Matoba T, Egashira K, Koga J, Hara K, Tsujimoto H, Sunagawa K
  • Organizer: 第15回日本血管生物医学会学術大会
  • Place of Presentation: 石川
  • Year and Date: 2008-12-03
• [Presentation] Mechanisms Underlying Coronary Vasopsasm at Distal Arterial Segments of Sirolimus-Eluting Stent Implantation in a Porcine Model、Scientific Sessions 2008 of the American Heart (2008)
  • Author(s): Matoba T, Egashira K, Masuda S, Iwata E, Miyagawa M, Nakano K, Tsukie N, Sunagawa K
  • Organizer: Association
  • Place of Presentation: Orlando
  • Year and Date: 2008-11-12
• [Presentation] Nanoparticle-based Monocyte-Selective Delivery of PPARY Agonist Pioglitazone Inhibits Plaque Rupture in ApoE-Deficient Mice (2008)
  • Author(s): Matoba T, Egashira K, Koga J, Hara K, Tsujimoto H, Sunagawa K
  • Organizer: Scientific Sessions 2008 of the American Heart Association
  • Place of Presentation: Orlando
  • Year and Date: 2008-11-11
• [Presentation] Nanoparticle-Mediated Monocyte-selective Transfection of Dominant-Negative Monocyte Chemoattractant Protein-1 (MCP-1) Gene Reduced Plaque Rupture in ApoE-Deficient Mice (2008)
  • Author(s): Koga J, Egashira K, Matoba T, Hara K, Tsujimoto H, Sunagawa K
  • Organizer: Scientific Sessions 2008 of the American Heart Association
  • Place of Presentation: Orlando
  • Year and Date: 2008-11-11
• [Presentation] Animal study muzzles macrophages to reduce role in plaque rupture (2008)
  • Author(s): Matoba T, Egashira K, Masuda S, Iwata E, Miyagawa M, Nakano K, Tsukie N, Sunagawa K
  • Organizer: AHA News Conference, Scientific Sessions 2008
  • Place of Presentation: Orlando
  • Year and Date: 2008-11-10
• [Presentation] Mechanisms Underlying Coronary Vasopsasm at Distal Arterial Segments of Sirolimus-Eluting Stent Implantation in a Porcine Model (2008)
  • Author(s): Matoba T, Egashira K, Masuda S,Iwata E, Miyagawa M, Nakano K, Tsukie N, Sunagawa K
  • Organizer: 第12回MolecularCardiovascular Conference
  • Place of Presentation: 北海道
  • Year and Date: 2008-09-06
• [Presentation] Monocyte-targeting Nanoparticle-based Delivery of Pioglitazone Inhibits Plaque Rupture in the Brachiocephalic Arteries of Apolipoprotein-E Deficient Mice (2008)
  • Author(s): Matoba T
  • Organizer: The 9th US-Japan-Asia Dialogue on Cardiovascular Diseases
  • Place of Presentation: 東京
  • Year and Date: 2008-08-23
• [Remarks]
  • URL: http://www.med.kyushu-u.ac.jp/cardiol/