A study of role of phospholipase A2 in pathogenosis of cardiovascular diseases and development of new drug for cardiovascular diseases

• Project/Area Number: 19390209
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: University of Yamanashi
• Principal Investigator: KUGIYAMA Kiyotaka University of Yamanashi, 大学院・医学工学総合研究部, 教授 (00225129)
• Co-Investigator(Kenkyū-buntansha): KAWABATA Kenichi 山梨大学, 医学部附属病院, 講師 (30345706) ; SAITO Yukio 山梨大学, 大学院・医学工学総合研究部, 助教 (50377511) ; KOBAYASHI Tsuyoshi 山梨大学, 医学部附属病院, 医員 (40402052) ; TEZUKA Hideo 山梨大学, 総合分析実験センター, 准教授 (70155456) ; FUJIOKA Daisuke 山梨大学, 医学部附属病院, 医員 (70377513)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2008: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2007: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: 心筋梗塞 / 心血管病 / ノックアウトマウス / 分泌型ホスホリパーゼA / 炎症 / 脂質メディエーター / 好中球

Research Abstract

ホスホリパーゼA_2(PLA_2)を介して産生されるアラキドン酸カスケード関連脂質は心血管病の発症・病態に深く関与していることが示唆されている。本研究では、secretory PLA_2の心血管病への関与を網羅的に解明し、PLA_2を標的とする有用な心血管病予防・治療薬を開発することを目的とした。その結果、X型およびV型secretory PLA_2が心筋梗塞発生の病態に関与することが判明した。さらにsecretory PLA_2活性阻害剤が心不全を予防することを明らかにした。

Research Products

• [Journal Article] Inhibition of secretory hospholipase A2 activity attenuates lipopolysaccharide-induced acute lung injury in a mouse model. (2010)
  • Author(s): Sato R, Yamaga S, Watanabe K, Hishiyama S, Kawabata K, Kobayashi T, Fujioka D, Saito Y, Yano T, Watanabe K, Watanabe Y, Ishihara H, Kugiyama K.
  • Journal Title: Exp Lung Res. 36,4 Pages: 191-200
  • Peer Reviewed
• [Journal Article] Mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia-reperfusion injury. (2010)
  • Author(s): Kobayashi T, Watanabe Y, Saito Y, Fujioka D, Nakamura T, Obata JE, Kitta Y, Yano T, Kawabata K, Watanabe K, Mishina H, Ito S, Kugiyama K.
  • Journal Title: Cardiovasc Res. 85,4 Pages: 785-95
  • Peer Reviewed
• [Journal Article] Mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia-reperfusion injury. (2010)
  • Author(s): Kobayashi T.
  • Journal Title: Cardiovasc Res 35 Pages: 785-95
  • Peer Reviewed
• [Journal Article] Novel insights of secretory phospholipase a(2) action in cardiology. (2009)
  • Author(s): Fujioka D, Kugiyama K.
  • Journal Title: Trends Cardiovasc Med. 19,3 Pages: 100-3
  • Peer Reviewed
• [Journal Article] Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. (2009)
  • Author(s): Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, Saito Y, Kawabata K, Sano K, Kobayashi T, Yano T, Nakamura K, Kugiyama K.
  • Journal Title: J Am Coll Cardiol. 53,4 Pages: 323-30
  • Peer Reviewed
• [Journal Article] Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome. (2009)
  • Author(s): Hirano M, Nakamura T, Kitta Y, Yano T, Kobayashi T, Sano K, Fujioka D, Saito Y, Kodama Y, Kawabata K, Nakamura K, Obata JE, Kugiyama K.
  • Journal Title: Atherosclerosis. 203,2 Pages: 483-8
  • Peer Reviewed
• [Journal Article] High serum levels of remnant lipoproteins predict ischemic stroke in patients with metabolic syndrome and mild carotid atherosclerosis. (2009)
  • Author(s): Nakamura T, Obata JE, Takano H, Kawabata K, Sano K, Kobayashi T, Fujioka D, Saito Y, Yano T, Kugiyama K.
  • Journal Title: Atherosclerosis. 202,1 Pages: 234-40
  • Peer Reviewed
• [Journal Article] Treatment of acute myocardial infarction with sirolimus-eluting stents results in chronic endothelial dysfunction in the infarct-related coronary artery. (2009)
  • Author(s): Obata JE.
  • Journal Title: Circ Cardiovasc Interv 2 Pages: 384-91
  • Peer Reviewed
• [Journal Article] Novel insights of secretory phospholipase a (2) action in cardiology. (2009)
  • Author(s): Fujioka D.
  • Journal Title: Trends Cardiovasc 19 Pages: 100-3
  • Peer Reviewed
• [Journal Article] Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. (2009)
  • Author(s): Kitta Y, Kugiyama K, et al.
  • Journal Title: J Am Coll Cardiol 53(4) Pages: 323-30
  • Peer Reviewed
• [Journal Article] Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice. (2008)
  • Author(s): Fujioka D, Saito Y, Kobayashi T, Yano T, Tezuka H, Ishimoto Y, Suzuki N, Yokota Y, Nakamura T, Obata JE, Kanazawa M, Kawabata K, Hanasaki K, Kugiyama K.
  • Journal Title: Circulation. 117,23 Pages: 2977-85
  • Peer Reviewed
• [Journal Article] Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice. (2008)
  • Author(s): Fujioka D, Kugiyama K, et al.
  • Journal Title: Circulation 117(23) Pages: 2977-85
  • Peer Reviewed
• [Journal Article] Measurement of the platelet retention rate in a column of collagen-coated beadsis useful for the assessment of efficacy of antiplatelet therapy. (2008)
  • Author(s): Mende A, Kugiyama K, et al
  • Journal Title: Thromb Res 123(6) Pages: 856-61
  • Peer Reviewed
• [Journal Article] Reduction in myocardial ischemia-reperfusion injury in group X secretory phospholipase A_2-deficient mice (2008)
  • Author(s): Fujioka D, Kugiyama K, et. al.
  • Journal Title: Ciruclation (In press)
  • Peer Reviewed
• [Journal Article] Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute myocardial infarction. (2007)
  • Author(s): Obata JE, Kitta Y, Takano H, Kodama Y, Nakamura T, Mende A, Kawabata K, Saitoh Y, Fujioka D, Kobayashi T, Yano T, Kugiyama K.
  • Journal Title: J Am Coll Cardiol. 50,14 Pages: 1305-9
  • Peer Reviewed
• [Journal Article] Statin reverses reduction of adiponectin receptor expression in infarcted heart and in TNFα-treated cardiomyocytes in association with improved glucose uptake. (2007)
  • Author(s): Saito Y, Kugiyama K, et. al.
  • Journal Title: Am J Physiol Heart Circ Physiol. 293(6)
  • Peer Reviewed
• [Journal Article] Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute myocardial infarction. (2007)
  • Author(s): Obata J, Kugiyama K, et. al.
  • Journal Title: J Am Coll Cardiol. 50(14) Pages: 1305-9
  • Peer Reviewed
• [Presentation] Reduction in Myocardial Ischemia-reperfusion Injury in Group V Secretory Phospholipase A2-deficient Mice. (2009)
  • Author(s): Toshiaki Yano; Keni-chi Kawabata; Yukio Saito; Tsuyoshi Kobayashi; Ryota Sato; Kazuhiro Watanabe; Yosuke Watanabe; Hideto Mishina; Jun-ei Obata; Kiyotaka Kugiyama
  • Organizer: American Heart Association Scientific Sessions.
  • Place of Presentation: Orlando.
• [Presentation] Reduction in Myocardial Ischemia-reperfusion Injury in Group IV Cytosolic Phospholipase A2-deficient Mice Partly Due to Inhibition of TNFα-mediated Pathway to Cell Injury. (2009)
  • Author(s): Yukio Saito; Yousuke Watanabe; Hideto Mishina; Kazuhiro Watanabe; Toshiaki Yano; Tsuyoshi Kobayashi; Jun-ei Obata; Ken-ichi Kawabata; Takao Shimizu; Kiyotaka Kugiyama
  • Organizer: American Heart Association Scientific Sessions.
  • Place of Presentation: Orlando.
• [Presentation] Inhibition of Secretory Phospholipase A2 Activity Attenuates Acute Cardiogenic Pulmonary Congestion Induced by Isoproterenol Infusion in Mice with Post-Myocardial Infarction. (2008)
  • Author(s): Kenichi Kawabata, Tsuyoshi Kobayashi, Yousuke Watanabe, Kazuhiro Watanabe, Toshiaki Yano, Ryota Sato, Yukio Saito, Kazuto Nakamura, Kiyotaka Kugiyama
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans
• [Presentation] Group X Secretory Phospholipase A2 has a Critical Role in Neutrophils Activation and Myocardial Ischemia-reperfusion Injury in Mice. (2007)
  • Author(s): Daisuke Fujioka, Kenichi Kawabata, Yoshikazu Ishimoto, Noriko Suzuki, Kohji Hansaki, Ryota Sato, Toshiaki Yano, Tsuyoshi Kobayashi, Yukio Saito, Masaki Kanazawa, Kiyotaka Kugiyama
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Orlando