1999 Fiscal Year Annual Research Report

遺伝子過剰発現マウスを用いたp38MAPキナーゼの心不全における役割の解明

Research Project

Project/Area Number	11307012
Research Category	Grant-in-Aid for Scientific Research (A)
Research Institution	Kyoto University
Principal Investigator	篠山重威京都大学, 大学院・医学研究科, 教授 (70109007)
Co-Investigator(Kenkyū-buntansha)	木原康樹京都大学, 大学院・医学研究科, 助手 (40214853) 松森昭京都大学, 大学院・医学研究科, 助教授 (70135573)
Keywords	心肥大 / 心不全 / サイトカイン / p38MAPK / MKK6 / トランスジェニック / マウス / PPAK
Research Abstract	【目的】これまでに我々は,心肥大・心不全においてサイトカインの果たす役割を検討してきた.心肥大・心不全の直接の引き金である物理的負荷はサイトカイン産生やp38MAPKなどの細胞内シグナル分子の活性化を誘導する. in vitroにおいては,p38MAPKが心筋細胞肥大・アポトーシス・サイトカイン産生に関わっていることがすでに報告されている.われわれの検討では,心肥大・心筋梗塞モデル動物においてもp38MAPKの活性化を認め,さらにその阻害薬を投与することにより病態の改善を認めた.そこで,p38MAPKの上流のMKK6のセリン/スレオニンをグルタミン酸に変換することによりconstitutively active form(MKK6E)を作製し,p38bとco-injectionすることによりdouble transgenic mouseの作製を試みた.プロモーターはいずれもCAGプロモーターを用いた.しかし,p38bを過剰発現するものはすべて胎生致死であり,MKK6Eの過剰発現マウスのみが得られた.驚くべきことに,MKK6E過剰発現マウスはまったく正常に発育し,体重の若干の増加以外はほどんど正常の表現型を呈した.そこでこのマウスに大動脈狭窄による心圧負荷および冠動脈結紮による心筋梗塞等の負荷を加えてその反応の違いを検討するとともに,体重増加について現在解析を続けている.さらに,PPAKについても現在過剰発現マウスを作製中である.

Research Products

(11 results)

All Other

All Publications (11 results)

[Publications] Furukawa Y.et al.: "Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries"Circ Res. 84. 306-314 (1999)
[Publications] Ono K.et al.: "Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1"Lab Invest. 79. 195-203 (1999)
[Publications] Okada M.et al.: "Hepatocyte growth factor is a major madiator in heparin-induced angiogenesis"Biochem Biophys Res Commun. 255. 80-87 (1999)
[Publications] Iwasaki A.et al.: "Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis"J Am Coll Cardiol. 33. 1400-1407 (1999)
[Publications] Matsumori A.et al.: "Apical hypertrophic cardiomyopathy and hepatitis C virus infection"Jpn Circ J. 63. 433-438 (1999)
[Publications] Hwang MW.et al.: "FTY720, a new immunosuppressant, promotes long-term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation"Circulation. 100. 1322-1329 (1999)
[Publications] Hara M.et al.: "Mast cells apoptosis of cardiomyocytes and proliferation of other intramyocardial cells in vivo"Circulation. 100. 1443-1449 (1999)
[Publications] Nishio R.et al.: "Treatment of experimental viral myocarditis with interleukin-10"Circulation. 100. 1102-1108 (1999)
[Publications] Ono K.et al.: "Contribution of endothelin-1 to myocardial injury in a murine model of myocarditis.Acute effects of bosentan, an endothelin receptor antagonist"Circulation. 100. 1823-1829 (1999)
[Publications] Furukawa Y.et al.: "Cytokine gene expression during the development of graft coronary artery disease in mice"Jpn Circ J. 63. 775-782 (1999)
[Publications] Matsumori A.et al.: "High doses of digitalis increase the myocardial production of proinflammatory cytokines and worsen myocardial injury in viral myocarditis: A possible mechanism of digitalis toxicity"Jpn Circ J. 63. 934-940 (1999)

1999 Fiscal Year Annual Research Report

遺伝子過剰発現マウスを用いたp38MAPキナーゼの心不全における役割の解明

Principal Investigator

篠山 重威 京都大学, 大学院・医学研究科, 教授 (70109007)

Research Products

[Publications] Furukawa Y.et al.: "Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries"Circ Res. 84. 306-314 (1999)

[Publications] Ono K.et al.: "Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1"Lab Invest. 79. 195-203 (1999)

[Publications] Okada M.et al.: "Hepatocyte growth factor is a major madiator in heparin-induced angiogenesis"Biochem Biophys Res Commun. 255. 80-87 (1999)

[Publications] Iwasaki A.et al.: "Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis"J Am Coll Cardiol. 33. 1400-1407 (1999)

[Publications] Matsumori A.et al.: "Apical hypertrophic cardiomyopathy and hepatitis C virus infection"Jpn Circ J. 63. 433-438 (1999)

[Publications] Hwang MW.et al.: "FTY720, a new immunosuppressant, promotes long-term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation"Circulation. 100. 1322-1329 (1999)

[Publications] Hara M.et al.: "Mast cells apoptosis of cardiomyocytes and proliferation of other intramyocardial cells in vivo"Circulation. 100. 1443-1449 (1999)

[Publications] Nishio R.et al.: "Treatment of experimental viral myocarditis with interleukin-10"Circulation. 100. 1102-1108 (1999)

[Publications] Ono K.et al.: "Contribution of endothelin-1 to myocardial injury in a murine model of myocarditis.Acute effects of bosentan, an endothelin receptor antagonist"Circulation. 100. 1823-1829 (1999)

[Publications] Furukawa Y.et al.: "Cytokine gene expression during the development of graft coronary artery disease in mice"Jpn Circ J. 63. 775-782 (1999)

[Publications] Matsumori A.et al.: "High doses of digitalis increase the myocardial production of proinflammatory cytokines and worsen myocardial injury in viral myocarditis: A possible mechanism of digitalis toxicity"Jpn Circ J. 63. 934-940 (1999)

篠山重威京都大学, 大学院・医学研究科, 教授 (70109007)