1989 年度実績報告書

心筋細胞の損傷・修復過程とその修飾因子

研究課題

研究課題/領域番号	01624002
研究機関	京都大学
研究代表者	河合忠一京都大学, 医学部, 教授 (70025659)
研究分担者	芹澤剛東京大学, 医学部, 助手 (90143429) 鈴木紘一東京都臨床研, 遺伝情報研究部, 部長 (80011948) 水上茂樹九州大学, 医学部, 教授 (90037325) 高井義美神戸大学, 医学部, 教授 (60093514) 豊岡照彦東京大学, 保健センター, 講師 (00146151)
キーワード	心筋細胞 / イノシトールリン酸代謝 / GTP結合蛋白質 / 癌遺伝子 / カルシウム依存性プロテアーゼ / 心筋虚血 / イオンチャネル / 心筋症
研究概要	モルモット心筋細胞を用いて、心筋のNaチャンネルがカテコールアミンーAキナーゼ系の活性化によりリン酸化され、Na電流が抑制されることを明らかにした。好中球が粘着した心筋細胞において膜脂質過酸化反応を起こしその連鎖反応により産生されるフリーラジカルがさらに周囲の心筋細胞障害を来し、また、NADPH oxidaseのNADPH結合成分は好中球細胞質分画に存在し、無細胞系における活性化の過程で細胞膜分画へ移行すると考えられた。一方、選択的5ーリポキシゲナーゼ阻害薬AA861はロイコトリエンLTB4生成を抑制し、心筋梗塞巣の拡大を阻止した。ラットの心臓では、細胞障害を伴わないCaの過剰負荷があり得ることが明らかとなり、心筋細胞障害には心筋細胞の成熟による膜機能の変化を必要とすることが示唆された。また、血小板からセロトニンが放出される際Caイオンは関与せず、チオール性の蛋白分解酵素が活性化する。心筋虚血時の拡張期伸展性の障害に筋小胞体Caの取り込み、細胞膜Caポンプなどの細胞質Ca除去機構の低下の関与が明らかとなった。単一心筋細胞内におけるCa^<++>濃度の変動を1/300秒で記録出来る装置を作製することにより、はじめてCaトランジエントの細胞内伝播形式を促えることに成功した。ウシ大脳から新しい低分子量G蛋白質を分離、精製し、そのcDNAをクローニングしたが、そのうちsmg p21はAキナーゼによってリン酸化された。cANP遺伝子発現は、シスおよびトランス因子によって抑制されることが解り、またプロテインキナーゼCによっても制御されている可能性を示した。心筋細胞での脂肪酸結合蛋白の一次構造を検討することにより各組織での機能との関連を明らかにした。筋ジストロフィーモデルmdxマウスで骨格筋基底膜のコラーゲンIVに異常が認められた。心筋炎・心筋症の新しい診断法として抗ミオシンモノクローナル抗体シンチグラフィーの臨床的有用性を示した。

研究成果
(33件)

すべてその他

すべて文献書誌 (33件)

[文献書誌] Matsumori A: "Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis." Circulation. 79. 400-405 (1989)
[文献書誌] Matsumori A: "Immunopathology of cardiac disease.Immunomodulating theraphy in experimental myocarditis." Springer seminars in immunopathology. 11. 77-88 (1989)
[文献書誌] Morii N: "Increased synthesids and secretion of atrial natriuretic Polypeptide during viral myocarditis." J Cardiovasc Pharmacol. 13(sup 6). S5-S8 (1989)
[文献書誌] Matsumori A: "Viral myocarditis:Immunopathogenesis and the effect of immunosuppressive treatment in a murine model." Jpn Circ J. 53. 58-60 (1989)
[文献書誌] Takemura G: "Ventricular expression of atrial natriuretic polypeptide and its relations with hemodynamics and histology in dilated human hearts:Immunohistochemical study of the endomyocardial biopsy specimens." Circulation. 80. 1137-1147 (1989)
[文献書誌] Yamada T: "Pharmacokinetics of indiumー111ーIabeled antimyosin monoclonal antibody in murine experimetal viral myocarditis." J Am Coll Cardiol.
[文献書誌] Ono K: "Isoproternol,DBcAMP,and forskolin inhibit cardiac sodium current." Am J physiol. 256. C1131-C1137 (1989)
[文献書誌] Toyoーoka T: "Collagenーstimulated human platelet aggregations is mediated by endogenous calciumーactivated neutral protease." Circ Res. 64. 407-410 (1989)
[文献書誌] Ohmori T: "Small molecular weight GTPーbinding proteins in human platelet membranesーpurification and characterization of a novel GTPーbinding protein with a molecular weight of 22,000." J Biol Chem. 264. 1877-1881 (1989)
[文献書誌] Ueda T: "GTPase activating proteins for the smgー21 GTPーbinding protein having the same effector domain as the ras proteins in human platelets." Biochem Biophys Res Commun. 159. 1411-1419 (1989)
[文献書誌] Kikuchi A: "Puriffication and characterization from bovine brain cytosol of two GTPaseーactivating proteins cpeciffic for smg p21,a GTPーbinding protein having the same effector domain as cーras p21s." J Biol Chem.
[文献書誌] Kawata M: "Phoshorylation of smg p21,a ras p21ーlike GTPーbinding protein,by cyclic AMPーdependent protein kinase in a cellーfree system and in response to prostaglandin E_1 in intact human platelets." J Biol Chem.
[文献書誌] Tamaki N: "Indiumー111 antimyosin antibody imaging for detecting different stages of myocardial infarction:Comparison with technetiumー99m pyrophosphate imaging." J Nucl Med.
[文献書誌] Matsumori A: "Inー111 antimyosin antibody imaging:Imaging of myocardial infarction and myocarditis." Jpn Circ J.
[文献書誌] Matoba Y: "A case of biopsyーproven myocarditis progressing to autopsyーproven dilated cardiomyopathy." Clin Cardiol.
[文献書誌] Kiyosue T: "Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes." Circ Res. 64. 389-397 (1989)
[文献書誌] Nakamura S: "Glucose reverses 2,4ーdinitrophenol induced changes in action potentials and membrane currents of guinea pig ventricular cells via enhanced giycolysis." Cardiovasc Res. 23. 286-294 (1989)
[文献書誌] Ono K: "Effects of ANー132,a novel antiarrhythmic lidocaine analogue,and of lidocaine on membrane ionic currents of guineaーpig ventricular myocytes." NaunynーSchmiedeberg's Arch Pharmacol. 339. 221-229 (1989)
[文献書誌] Gotoh Y: "Purification and characterization of 20ーhydroxyーleukotriene B_4 dehydrogenase in human neutrophils." Eur J Biochem. 179. 315-321 (1989)
[文献書誌] Hata A: "Tandemly reiterated negative enhancerーlike elements regulate transcription of a human gene for the large subunit of calciumーdependent protease." J Biol Chem. 264. 6404-6411 (1989)
[文献書誌] Katori M: "Biphasic accumulation of leukocytes in rat cardiac infarct tissue caused by leukotriene B_4 and complement." Jpn J Pharmacol. 50. 234-238 (1989)
[文献書誌] Katori M: "A site of action of dexamethasone on leukocyte extravasation in microcirculation." Agents and Actions.
[文献書誌] Stemmer P: "Isolation and enrichment of Ca^<2+>ーtolerant myocytes for biochemical experiments from guineaーpig heart." Life Sci. 44. 1231-1237 (1989)
[文献書誌] Kimura T: "Rat heart fatty acidーbinding protein:Evidence that supports the amino acid sequence predicted from cDNA." Biochem J. 260. 303-306 (1989)
[文献書誌] Kanda T: "Purification and characterization of fatty acidーdinding protein from gastric mucosa of rats:Possible identity with heart FABP and its parietal cell locarization." Eur J Biochem.
[文献書誌] Watanabe M: "Immunohistochemical studies on the localization and ontogeny of heart fatty acid binding protein in the rat." Histochemistry.
[文献書誌] 松森昭: "^<111>In標識抗ミオシンモノクローナルによる心筋シンチグラフィーの臨床応用" 医学のあゆみ. 148. 277-278 (1989)
[文献書誌] 玉木長良: "^<111>In標識抗ミオシンモノクローナルーFabイメージングの臨床応用(第3報)^<99m>Tcーピロリン酸イメージングとの対比検討" 核医学. 26. 1199-1205 (1989)
[文献書誌] 山田武彦: "^<111>In標識抗ミオシンモノクローナルーFabイメージングの臨床応用(第4報)急性心筋梗塞における再潅流の影響" 核医学. 27. 133-137 (1990)
[文献書誌] Matsumori A: "Cardiomyopathy update 3.Morphological features and electric disturbances in experimental viral myocarditis." University of Tokyo Press.,
[文献書誌] Matsumori A: "Advances in cardiomyopathies.Experimental viral myocarditis;Immunopathogenetic aspects." SpringerーVerlag,
[文献書誌] Toyoーoka: "Muscle Energetics.In vivo ^<31>PーNMR spectroscopy of heart and identification of biochemical factors responsible for the contractility loss:" Alan Liss Publishing.,
[文献書誌] Serizawa T: "Cardiac Mechanics and Function in the Normal and Disease Heart.Slow relaxation was separated from increased myocardial stiffness in rabbits." SpringerーVerlag,

1989 年度 実績報告書

心筋細胞の損傷・修復過程とその修飾因子

研究代表者

河合 忠一 京都大学, 医学部, 教授 (70025659)

研究成果

[文献書誌] Matsumori A: "Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis." Circulation. 79. 400-405 (1989)

[文献書誌] Matsumori A: "Immunopathology of cardiac disease.Immunomodulating theraphy in experimental myocarditis." Springer seminars in immunopathology. 11. 77-88 (1989)

[文献書誌] Morii N: "Increased synthesids and secretion of atrial natriuretic Polypeptide during viral myocarditis." J Cardiovasc Pharmacol. 13(sup 6). S5-S8 (1989)

[文献書誌] Matsumori A: "Viral myocarditis:Immunopathogenesis and the effect of immunosuppressive treatment in a murine model." Jpn Circ J. 53. 58-60 (1989)

[文献書誌] Takemura G: "Ventricular expression of atrial natriuretic polypeptide and its relations with hemodynamics and histology in dilated human hearts:Immunohistochemical study of the endomyocardial biopsy specimens." Circulation. 80. 1137-1147 (1989)

[文献書誌] Yamada T: "Pharmacokinetics of indiumー111ーIabeled antimyosin monoclonal antibody in murine experimetal viral myocarditis." J Am Coll Cardiol.

[文献書誌] Ono K: "Isoproternol,DBcAMP,and forskolin inhibit cardiac sodium current." Am J physiol. 256. C1131-C1137 (1989)

[文献書誌] Toyoーoka T: "Collagenーstimulated human platelet aggregations is mediated by endogenous calciumーactivated neutral protease." Circ Res. 64. 407-410 (1989)

[文献書誌] Ohmori T: "Small molecular weight GTPーbinding proteins in human platelet membranesーpurification and characterization of a novel GTPーbinding protein with a molecular weight of 22,000." J Biol Chem. 264. 1877-1881 (1989)

[文献書誌] Ueda T: "GTPase activating proteins for the smgー21 GTPーbinding protein having the same effector domain as the ras proteins in human platelets." Biochem Biophys Res Commun. 159. 1411-1419 (1989)

[文献書誌] Kikuchi A: "Puriffication and characterization from bovine brain cytosol of two GTPaseーactivating proteins cpeciffic for smg p21,a GTPーbinding protein having the same effector domain as cーras p21s." J Biol Chem.

[文献書誌] Kawata M: "Phoshorylation of smg p21,a ras p21ーlike GTPーbinding protein,by cyclic AMPーdependent protein kinase in a cellーfree system and in response to prostaglandin E_1 in intact human platelets." J Biol Chem.

[文献書誌] Tamaki N: "Indiumー111 antimyosin antibody imaging for detecting different stages of myocardial infarction:Comparison with technetiumー99m pyrophosphate imaging." J Nucl Med.

[文献書誌] Matsumori A: "Inー111 antimyosin antibody imaging:Imaging of myocardial infarction and myocarditis." Jpn Circ J.

[文献書誌] Matoba Y: "A case of biopsyーproven myocarditis progressing to autopsyーproven dilated cardiomyopathy." Clin Cardiol.

[文献書誌] Kiyosue T: "Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes." Circ Res. 64. 389-397 (1989)

[文献書誌] Nakamura S: "Glucose reverses 2,4ーdinitrophenol induced changes in action potentials and membrane currents of guinea pig ventricular cells via enhanced giycolysis." Cardiovasc Res. 23. 286-294 (1989)

[文献書誌] Ono K: "Effects of ANー132,a novel antiarrhythmic lidocaine analogue,and of lidocaine on membrane ionic currents of guineaーpig ventricular myocytes." NaunynーSchmiedeberg's Arch Pharmacol. 339. 221-229 (1989)

[文献書誌] Gotoh Y: "Purification and characterization of 20ーhydroxyーleukotriene B_4 dehydrogenase in human neutrophils." Eur J Biochem. 179. 315-321 (1989)

[文献書誌] Hata A: "Tandemly reiterated negative enhancerーlike elements regulate transcription of a human gene for the large subunit of calciumーdependent protease." J Biol Chem. 264. 6404-6411 (1989)

[文献書誌] Katori M: "Biphasic accumulation of leukocytes in rat cardiac infarct tissue caused by leukotriene B_4 and complement." Jpn J Pharmacol. 50. 234-238 (1989)

[文献書誌] Katori M: "A site of action of dexamethasone on leukocyte extravasation in microcirculation." Agents and Actions.

[文献書誌] Stemmer P: "Isolation and enrichment of Ca^<2+>ーtolerant myocytes for biochemical experiments from guineaーpig heart." Life Sci. 44. 1231-1237 (1989)

[文献書誌] Kimura T: "Rat heart fatty acidーbinding protein:Evidence that supports the amino acid sequence predicted from cDNA." Biochem J. 260. 303-306 (1989)

[文献書誌] Kanda T: "Purification and characterization of fatty acidーdinding protein from gastric mucosa of rats:Possible identity with heart FABP and its parietal cell locarization." Eur J Biochem.

[文献書誌] Watanabe M: "Immunohistochemical studies on the localization and ontogeny of heart fatty acid binding protein in the rat." Histochemistry.

[文献書誌] 松森昭: "^<111>In標識抗ミオシンモノクローナルによる心筋シンチグラフィーの臨床応用" 医学のあゆみ. 148. 277-278 (1989)

[文献書誌] 玉木長良: "^<111>In標識抗ミオシンモノクローナルーFabイメージングの臨床応用(第3報)^<99m>Tcーピロリン酸イメージングとの対比検討" 核医学. 26. 1199-1205 (1989)

[文献書誌] 山田武彦: "^<111>In標識抗ミオシンモノクローナルーFabイメージングの臨床応用(第4報)急性心筋梗塞における再潅流の影響" 核医学. 27. 133-137 (1990)

[文献書誌] Matsumori A: "Cardiomyopathy update 3.Morphological features and electric disturbances in experimental viral myocarditis." University of Tokyo Press.,

[文献書誌] Matsumori A: "Advances in cardiomyopathies.Experimental viral myocarditis;Immunopathogenetic aspects." SpringerーVerlag,

[文献書誌] Toyoーoka: "Muscle Energetics.In vivo ^<31>PーNMR spectroscopy of heart and identification of biochemical factors responsible for the contractility loss:" Alan Liss Publishing.,

[文献書誌] Serizawa T: "Cardiac Mechanics and Function in the Normal and Disease Heart.Slow relaxation was separated from increased myocardial stiffness in rabbits." SpringerーVerlag,

1989 年度実績報告書

河合忠一京都大学, 医学部, 教授 (70025659)