2000 年度実績報告書

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

研究課題

研究課題/領域番号	11307012
研究機関	京都大学
研究代表者	篠山重威京都大学, 医学研究科, 教授 (70109007)
研究分担者	木原康樹京都大学, 医学研究科, 助手 (40214853) 松森昭京都大学, 医学研究科, 助教授 (70135573)
キーワード	心不全 / サイトカイン / p38MAPK / MKK6 / アポトーシス / 酸化ストレス / 心肥大 / 心筋梗塞
研究概要	我々はこれまでに、心筋炎・心肥大・心筋梗塞モデルにおける心筋傷害の機序として、サイトカインの関与について検討を重ねてきた。これらの検討から導かれる一つの結論として、心筋傷害の原因の如何に関わらず不全心の発症・進展にサイトカインが関与している可能性が示された。ストレス応答性MAPKカスケードはサイトカイン調節に関与する重要なシグナルの一つであり、中でもp38MAPKは心筋細胞においては肥大・アポトーシス・酸化ストレスに深く関与している可能性が示唆されている。肥大刺激・酸化ストレスなどにより他のMAPKとともにp38の活性が亢進することがすでに示されている。そこで、本研究ではp38MAPKを中心としたカスケードの機能をトランスジェニックマウスを用いて検討した。CAGプロモーターによるp38MAPKの過剰発現マウスは耐性致死であった。そこで、p38の上流のMAPKKであるMKK6の活性型(MKK6EE)を用いて過剰発現マウスを作成したところ、1系統のみが得られた。しかしこれもmRNAレベルでの発現はみとめたものの蛋白レベルでの発現や活性はまったく検出されなかった。さらにこのマウスに大動脈狭窄による心圧負荷モデル、および冠動脈結紮による心筋梗塞モデルを作成したが、同腹対照群にくらべて心筋肥大や心筋傷害の程度に差はなかった。これらのことから、MKK6-p38シグナルの発生段階における役割が示唆された。

研究成果

(19件)

すべてその他

すべて文献書誌 (19件)

[文献書誌] Matsumori A, et al.: "Amlodipine inhibits the production of cytokine induced by ouabain. Amlodipine inhibits the production of cytokine induced by ouabain."Cytokine. 12. 294-297 (2000)
[文献書誌] Matsumori A, et al.: "Hepatitis C virus and cardiomyopathy."Herz. 25. 249-254 (2000)
[文献書誌] Kakio T, et al.: "Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart."Lab Invest. 80. 1121-1126 (2000)
[文献書誌] Matsumori A, et al.: "Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy."Lab Invest. 80. 1137-1142 (2000)
[文献書誌] Naruse TK, et al.: "HLA-DQB1^*0601 is primarily associated with the susceptibility to cardiac sarcoidosis."Tissue Antigens. 56. 52-57 (2000)
[文献書誌] Nakamura K, et al.: "Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction."Jpn Circ J. 64. 623-626 (2000)
[文献書誌] Matsumori A, et al.: "Hypertrophic cardiomyopathy as a manifestation of cardiac sarcoidosis."Jpn Circ J. 64. 679-683 (2000)
[文献書誌] Matsumori A, et al.: "Circulating hepatocyte growth factor as a marker of thrombus formation in unstable angina pectoris."Jpn Circ J. 64. 805-807 (2000)
[文献書誌] Matsumori A, et al.: "Pimobendan inhibits the activation of transcription factor NF-κB. A mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase."Life Sci. 67. 2513-2519 (2000)
[文献書誌] Matsumori A, et al.: "Nifedipine inhibits of transcription factor NF-κB."Life Sci. 67. 2655-2561 (2000)
[文献書誌] Tadamura E, et al.: "Significant regional heterogeneity of coronary flow reserve in paediatric hypertrophic cardiomyopathy."Eur J Nucl Med. 27. 1340-1348 (2000)
[文献書誌] Arimura T, et al.: "Characterization of human nebulette gene : A polymorphism in an actin-binding morif is associated with non-familial dilated cardiomyopathy."Human Genetics. 107. 440-451 (2000)
[文献書誌] Ohashi N, et al.: "Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury."Arterioscler Thromb Vasc Biol. 20. 2521-2526 (2000)
[文献書誌] Nishimura H, et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 391-322 (2001)
[文献書誌] Matsumori A.: "The role of inflammatory mediators in the failing heart : Immunomodulation of cytokines in experimental models of heart failure."Heart Failure Reviews. 6. 129-136 (2001)
[文献書誌] Sato Y, et al.: "Persistently increased serum concentrations of cardiac troponin T in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes."Circulation. 103. 369-374 (2001)
[文献書誌] Matsumori A.: "Insights into the pathophysiology of heart failure based on a new concept."Asian Medical Journal. 44. 36-41 (2001)
[文献書誌] Matsumori A.: "1.3 Cytokines and heart failure : Pathophysiological roles and therapeutic implications."Heart Failure Frontiers in Cardiology ed. by A. Kitabatake, S. Sasayama, G. S. Francis, Springer. 11 (2000)
[文献書誌] Matsumori A.: "Hepatitis C virus infection in hypertrophic or dilated cardiomyopathy"The Hypertrophied heart N. Takeda, M. Nagano and N. S. Dhalla (eds). Kluwer Academic. 9 (2000)

2000 年度 実績報告書

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

研究代表者

篠山 重威 京都大学, 医学研究科, 教授 (70109007)

研究成果

[文献書誌] Matsumori A, et al.: "Amlodipine inhibits the production of cytokine induced by ouabain. Amlodipine inhibits the production of cytokine induced by ouabain."Cytokine. 12. 294-297 (2000)

[文献書誌] Matsumori A, et al.: "Hepatitis C virus and cardiomyopathy."Herz. 25. 249-254 (2000)

[文献書誌] Kakio T, et al.: "Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart."Lab Invest. 80. 1121-1126 (2000)

[文献書誌] Matsumori A, et al.: "Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy."Lab Invest. 80. 1137-1142 (2000)

[文献書誌] Naruse TK, et al.: "HLA-DQB1^*0601 is primarily associated with the susceptibility to cardiac sarcoidosis."Tissue Antigens. 56. 52-57 (2000)

[文献書誌] Nakamura K, et al.: "Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction."Jpn Circ J. 64. 623-626 (2000)

[文献書誌] Matsumori A, et al.: "Hypertrophic cardiomyopathy as a manifestation of cardiac sarcoidosis."Jpn Circ J. 64. 679-683 (2000)

[文献書誌] Matsumori A, et al.: "Circulating hepatocyte growth factor as a marker of thrombus formation in unstable angina pectoris."Jpn Circ J. 64. 805-807 (2000)

[文献書誌] Matsumori A, et al.: "Pimobendan inhibits the activation of transcription factor NF-κB. A mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase."Life Sci. 67. 2513-2519 (2000)

[文献書誌] Matsumori A, et al.: "Nifedipine inhibits of transcription factor NF-κB."Life Sci. 67. 2655-2561 (2000)

[文献書誌] Tadamura E, et al.: "Significant regional heterogeneity of coronary flow reserve in paediatric hypertrophic cardiomyopathy."Eur J Nucl Med. 27. 1340-1348 (2000)

[文献書誌] Arimura T, et al.: "Characterization of human nebulette gene : A polymorphism in an actin-binding morif is associated with non-familial dilated cardiomyopathy."Human Genetics. 107. 440-451 (2000)

[文献書誌] Ohashi N, et al.: "Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury."Arterioscler Thromb Vasc Biol. 20. 2521-2526 (2000)

[文献書誌] Nishimura H, et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 391-322 (2001)

[文献書誌] Matsumori A.: "The role of inflammatory mediators in the failing heart : Immunomodulation of cytokines in experimental models of heart failure."Heart Failure Reviews. 6. 129-136 (2001)

[文献書誌] Sato Y, et al.: "Persistently increased serum concentrations of cardiac troponin T in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes."Circulation. 103. 369-374 (2001)

[文献書誌] Matsumori A.: "Insights into the pathophysiology of heart failure based on a new concept."Asian Medical Journal. 44. 36-41 (2001)

[文献書誌] Matsumori A.: "1.3 Cytokines and heart failure : Pathophysiological roles and therapeutic implications."Heart Failure Frontiers in Cardiology ed. by A. Kitabatake, S. Sasayama, G. S. Francis, Springer. 11 (2000)

[文献書誌] Matsumori A.: "Hepatitis C virus infection in hypertrophic or dilated cardiomyopathy"The Hypertrophied heart N. Takeda, M. Nagano and N. S. Dhalla (eds). Kluwer Academic. 9 (2000)

2000 年度実績報告書

篠山重威京都大学, 医学研究科, 教授 (70109007)