2000 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 Institution	KYOTO UNIVERSITY
Principal Investigator	篠山重威京都大学, 医学研究科, 教授 (70109007)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	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
Research Abstract	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。

Research Products

(19 results)

All Other

All Publications (19 results)

[Publications] 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)
[Publications] Matsumori A, et al.: "Hepatitis C virus and cardiomyopathy."Herz. 25. 249-254 (2000)
[Publications] 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)
[Publications] Matsumori A, et al.: "Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy."Lab Invest. 80. 1137-1142 (2000)
[Publications] Naruse TK, et al.: "HLA-DQB1^*0601 is primarily associated with the susceptibility to cardiac sarcoidosis."Tissue Antigens. 56. 52-57 (2000)
[Publications] Nakamura K, et al.: "Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction."Jpn Circ J. 64. 623-626 (2000)
[Publications] Matsumori A, et al.: "Hypertrophic cardiomyopathy as a manifestation of cardiac sarcoidosis."Jpn Circ J. 64. 679-683 (2000)
[Publications] 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)
[Publications] 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)
[Publications] Matsumori A, et al.: "Nifedipine inhibits of transcription factor NF-κB."Life Sci. 67. 2655-2561 (2000)
[Publications] Tadamura E, et al.: "Significant regional heterogeneity of coronary flow reserve in paediatric hypertrophic cardiomyopathy."Eur J Nucl Med. 27. 1340-1348 (2000)
[Publications] 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)
[Publications] 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)
[Publications] Nishimura H, et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 391-322 (2001)
[Publications] 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)
[Publications] 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)
[Publications] Matsumori A.: "Insights into the pathophysiology of heart failure based on a new concept."Asian Medical Journal. 44. 36-41 (2001)
[Publications] 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)
[Publications] 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 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, 医学研究科, 教授 (70109007)

Research Products

[Publications] 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)

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

[Publications] 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)

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

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

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

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

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

篠山重威京都大学, 医学研究科, 教授 (70109007)