c-Jun NH_2 terminal kinaseの抑制による心不全治療の試み

• Project/Area Number: 13770356
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka City University
• Principal Investigator: 大村 崇 大阪市立大学, 大学院・医学研究科, 助手 (70295707)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥2,400,000 (Direct Cost: ¥2,400,000); Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: 心筋梗塞 / 心臓リモデリング / MAPK / JNK / AP-1 / アンジオテンシン / 心不全 / 心筋肥大 / c-Jun / 遺伝子導入 / dominant negative mutant / activator protein-1

Research Abstract

細胞内情報伝達系のmitogen-activated protein kinase(MAPK)はERK、JNK、p38MAPKがあり、細胞増殖因子、サイトカイン、機械的刺激などで活性化され、細胞の肥大、増殖、分化、アポトーシス、遺伝子発現制御などに関係する。我々の検討では、ラットの心筋梗塞の心筋MAPKは、ERK、JNK、p38MAPKのすべてが、梗塞部位と非梗塞部位の両方で活性亢進が認められた。この結果より心筋でのMAPKの活性化が心筋梗塞後心臓リモデリングに関与していると考えられた。さらに、JNKの下流に位置するc-Junのdominant negative mutantをアデノウイルスベクターをもちいて培養心筋細胞に遺伝子導入し、シグナルを抑制することによりエンドセリンやフェニレフリンによる心筋肥大を検討した。その結果、c-Junのdominant negative mutantは転写因子activator protein-1(AP-1)の活性化を抑制し、さらにcell sizeの増大、タンパク合成促進、ANP、BNPのmRNA発現亢進を抑制した。このことより、JNKの下流のc-Junを抑制することで、AP-1の転写活性を阻害し、生体でも心筋細胞肥大を抑制できる可能性があることが判明した。又、ACE阻害薬、アンギオテンシンI型受容体拮抗薬はJNK、AP-1の活性を阻害し心筋梗塞後心臓リモデリングの抑制に関与していると考えられた。

Research Products

• [Publications] Nakamura Y, Yoshiyama M, Omura T, Yoshida K, Izumi Y, Takeuchi K, Kim S, Iwao H, Yoshikawa J.: "Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction"Cardiovascular Research. 57. 48 (2003)
• [Publications] Omura T, Yoshiyama M, Yoshida, K, Nakamura Y, Kim S, Iwao H, Takeuchi K, Yoshikawa J.: "Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine"Hypertension. 39. 81 (2002)
• [Publications] Nakamura Y, Yoshiyama M, Omura T, Yoshida K, Kim S, Takeuchi K, Iwao H, Yoshikawa J.: "Transmitral inflow pattern assessed by Doppler echocardiography in angiotensin II type 1A receptor knockout mice with myocardial infarction"Circulation Journal. 66. 192 (2002)
• [Publications] Izutani S.Yoshiyama M, Omura T, Yoshida K, Nakamura Y, Kim S, Takeuchi K, Yoshikawa J.: "Nipradilol can prevent left ventricular systolic and diastolic dysfunction after myocardial infarction in rats"Circulation Journal. 66. 289 (2002)
• [Publications] Omura T, Yoshiyama M, Ishikura F, Kobayashi H, Takeuchi K, Beppu S, Yoshikawa J.: "Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats"Journal of Molecular and Cellular Cardiology. 33. 307 (2001)
• [Publications] Yoshiyama M, Omura T, Takeuchi, K, Kim S, Yamagishi H, Akioka K, Iwao H, Yoshikawa J.: "Angiotensin blockade inhibits increased JNKs, AP-1 and NF-kappa B DNA-binding activities in myocardial infarcted rats"Journal of Molecular and Cellular Cardiology. 33. 799 (2001)
• [Publications] Omura, T., Yoshiyama, M., Yoshida, K., Nakamura, Y., Kim, S., Iwao, H., Takeuchi, K., Yoshikawa, I.: "Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine"Hypertension. 39,1. 81-86 (2002)
• [Publications] Omura, T., Yoshiyama, M., Ishikura, F., Kobayashi, H., Takeuchi.K., Beppu, S., Yoshikawa, J.: "Myocardial isehemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats"Journal of Molecular and Cellular Cardiology. 33,2. 307-316 (2001)
• [Publications] Yoshida, K., Yoshiyama, M., Omura, T., Nakamura, Y., Kim, S., Takeuchi, K., Iwao, H., Yoshikawa, J.: "Activation of mitogen-activated protein kinases in the non-ischemic myocardium of an acute myocardial infarction in rats"Japanese Circulation Journal. 65,9. 808-814 (2001)
• [Publications] Yoshiyama, M., Omura, T., Takeuchi, K., Kim, S., Shimada, K., Yamagishi, H., Akioka, K., Iwao, H., Yoshikawa, J.: "Angiotensin blockade inhibits increased JNKs, AP-1 and NF-kappa B DNA-binding activities in myocardial infarcted rats"Journal of Molecular and Cellular Cardiology. 33,4. 799-810 (2001)
• [Publications] Fukui, T., Yoshiyama, M., Hanatani, A., Omura, T., Yoshikawa, J., Abe, Y.: "Expression of p22-phox and gp91-phox, Essential Components of NADPH Oxidase, Increases after Myocardial Infarction"Biochemical and Biophysical Research Communications. 281,5. 1200-1206 (2001)