Establishment of a role of reactive oxygen species as a second messenger

• Project/Area Number: 15390027
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: KYUSHU UNIVERSITY
• Principal Investigator: KUROSE Hitoshi Kyushu University, Graduate School of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, Professor, 大学院・薬学研究院, 教授 (10183039)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Hiroyuki Kyushu University, Graduate School of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, Research associate, 大学院・薬学研究院, 助手 (20346810)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥15,500,000 (Direct Cost: ¥15,500,000); Fiscal Year 2004: ¥5,200,000 (Direct Cost: ¥5,200,000); Fiscal Year 2003: ¥10,300,000 (Direct Cost: ¥10,300,000)
• Keywords: NFAT / G protein / angiotensin receptor / MAP kinase / heart / fibrosis / hypertrophy / reactive oxygen species / 酸化ストレス / システイン修飾

Research Abstract

We examined the role of reactive oxygen species (ROS) as a second messenger using rat neonatal cardiac myocytes and fibroblasts. When cardiac myocytes were stimulated by angiotensin II, three MAP kinases (ERK, JNK and p38 MAPK) were activated. Among three MAP kinases, JNK and p38 MAPK but not ERK were activated in a ROS-dependent manner. We examined the signaling pathway leading to JNK activation in detail, and have found the following results. Heterotrimeric G_<α12> and G_<α13> that belong to G_<12> family G proteins were directly activated by angiotensin receptor stimulation, and G12 family G proteins activated small G protein Rho. Then, Rho activated another small G protein Rae, and Rac increased NADPH oxidase that resulted in ROS production. Inhibition of ROS production suppressed hypertrophy induced by angiotensin stimulation. These results suggested that ROS indirectly mediated hypertrophic responses through JNK and p38 MAPK activation. On the other hand, it is believed that cardiac fibroblasts are involved in fibrosis by production of cytokines through activation of NFAT and other transcriptional factors. When cardiac fibroblasts were stimulated by angiotensin II, NFAT transcriptional activation was observed in a ROS-dependent manner. However, nuclear translocation of NFAT was not affected by elimination of ROS. We analyzed NEAT activation pathway and demonstrated that G_<α12>- and G_<α13>-mediated ROS production is involved in JNK activation, and JNK activated another factor that is necessary for NFAT-dependent transcriptional activation. These results indicated that G_<12> family G proteins regulate ROS production, and ROS play an essential role of JNK activation.

Research Products

• [Journal Article] Gα_<12/13>- and reactive oxygen species-dependent activation of c-Jun NH_2-terminal kinase and p38 MAPK by angiotensin II receptor stimulation in rat neonatal cardiomyocytes. (2005)
  • Author(s): Nishida, M. et al.
  • Journal Title: Journal of Biological Chemistry 280 Pages: 18434-18441
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Small GTP-binding Protein Rho-mediated Signaling Promotes Proliferation of Rheumatoid Synovial Fibroblasts. (2005)
  • Author(s): Nakayamada, S. et al.
  • Journal Title: Arthritis Research & Therapy 7
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] β-Arrestin2 enhances β_2-adrenergic receptor-mediated nuclear translocation of extracellular signal-regulated kinase. (2005)
  • Author(s): Kobayashi, H. et al.
  • Journal Title: Cellular Signaling 17(in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] G_<α12/13>- and reactive oxygen species-dependent activation of c-Jun NH_2-terminal kinase and p38 mitogen -activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. (2005)
  • Author(s): Nishida, M., Tanabe, S., Maruyma, Y., Mangmool, S., Urayama, K., Nagamatsu, Y., Takagahara, S., Turner, J.H., Kozasa, T., Kobayashi, H., Sato, Y., Kawanishi, T., Inoue, R., Nagao, T., Kurose, H.
  • Journal Title: J.Biol.Chem. 280 Pages: 18434-18441
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts. (2005)
  • Author(s): Nakayamada, S., Kurose, H., Saito, K., Mogami, A., Tanaka, Y.
  • Journal Title: Arth.Reas.Ther. 7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] β-Arrestin2 enhances β_2-adrenergic receptor-mediated nuclear translocation of ERK. (2005)
  • Author(s): Kobayashi, H., Narita, Y., Nishida, M., Kurose, H.
  • Journal Title: Cell.Signal. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] G_<α12/13> and reactive oxygen species-dependent activation of c-Jun NH_2-terminal kinase and p38 MAPK by angiotensin II receptor stimulation in rat neonatal cardiomyocytes. (2005)
  • Author(s): Nishida, M. et al.
  • Journal Title: Journal of Biological Chemistry 280(in press)
• [Journal Article] Small GTP-binding Protein Rho-mediated Signaling Promotes Proliferation of Rheumatoid Synovial Fibroblasts. (2005)
  • Author(s): Nakayama S. et al.
  • Journal Title: Arthritis Research & Therapy 7(in press)
• [Journal Article] TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. (2004)
  • Author(s): Wang, J-Q. et al.
  • Journal Title: Journal of Biological Chemistry 279 Pages: 45626-45633
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Properties of rat melanin-concentrating hormone receptor 1 internalization. (2004)
  • Author(s): Saito, Y. et al.
  • Journal Title: Peptides 25 Pages: 1597-1604
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human neuroblastoma cells. (2004)
  • Author(s): Arai, K. et al.
  • Journal Title: Journal of Neurochemistry 89 Pages: 232-239
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TDAG8 is a proteon-sensing and psychosine-sensitive G-protein-coupled receptor. (2004)
  • Author(s): Wang, J-Q., Kon, J., Magi, C., Tobo, M., Damirin, A., Sato, K., Komachi, M., Malchinkhuu, E., Murata, N., Kimura, T., Kuwabara, A., Wakamatsu, K., Koizumi, H., Uede, T., Tsujimoto, G., Kurose, H., Sato, T., Harada, A., Misawa, N., Tonomura, H., Okajima, F.
  • Journal Title: J.Biol.Chem. 279 Pages: 45626-45633
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Properties of rat melanin-concentrating receptor 1 internalization. (2004)
  • Author(s): Saito, Y., Tetsuka, M., Li, Y., Kurose, H., Maruyama, K.
  • Journal Title: Peptide 25 Pages: 1597-1604
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human neuroblastoma cells. (2004)
  • Author(s): Arai, K., Lee, S-R., van Leyen, K., Kurose, H., Lo, E.H.
  • Journal Title: J.Neurochem. 89 Pages: 232-239
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TDAG8 is a protein-sensing and psychosine-sensitive G-protein-coupled receptor. (2004)
  • Author(s): Wang, J-Q. et al.
  • Journal Title: Journal of Biological Chemistry 279 Pages: 45626-45633
• [Publications] Arai, K: "Differential requirement of G?_<12>,G?_<13>, G ?_q and G? ? for endothelin-1-induced JNK and ERK activation."Molecular Pharmacology. 63巻. 478-488 (2003)
• [Publications] Tashiro, K.: "Role of Rho in rabbit parietal cell."Journal of Cellular Physiology. 197巻・3号. 409-417 (2003)