The mechanism of G protein-mediated cardiac fibrosis

• Project/Area Number: 18390028
• 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, Professor (10183039)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,170,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥1,770,000); Fiscal Year 2007: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2006: ¥9,500,000 (Direct Cost: ¥9,500,000)
• Keywords: cardiac hypertrophy / cardiac fibrosis / G proteins / intracellular Ca^2+ / TRPC channels / angiotensin receptor / TGF-β / connective tissue growth factor / 心筋線維化応答 / G_qタンパク質 / アンジオテンシン受容体 / ホスホリパーゼC / G_<12>タンパク質

Research Abstract

Sustained elevation of intracellular Ca^2+ concentration ([Ca^2+]i) has been implicated in many cellular events. We reported that sustained Ca^2+ influx through canonical transient receptor potential 3/6 (TRPC3/6) channels pathway leads to the activation of nuclear factor of activated T cells (NFAT), a Ca^2+-responsive transcriptional factor, and meditates hypertrophic responses in rat neonatal cardiac myocytes. We also demonstrated that TRPC6 channels participates in sustained Ca^2+ influx and NFAT activation by endothelin (ET)-1 treatment in cardiac fibroblasts. Expression of constitutively active (CA) G_α<12> or G_α<13> increased the expression of TRPC6 proteins and basal Ca^2+ influx activity. The treatment with ET-1 increased TRPC6 protein levels through G_α<12/13>, reactive oxygen species (ROS), and c-Jun N-terminal kinase (JNK)-dependent pathways. NFAT is activated by sustained increase in [Ca^2+]; through upregulated TRPC6. A G_α<12/13>-inhibitory polypeptide derived from regulator of G-protein signaling domain of p115-RhoGEF and a JNK inhibitor, SP600125, suppressed the ET-1-induced increase in expression of marker proteins of myofibroblast formation through G_α<12/13>-ROS-JNK pathway. The ET-1-induced myofibroblast formation was suppressed by overexpression of TRPC6 and CA-NFAT, while enhanced by TRPC6 siRNAs and cyclosporine A. These results suggest two opposite roles of G_α<12/13> in cardiac fibroblasts. First, G_α<12/13> mediate ET-1-induced myofibroblast formation. Second, G_α<12/13> mediate TRPC6 upregulation and NFAT activation that negatively regulates ET-1-induced myofibroblast formation. Furthermore, TRPC6 mediates hypertrophic responses in cardiac myocytes but suppresses fibrotic responses in cardiac fibroblasts. Thus, TRPC6 mediates opposite responses in cardiac myocytes and fibroblasts.

Research Products

• [Journal Article] Small GTPase Rho signaling is involved in (β1 integrin-mediated up-regulation of intercellular adhesion molecule 1 and receptor activator of nuclear factor KB lig and on osteoblasts and osteoclast maturation (2007)
  • Author(s): Hirai, F., Nakayamada, S., Okada, Y.Saito, K., Kurose, H., Mogami, A., and Tanaka, Y
  • Journal Title: Biochemical and Biophysical Research Communications 356 Pages: 275-285
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Previously postulated 'ligand-independent'signaling of GPR4 is mediated through proton-sensing mechanism (2007)
  • Author(s): Tobo, M., Tomura, H., Mogi, C., Wang, J.Q., Liu, J.P., Komachi, M., Damirin, A., Kimura, T., Murata, N., kurose, H., Sato, K., and Okajima, F
  • Journal Title: Cellular Signalling 19 Pages: 1745-1753
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] イオンチャネルと心疾患-心肥大形成とTRPC-NFATシグナリング (2007)
  • Author(s): 黒瀬 等、西田 基宏
  • Journal Title: 医学のあゆみ 223 Pages: 464-468
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Small GTPase Rho signaling is involved in β1 integrin- mediated up-regulation of intercellular adhesion molecule 1 and receptor activator of nuclear factor KB ligand on osteoblasts and osteoclast maturation (2007)
  • Author(s): Hirai, F., Nakayamada, S., Okada, Y., Saito, K., Kurose, H., Mogami, A., Tanaka, Y
  • Journal Title: Biochemical Biophysical Research Communications 356 Pages: 279-285
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanism (2007)
  • Author(s): Tobo, M., Tomura, H., Mogi, C. Wang, ,JQ, Liu, JP., Komachi, M., Damirin, A., Kimura, T., Murata, N., Kurose, H., Sato, K., Okajima, F
  • Journal Title: Cellular Signalling 19 Pages: 1745-1753
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis (2007)
  • Author(s): Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Steenman, M., Kurose, H., Ert, G., Nebigil, CG
  • Journal Title: FASEB Journal 21 Pages: 2980-2993
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gα12/13-mediated upregulation of TRPC6 negatively regulates endothelin-1-induced cardiac myofibroblast formation and collagen synthesis through NFAT activation (2007)
  • Author(s): Nishida, M., Onohara, N., Sato, Y., Suda, R., Ogushi, M., Tanabe, S., Inoue, R., Mori, Y., Kurose, H
  • Journal Title: Journal of Biological Chemistry 282 Pages: 23117-23128
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor (2007)
  • Author(s): Cho, EY, Cho, DI, Park, JH, Kurose, H., Caron, MG, Kim, KM
  • Journal Title: Molecular Endocrinology 21 Pages: 2242-2254
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Small GTPase Rho signaling is involved in β1 integrin-mediated up-regulation of intercellular adhesion molecule 1 and receptor activator of nuclear factor κB lig and on osteoblasts and osteoclast maturation. (2007)
  • Author(s): Hirai, F., Nakayamada, S., Okada, Y.Saito, K., Kurose, H., Mogami, A., and Tanaka, Y.
  • Journal Title: Biochemical and Biophysical Research Communications 356 Pages: 279-285
  • Peer Reviewed
• [Journal Article] Previously postulated 'ligand-independent' signaling of GPR4 is mediated through proton-sensing mechanism. (2007)
  • Author(s): Tobo, M., Tomura, H., Mogi, C., Wang, J.Q., Liu, J.P., Komachi, M., Damirin, A., Kimura, T., Murata, N., Kurose, H., Sato, K., and Okajima, F.
  • Journal Title: Cellular Signalling 19 Pages: 1745-1753
  • Peer Reviewed
• [Journal Article] イオンチャネルと心疾患-心肥大形成とTRPC-NFATシグナリング- (2007)
  • Author(s): 黒瀬 等、西田 基宏
  • Journal Title: 医学のあゆみ 223 Pages: 464-468
• [Journal Article] Clathrin required for phosphorylation and internalization of β2-adrenergic receptor by G protein-coupled receptor kinase (GRK2). (2006)
  • Author(s): Mangmool, S., Haga, T., Kobayashi, H., Kim, K.-M., Nakata, H., Nishida, M., Kurose, H
  • Journal Title: Journal of Biological Chemistry 281 Pages: 31940-31949
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy (2006)
  • Author(s): Onohara, N., Nishida, N., Inoue, R., Kobayashi, H., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H
  • Journal Title: EMBO Journal 25 Pages: 5305-5316
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells (2006)
  • Author(s): Kimura, T., Tomura, H., Mogi, C., Kuwabara, A., Ishiwara, M., Shibasawa, K., Sato, K., Ohwada, S., Im, DS, Kurose, H., Ishizuka, T., Murakami, M., Okajima, F
  • Journal Title: Cellular Signalling 18 Pages: 841-850
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heterotrimeric G protein Gα13- induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts (2006)
  • Author(s): Nagamatsu, Y., Nishida, M., Onohara, N., Fukutomi, M., Maruyama, Y., Kobayashi, H., Sato, Y., Kurose, H
  • Journal Title: Journal of Pharmacological Sciences 101 Pages: 144-150
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Beta-blockers shows inverse agonism to a novel constitutively active mutant of β1-adrenoceptor (2006)
  • Author(s): Ahmed, M., Muntasir, H.A., Hossain, M., Isiguro, M., Komiyama, T., Muramatsu, I., Kurose, H., Nagatomo, T.
  • Journal Title: Journal of Pharmacological Sciences 102 Pages: 167-172
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Thromboxane A_2 receptor-mediated G_<12/13>-dependent glial morphological change (2006)
  • Author(s): Honma, S., Saika, M., Ohkubo, S., Kurose, H., Nakahata, N
  • Journal Title: European Journal of Pharmacology 545 Pages: 100-108
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clathrin required for phosphorylation and internalization of β_2-adrenergic receptor by G protein-coupled receptor kinase 2 (GRK2). (2006)
  • Author(s): Mangmool, S., Haga, T., Kobayashi, H., Kim, K-M., Nakata, H., Nishida, M., Kurose, H.
  • Journal Title: Journal of Biological Chemistry 281(42) Pages: 31940-31949
• [Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. (2006)
  • Author(s): Onohara, N., Nishida, N., Inoue, R., Kobahasyi, H., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H.
  • Journal Title: EMBO Journal 25(22) Pages: 5305-5316
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. (2006)
  • Author(s): Kimura, T., Tomura, H., Mogi, C., Kuwabara, A., Ishiwara, M., Shibasawa, K., Sato, K., Ohwada, S., Im, D.S, Kurose, H., Ishizuka, T., Murakami, M., Okajima, F.
  • Journal Title: Cellular Signalling 18(6) Pages: 841-850
• [Journal Article] Heterotrimeric G protein Gα_<13>-induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts. (2006)
  • Author(s): Naganatsu, Y., Nishida, M., Onohara, N., Fukutomi, M., Maruyama, Y., Kobayashi, H., Sato, Y., Kurose, H.
  • Journal Title: Journal of Pharmacological Sciences 101 Pages: 144-150
  • NAID: 10018237777
• [Journal Article] Beta-blockers shows inverse agonism to a novel constitutively active mutant of β_1-adrenoceptor. (2006)
  • Author(s): Ahmed, M., Muntasir, H.A., Hossain, M., Isiguro, M., Komiyama, T., Muramatsu, I., Kurose, H., Nagatomo, T.
  • Journal Title: Journal of Pharmacological Sciences 102 Pages: 167-172
  • NAID: 10020345451
• [Journal Article] Thromboxane A_2 receptor-mediated G_<12/13>-dependent glial morphological change. (2006)
  • Author(s): Honma, S., Saika, M., Ohkubo, S., Kurose, H., Nakahata, N.
  • Journal Title: European Journal of Pharmacology 545(2-3) Pages: 100-108
• [Presentation] G_α<13>-TRPC6-NFAT signaling pathway negatively regulates cardiac myofibroblast formation (2007)
  • Author(s): Nishida, M., Onohara, N., Kurose, H.
  • Organizer: G_α<13>-TRPC6-NFAT signaling pathway negatively regulates cardiac myofibroblast formation
  • Place of Presentation: Belogna, Italy
  • Year and Date: 2007-06-24
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Roles of TRPCchannel in the heart (2007)
  • Author(s): 黒瀬 等
  • Organizer: The 5th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects
  • Place of Presentation: 静岡コンベンションセンター
  • Year and Date: 2007-05-10
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Roles of TRPC channel in the heart (2007)
  • Author(s): 黒瀬 等
  • Organizer: The 5th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects
  • Place of Presentation: 静岡コンベンションセンター
  • Year and Date: 2007-05-10
• [Presentation] Role of TRPC3/TRPC6 in angiotensin II receptor-induced hypertrophic responses in cardiomyocytes
  • Author(s): Nishida, M., Onohara, N., Inoue, R., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H
  • Organizer: The 80th Japan Pharmacological Society Meeting
  • Place of Presentation: Nagoya International Conference Center
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of superoxide anion in TNF-a-induced p38 MAPK activation in cardiac fibroblasts
  • Author(s): Murakami, T., Takakuri, S., Sumimoto, H., INishida, M., Ichihara, K., Kurose, H
  • Organizer: The 80th Japan Pharmacological Society Meeting
  • Place of Presentation: Nagoya International Convention Center
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Inhibition of angiotensin II signaling by ATP-stimulated NFAT activation in rat cardiac fibroblasts
  • Author(s): Suda, R., Onohara, N., Sato, Y., Nishida, M., Kurose, H
  • Organizer: The 80th Japan Pharmacological Society Meeting
  • Place of Presentation: Nagoya International Convention Center
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of G_α<12/13> in angiotensin II-induced cardiac fibrosis
  • Author(s): Narita, Y., Onohara, N., Nishida, M., Sato, Y., Nagao, T., Kurose, H
  • Organizer: The 80th Japan Pharmacological Society Meeting
  • Place of Presentation: Nagoya International Convention Center
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Roles of TRPC channel in the heart
  • Author(s): Kurose, H
  • Organizer: The 5th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects
  • Place of Presentation: Shizuoka Convention Center
  • Description: 「研究成果報告書概要(欧文)」より