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 *help |
¥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.
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Report
(3 results)
Research Products
(31 results)
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[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 maturation2007
Author(s)
Hirai, F., Nakayamada, S., Okada, Y.Saito, K., Kurose, H., Mogami, A., and Tanaka, Y
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Journal Title
Biochemical and Biophysical Research Communications 356
Pages: 275-285
Description
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[Journal Article] Previously postulated 'ligand-independent'signaling of GPR4 is mediated through proton-sensing mechanism2007
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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
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Cellular Signalling 19
Pages: 1745-1753
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[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 maturation2007
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Hirai, F., Nakayamada, S., Okada, Y., Saito, K., Kurose, H., Mogami, A., Tanaka, Y
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Journal Title
Biochemical Biophysical Research Communications 356
Pages: 279-285
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[Journal Article] Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanism2007
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Tobo, M., Tomura, H., Mogi, C. Wang, ,JQ, Liu, JP., Komachi, M., Damirin, A., Kimura, T., Murata, N., Kurose, H., Sato, K., Okajima, F
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Cellular Signalling 19
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[Journal Article] The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis2007
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Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Steenman, M., Kurose, H., Ert, G., Nebigil, CG
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FASEB Journal 21
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[Journal Article] Gα12/13-mediated upregulation of TRPC6 negatively regulates endothelin-1-induced cardiac myofibroblast formation and collagen synthesis through NFAT activation2007
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Nishida, M., Onohara, N., Sato, Y., Suda, R., Ogushi, M., Tanabe, S., Inoue, R., Mori, Y., Kurose, H
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Cho, EY, Cho, DI, Park, JH, Kurose, H., Caron, MG, Kim, KM
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Molecular Endocrinology 21
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[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
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Biochemical and Biophysical Research Communications 356
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[Journal Article] Previously postulated 'ligand-independent' signaling of GPR4 is mediated through proton-sensing mechanism.2007
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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.
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[Journal Article] Clathrin required for phosphorylation and internalization of β2-adrenergic receptor by G protein-coupled receptor kinase (GRK2).2006
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Mangmool, S., Haga, T., Kobayashi, H., Kim, K.-M., Nakata, H., Nishida, M., Kurose, H
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Journal of Biological Chemistry 281
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[Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy2006
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Onohara, N., Nishida, N., Inoue, R., Kobayashi, H., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H
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[Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells2006
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Cellular Signalling 18
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[Journal Article] Heterotrimeric G protein Gα13- induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts2006
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Nagamatsu, Y., Nishida, M., Onohara, N., Fukutomi, M., Maruyama, Y., Kobayashi, H., Sato, Y., Kurose, H
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[Journal Article] Beta-blockers shows inverse agonism to a novel constitutively active mutant of β1-adrenoceptor2006
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[Journal Article] Clathrin required for phosphorylation and internalization of β_2-adrenergic receptor by G protein-coupled receptor kinase 2 (GRK2).2006
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[Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy.2006
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[Journal Article] Heterotrimeric G protein Gα_<13>-induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts.2006
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Journal of Pharmacological Sciences 102
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[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
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[Presentation] Role of superoxide anion in TNF-a-induced p38 MAPK activation in cardiac fibroblasts
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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
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[Presentation] Role of G_α<12/13> in angiotensin II-induced cardiac fibrosis
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Organizer
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[Presentation] Roles of TRPC channel in the heart
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