The mechanism of G protein-mediated cardiac fibrosis
G蛋白介导的心肌纤维化机制
基本信息
- 批准号:18390028
- 负责人:
- 金额:$ 10.99万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2006
- 资助国家:日本
- 起止时间:2006 至 2007
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
细胞内Ca^2+浓度([Ca^2+]i)的持续升高与许多细胞事件有关。我们报道了通过典型瞬时受体电位3/6 (TRPC3/6)通道途径持续的Ca^2+内流导致活化T细胞核因子(NFAT)的激活,这是一种Ca^2+应答转录因子,并介导大鼠新生心肌细胞的肥厚反应。我们还证明了TRPC6通道参与内皮素(ET)-1治疗心脏成纤维细胞持续Ca^2+内流和NFAT激活。组成活性(CA) G_α<12>或G_α<13>的表达增加了TRPC6蛋白的表达和基础CA ^2+内流活性。ET-1通过G_α<12/13>、活性氧(ROS)和c-Jun n -末端激酶(JNK)依赖途径增加TRPC6蛋白水平。NFAT被持续增加的[Ca^2+]激活;通过上调TRPC6。来自p115-RhoGEF g蛋白信号域调控因子和JNK抑制剂SP600125的G_α<12/13>-ROS-JNK途径抑制et -1诱导的肌成纤维细胞形成标记蛋白表达的增加。过表达TRPC6和CA-NFAT可抑制et -1诱导的肌成纤维细胞形成,而TRPC6 sirna和环孢素a可增强其形成。这些结果提示G_α<12/13>在心脏成纤维细胞中具有两种相反的作用。首先,G_α<12/13>介导et -1诱导的肌成纤维细胞形成。其次,G_α<12/13>介导TRPC6上调和NFAT激活,负调控et -1诱导的肌成纤维细胞形成。此外,TRPC6介导心肌细胞的肥厚反应,但抑制心脏成纤维细胞的纤维化反应。因此,TRPC6在心肌细胞和成纤维细胞中介导相反的反应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
- DOI:10.1096/fj.07-8116com
- 发表时间:2007-09-01
- 期刊:
- 影响因子:4.8
- 作者:Urayama, Kyoji;Guilini, Celia;Nebigil, Canan G.
- 通讯作者:Nebigil, Canan G.
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
小 GTPase Rho 信号传导参与(β1 整合素介导的细胞间粘附分子 1 和核因子 KB lig 受体激活剂的上调以及成骨细胞和破骨细胞的成熟
- DOI:
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者:Hirai;F.;Nakayamada;S.;Okada;Y.Saito;K.;Kurose;H.;Mogami;A.;and Tanaka;Y
- 通讯作者:Y
Heterotrimeric G protein Gα_<13>-induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts.
异源三聚体G蛋白Gα_13通过心脏成纤维细胞中的两个不同途径诱导细胞因子mRNA的诱导。
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:Naganatsu;Y.;Nishida;M.;Onohara;N.;Fukutomi;M.;Maruyama;Y.;Kobayashi;H.;Sato;Y.;Kurose;H.
- 通讯作者:H.
Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells
- DOI:10.1016/j.cellsig.2005.07.011
- 发表时间:2006-06-01
- 期刊:
- 影响因子:4.8
- 作者:Kimura, T;Tomura, H;Okajima, F
- 通讯作者:Okajima, F
Previously postulated 'ligand-independent'signaling of GPR4 is mediated through proton-sensing mechanism
先前假设的 GPR4 的“配体独立”信号传导是通过质子传感机制介导的
- DOI:
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者: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
- 通讯作者:F
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KUROSE Hitoshi其他文献
KUROSE Hitoshi的其他文献
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{{ truncateString('KUROSE Hitoshi', 18)}}的其他基金
Role of GRK in engulfment of apoptotic cells
GRK 在吞噬凋亡细胞中的作用
- 批准号:23659043 
- 财政年份:2011
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Roles of Voltage- and cation-independent TRPC channels in cardiac hypertrophy
电压和阳离子无关的 TRPC 通道在心脏肥大中的作用
- 批准号:20390025 
- 财政年份:2008
- 资助金额:$ 10.99万 
- 项目类别:Grant-in-Aid for Scientific Research (B) 
mechanistic analysis of cardiac functions by building G protein signal network
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- 批准号:17079007 
- 财政年份:2005
- 资助金额:$ 10.99万 
- 项目类别:Grant-in-Aid for Scientific Research on Priority Areas 
Establishment of a role of reactive oxygen species as a second messenger
活性氧作为第二信使的作用的确立
- 批准号:15390027 
- 财政年份:2003
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Redox Regulation of Signal Transduction Mechanism in the Heart
心脏信号转导机制的氧化还原调节
- 批准号:13470483 
- 财政年份:2001
- 资助金额:$ 10.99万 
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Structural analysis and molecular modeling of high affinity binding and activation of β1-adrenergic receptor
β1-肾上腺素受体高亲和力结合和激活的结构分析和分子建模
- 批准号:11672210 
- 财政年份:1999
- 资助金额:$ 10.99万 
- 项目类别:Grant-in-Aid for Scientific Research (C) 
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