The mechanism of G protein-mediated cardiac fibrosis

G蛋白介导的心肌纤维化机制

• 批准号: 18390028
• 负责人: KUROSE Hitoshi
• 金额: $ 10.99万
• 依托单位: Kyushu University
• 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: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390028/
• 关键词: 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

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

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: FASEB JOURNAL
• 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

• 发表时间: 2007
• 期刊: Biochemical and Biophysical Research Communications 356
• 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。

• 发表时间: 2006
• 期刊: Journal of Pharmacological Sciences 101
• 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: CELLULAR SIGNALLING
• 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

• 发表时间: 2007
• 期刊: Cellular Signalling 19
• 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