Linkage between G protein-coupled receptors and the Jak/STAT pathway in cardiovascular cells

心血管细胞中 G 蛋白偶联受体与 Jak/STAT 通路之间的联系

基本信息

批准号：
10670695
负责人：
SASAGURI Toshiyuki
金额：
$ 0.83万
依托单位：
National Cardiovascular Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

The Janus-activated kinase/signal transducers and activators of transcription pathway (Jak/STAT pathway) is an established signal transduction system for cytokines. This pathway is activated following stimulation of the type I angiotensin II (ATィイD21ィエD2) receptor in vascular smooth muscle cells. To examine whether this pathway is shared among other G-protein-coupled receptors, we studied the linkage between the αィイD21ィエD2 adrenergic receptor and this pathway. The αィイD21ィエD2 agonist phenylephrine (100nM) induced tyrosine phosphorylation of Jak2, Tyk2, and STAT1 in human umbilical artery smooth muscle cells. The phosphorylation of Jak2 was prevented by the αィイD21ィエD2 receptor antagonists prazosin and αィイD21BィエD2-specific chloroethylcolonidine, but not by αィイD21AィエD2-specific WB4101, and the phosphorylation of STAT1 was inhibited by prazosin and Jak2-specific tyrosine kinase inhibitor AG490. After stimulation with phenylephrine, Jak2 and STAT1 were found to associate with αィイD21BィエD2 receptor. Phenylephrine stimulated the DNA binding activity of STAT1. However, phenylephrine did not promote that of STAT3. Recently the Jak/STAT pathway has been suggested to play a key role in the development of cardiac myocyte hypertrophy induced by interleukin 6-related cytokines. Therefore we were interested in whether this pathway mediates vascular smooth muscle hypertrophy induced by αィイD21ィエD2 agonists. Protein synthesis promoted by phenylephrine was inhibited by prazosin, AG490, and the introduction of a decoy oligonucleotide for STAT1. However a decoy for STAT3 was ineffective. These results suggested that αィイD21ィエD2 agonist stimulates STAT1 through activation of Jak2 and Tyk2 and that this pathway mediates αィイD21ィエD2 agonist-induced smooth muscle hypertrophy.

Janus 激活激酶/信号转导器和转录通路激活器（Jak/STAT 通路）是一种已建立的细胞因子信号转导系统，该通路在血管平滑肌细胞中的 I 型血管紧张素 II (ATiD21D2) 受体受到刺激后被激活。为了检查该途径是否在其他 G 蛋白偶联受体之间共享，我们研究了 αD21D2 肾上腺素能受体与该受体之间的联系。 αD21D2 激动剂苯肾上腺素 (100nM) 诱导人脐动脉平滑肌细胞中 Jak2、Tyk2 和 STAT1 的酪氨酸磷酸化。αD21D2 受体拮抗剂哌唑嗪和 α 特异性氯乙基可乐定可阻止 Jak2 的磷酸化。 αD21A D2 特异性 WB4101 和 STAT1 的磷酸化被哌唑嗪和 Jak2 特异性酪氨酸激酶抑制剂 AG490 抑制。在用去氧肾上腺素刺激后，发现 Jak2 和 STAT1 与 αD21B D2 受体相关，去氧肾上腺素刺激了 STAT1 的 DNA 结合活性。然而，去氧肾上腺素并没有促进最近，Jak/STAT 通路被认为在白介素 6 相关细胞因子诱导的心肌细胞肥大的发展中发挥关键作用，因此我们对该通路是否介导 αiiD21 蛋白合成促进的血管平滑肌肥大感兴趣。去氧肾上腺素的作用被哌唑嗪、AG490 和引入 STAT1 的诱饵寡核苷酸所抑制。这些结果表明 αD21D2 激动剂通过激活 Jak2 和 Tyk2 刺激 STAT1，并且该途径介导 αD21D2 激动剂诱导的平滑肌肥大。