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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激活的激酶/信号转导和转录激活因子途径（Jak/STAT途径）是一个已建立的细胞因子信号转导系统。该途径在血管平滑肌细胞中的I型血管紧张素II（AT血管紧张素D21受体D2）受体刺激后被激活。为了研究这一通路是否在其他G蛋白偶联受体中共享，我们研究了α-肾上腺素D21受体和肾上腺素D2受体之间的联系。α-肾上腺素D21受体激动剂phenylalcine（100 nM）诱导人脐动脉平滑肌细胞中Jak 2、Tyk 2和STAT 1的酪氨酸磷酸化。α α 2 1受体拮抗剂哌唑嗪和α 2 1 B受体拮抗剂特异性氯乙可洛尼定可抑制Jak 2的磷酸化，而α 2 1 A受体拮抗剂WB 4101则不能抑制Jak 2的磷酸化;哌唑嗪和Jak 2特异性酪氨酸激酶抑制剂AG 490可抑制STAT 1的磷酸化。苯肾上腺素刺激后，Jak 2和STAT 1与α-肾上腺素D21 B受体结合。苯丙氨酸刺激STAT 1的DNA结合活性。然而，苯乙双胍没有促进STAT 3的表达。最近的研究表明，Jak/STAT信号通路在白细胞介素6相关细胞因子诱导的心肌细胞肥大的发展中起关键作用。因此，我们感兴趣的是，该途径是否介导α受体D21受体D2激动剂诱导的血管平滑肌肥大。哌唑嗪、AG 490和STAT 1诱饵寡核苷酸的引入抑制了苯丙氨酸促进的蛋白质合成。然而，STAT 3的诱饵是无效的。这些结果表明，α β D21 β D2激动剂通过激活Jak 2和Tyk 2刺激STAT 1，并且该途径介导α β D21 β D2激动剂诱导的平滑肌肥大。