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/信号换能器和转录途径的激活因子（JAK/STAT途径）是细胞因子的已建立信号转导系统。在血管平滑肌细胞中刺激I型血管紧张素II（ATII D21 E D2）受体后，该途径被激活。为了检查该途径是否在其他G蛋白偶联受体中共享，我们研究了αIID21 E D2肾上腺素受体与该途径之间的联系。人脐动脉平滑肌细胞中的JAK2，TYK2和STAT1诱导JAK2，TYK2和STAT1诱导α-D21E D2激动剂苯乙烯（100nm）诱导酪氨酸磷酸化。 α-D21E D2受体拮抗剂帕唑嗪和α-D21BIE D2特异性氯乙基苯基苯胺可预防JAK2的磷酸化，但不能抑制STAT1的磷酸化和JAK2-ST-SP-SP-SPINICIC KIN0 KIN 0。用苯肾上腺素刺激后，发现JAK2和STAT1与α-D21BIE D2受体相关。苯肾上腺素刺激了STAT1的DNA结合活性。但是，苯肾上腺素并未促进STAT3的苯丙胺。最近，建议JAK/STAT途径在白介素6与6个与白介素相关的细胞因子引起的心肌肥大的发展中起关键作用。因此，我们对这种途径是否介导α-I D21 E D2激动剂诱导的血管平滑肌肥大感兴趣。由苯肾上腺素促进的蛋白质合成受Prazosin，AG490抑制，并引入了STAT1的诱饵寡核苷酸。但是，STAT3的诱饵无效。这些结果表明，α-I D21 E D2激动剂通过激活JAK2和TYK2刺激了STAT1，并且该途径介导α-D21E D2激动剂诱导的平滑肌肥大。