CLIC4通过通过RhoA调解PAR1信号来调节内皮屏障控制
Matthew L Kleinjan1, De Yu Mao1, L A Naiche1
1Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago.
Arteriosclerosis, thrombosis, and vascular biology
|June 15, 2023
概括
化物细胞内通道蛋白4 (CLIC4) 对于血栓信号传递和维持内皮屏障完整性至关重要. CLIC4调节RhoA激活和破坏内皮屏障,而CLIC1有助于屏障恢复.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 身体生理学 身体生理学
背景情况:
- 已知内皮化物细胞内通道蛋白 (CLICs),CLIC1和CLIC4介导G蛋白合受体 (GPCR) 信号传递.
- 这些CLICs参与激活小GTPases Rac1和RhoA,这些GPCRs的下游,如S1PR1和S1PR3.
研究的目的:
- 研究CLIC1和CLIC4在内皮G蛋白结合受体 (GPCR) 途径中的作用,特别是通过蛋白酶激活受体1 (PAR1) 传递血栓蛋白信号.
- 为了确定CLIC蛋白是否调节RhoA激活和内皮屏障功能,以应对血栓.
主要方法:
- 在血栓刺激后,评估了CLIC1和CLIC4膜在人静脉内皮细胞 (HUVEC) 的重新定位.
- 在HUVEC中利用CLIC1和CLIC4的淘汰来检查血栓介导的RhoA/Rac1激活,ERM酸化和内皮屏障功能.
- 产生了Clic4的有条件的小鼠等位基因,以研究PAR1介导的肺微血管透性和视网膜血管生成中的内皮特异性Clic4损失.
主要成果:
- 血栓诱导的CLIC4,但不是CLIC1,重新定位到HUVEC膜.
- 通过CLIC4的敲除,减少了由血栓激发的RhoA激活,ERM酸化和内皮屏障破坏.
- 降低CLIC1并没有影响最初的RhoA活性,但延长了对血栓的内皮屏障反应.
- 在小鼠中,Clic4的内皮特异性缺失减少了PAR1激活后的肺和微血管透性.
结论:
- CLIC4是内皮PAR1信号传递的关键媒介,对于调节RhoA依赖的内皮屏障破坏至关重要.
- 在血栓激素引起的干扰后,CLIC1在内皮屏障的恢复阶段发挥作用.
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