Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP
Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP
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DOI：
10.1016/j.mvr.2009.11.007
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发表时间：
2010-03-01
影响因子：
3.1
通讯作者：
Birukov, Konstantin G.
中科院分区：
文献类型：
--
作者：
Birukova, Anna A.;Burdette, Dylan;Birukov, Konstantin G.
细胞内cAMP水平的升高与内皮屏障完整性的增加有关，并与蛋白激酶A（PKA）的激活有关。最近的研究表明，cAMP介导的内皮屏障调节的新机制是通过cAMP依赖性核苷酸交换因子Epac 1和Rap 1 GT3。本研究检测了PKA依赖性和PKA非依赖性途径在cAMP保护人肺内皮屏障中的作用。合成的cAMP类似物8-溴腺苷-3 '，5'-环一磷酸（Br-cAMP）诱导了与PKA激活相关的EC跨内皮电阻的剂量依赖性增加。Epac/Rap 1和Tiam/Vav/Rac级联并显著减弱凝血酶诱导的EC屏障破坏特异性Epac/Rap 1激活剂8 CPT-2 Me-cAMP（8 CPT）和特异性PKA激活剂N-6-苯甲酰基-腺苷-3 '，5'-环（6 Bnz）均增强EC屏障，抑制凝血酶诱导的EC通透性，和独立激活的小GTdR ac siRNA-诱导的Rac敲低抑制肺EC中PKA和Epac信号传导的屏障保护作用静脉内施用6 Bnz或8 CPT，显著减少了在由高潮气量机械通气（HTV，30 ml/kg. 4 h）。而用6 Bnz和8 CPT组合处理没有显示进一步的累加效应。本研究首次剖析了cAMP升高引起的肺EC屏障保护的PKA和Epac通路，并确定Rac GTdR是PKA和Epac信号传导的枢纽，导致肺血管屏障的增强（C）2009 Elsevier Inc版权所有
Elevation in intracellular cAMP level has been associated with increased endothelial barrier integrity and linked to the activation of protein kinase A (PKA) Recent studies have shown a novel mechanism of cAMP-mediated endothelial barrier regulation via cAMP-dependent nucleotide exchange factor Epac1 and Rap1 GTPase. This study examined a contribution of PKA-dependent and PKA-independent pathways in the human pulmonary endothelial (EC) barrier protection by cAMP Synthetic cAMP analog, 8-bromoadenosine-3',5'-cyclic monophosphate (Br-cAMP), induced dose-dependent increase in EC transendothelial electrical resistance which was associated with activation of PKA. Epac/Rap1, and Tiam/Vav/Rac cascades and significantly attenuated thrombin-induced EC barrier disruption Both specific Epac/Rap1 activator 8CPT-2Me-cAMP (8CPT) and specific PKA activator N-6-benzoyl-adenosine-3',5'-cyclic (6Bnz) enhanced EC barrier, suppressed thrombin-induced EC permeability, and independently activated small GTPase Rac SiRNA-induced Rac knockdown suppressed barrier protective effects of both PKA and Epac signaling in pulmonary EC Intravenous administration of either 6Bnz, or 8CPT, significantly reduced lung Vascular leak in the murine model of lung injury induced by high tidal volume mechanical ventilation (HTV, 30 ml/kg. 4 h). whereas combined treatment with 6Bnz and 8CPT showed no further additive effects. This study dissected for the first time PKA and Epac pathways of lung EC barrier protection caused by cAMP elevation and identified Rac GTPase as a hub for PKA and Epac signaling leading to enhancement Of lung vascular barrier (C) 2009 Elsevier Inc All rights reserved