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  • EC barrier dysfunction triggered by inflammatory mediators


    EC barrier dysfunction triggered by inflammatory mediators involves more than one mechanism, explaining the partial attenuation of EC barrier compromise obtained with PKA and Epac activators. PKA-dependent phosphorylation of vasodilator-stimulated phosphoprotein (VASP) has been shown to make a positive contribution to the cAMP-mediated protection from LPS-induced barrier compromise [30]. PKA-independent mechanisms of EC barrier enhancement mediated by the activation of Epac/Rap1/T cell lymphoma invasion and metastasis 1 (Tiam1)/Vav2/Rac cascades protect against thrombin-induced EC hyperpermeability [31], [32], [33]. Furthermore, the Epac/Rap1 pathway has been shown to attenuate the platelet-activating factor (PAF)-induced acute increase in vascular permeability [34]. As shown in several previous studies, LPS-induced endothelial barrier dysfunction might be mediated by several pathways, one of which involves the activation of MAP kinases, but controversy regarding whether ERK1/2 or p38 is more important still exists [35]. Another critical mechanism is involved in the activation of Rho pathways, such as Rac/Cdc42 [36] and Rap1 [32]. Rac1 mediates peripheral Glutathione (GSH/GSSG/Total) Fluorometric Assay Kit enhancement and the enlargement of adherens junction complexes in pulmonary endothelial monolayers [37], [38], [39]. Rac1 activation mediates endothelial barrier recovery after thrombin or LPS challenge [40], [41]. However, a Rac1 inhibitor also exerts a protective effect on LPS-induced lung injury, and inhibit the inflammation and microvascular permeability [38]. So, Rac1 maybe have different character in different situation. In our study, Rac1 activation was increased throughout the LPS induced lung (Fig. 7). We have not identified the exact mechanism through which Epac activation regulates LPS-induced acute lung vascular barrier dysfunction, but we speculate that the possible target of Epac activators might be the direct stimulation of Rac1/2. In summary as Fig. 8 the major finding of the current study is that activation of Epac by 8CPT effectively reduces LPS-induced inflammation and pulmonary vascular permeability, which suggests that Epac might play important physiological roles as signals for pulmonary inflammation and vascular permeability. Regarding defective drugs, further studies that directly target Epac1/2 or PKA in LPS-induced ALI are needed. Based on our limited experimental data, we believe that more detailed work using Epac1- and Epac2-knockout mice might reveal the precise roles of Epac.
    Conflict of interest
    Introduction Epac, an abbreviation for exchange protein directly activated by cAMP, belongs to a family of guanine nucleotide exchange factors and has only recently emerged as an important cyclic adenosine 3′,5′-monophosphate (cAMP) effector [1]. cAMP is one of the most important second messengers in the heart, Glutathione (GSH/GSSG/Total) Fluorometric Assay Kit regulating many physiological processes, such as cardiac contractility, relaxation, and automaticity. Although protein kinase A (PKA) is generally recognized as the primary effector of cAMP signaling [2], other effectors are known to transduce cyclic nucleotide-encoded information. They encompass a class of cyclic nucleotide gated (CNG) cation channels and phosphodiesterases (PDEs) [3], [4]. With the development of specific Epac agonists such as 8-pCPT-2′-O-Me-cAMP (8pCPT) [5], [6], many data in the literature point out now the critical role of Epac proteins in multiple cellular events mediated by the second messenger cAMP [7]. The multidomain structure of Epac indicates that it may have multiple binding partners. Compelling evidence is now accumulating about the formation of molecular complexes in distinct cellular compartments that influence Epac signaling and cellular function. A relevant question in cardiac signaling is how cAMP can differentially relay environmental signals associated with a large number of surface neurotransmitter or hormone receptors to effectively regulate cardiac function and to understand how these signals are deregulated in pathological conditions such as cardiac hypertrophy.