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  • br Conflict of interest br Acknowledgments


    Conflict of interest
    Acknowledgments This work was supported in part by grants from the , Spain (INCITE08PXIB203092PR). VGM was supported by a FPU pre-doctoral scholarship from the , Spain. MLR was supported in part by a crowdfunding campaign (PRECIPITA), coordinated by the Spanish Foundation for Science and Technology (FECYT). We are very grateful to all the donors who have participated in this campaign.
    The following are the supplementary data related to this article. Introduction Cardiac fibroblasts (CF) are the major non-myocyte cell constituent in the myocardium and actively participate in the maintenance of myocardial structure by controlling the homeostasis of the extracellular matrix (ECM) in normal tissue (Mc Anulty, 2006, Porter and Turner, 2009). CF are differentiated to cardiac myofibroblasts (CMF), by transforming growth factor β1 (TGF-β1), and these differentiated dexdomitor receptor are actively involved in wound healing after cardiac injury and in tissue remodeling (Tomasek et al., 2002, Van den Borne et al., 2009). We have shown that the β2-adrenergic receptor (β2-AR) is the most expressed β-AR subtype in CF and CMF (Aránguiz-Urroz et al., 2011). Indeed, β-ARs have been identified on both neonatal and adult rat CF, and the stimulation with β-adrenergic agonists promotes proliferation, reduces collagen secretion (Copaja et al., 2008, Ocaranza et al., 2002, Sun and Weber, 2005), and induces autophagy (Aránguiz-Urroz et al., 2011). EPACs exert their function on GTPases Rap1 and 2, and both regulate many biological functions that are cell-specific such as proliferation, survival and differentiation, as well as intercellular adhesion, protein secretion and ion transport (Bos, 2006). Experiments performed on mice hearts demonstrated that EPAC-1/EPAC-2 mRNA levels decrease with heart development. Furthermore, it was shown that in mice with cardiac hypertrophy, EPAC-1 expression levels were increased, and the cAMP–EPAC–Rap1 signaling pathway was functioning, which suggests EPAC-1 participation in the cardiac hypertrophic process (Ulucan et al., 2007). Data presented by Yokoyama et al. showed that CF have higher EPAC-1 protein expression levels than EPAC-2 protein; and that TGF-β1, a cytokine closely related to cardiac fibrosis, was able to promote only the decrease in EPAC-1 mRNA and protein expression levels in CF (Yokoyama et al., 2008). In addition, it has been observed that EPAC participates in collagen synthesis. EPAC through PI3K signaling pathway activation might be related to the decrease in collagen synthesis in CF induced by adenosine agonists (Villarreal et al., 2009).
    Conflict of interest
    Acknowledgments This work was supported by FONDECYT (grant 1100443 to G.D.A.) and CONICYT (grant 24110021 to IO). IO, CR, MC, CH and RV hold doctoral fellowships from CONICYT, Chile. PA holds doctoral fellowships from MECESUP, Chile.
    Introduction Exchange proteins directly activated by cAMP (Epacs) are key downstream signaling effectors of cAMP that function as guanine nucleotide exchange factors (GEFs) for the Ras superfamily of small GTPases (Holz et al., 2006). Recently, an important role of Epacs in mediating pain hypersensitivity in animal models of chronic inflammation has emerged. This hypersensitivity is a consequence of increased excitability of sensory neurons that convey noxious information to the spinal cord (Gold and Gebhart, 2010, Richardson and Vasko, 2002, Woolf and Ma, 2007), a process termed peripheral sensitization. Although much work has described the signal transduction cascades in sensory neurons that mediate sensitization under acute inflammation (Basbaum et al., 2009, Hucho and Levine, 2007, Richardson and Vasko, 2002), less is known about signaling that maintains sensitization under chronic inflammatory conditions. Recent evidence suggests, however, that the transition from acute to persistent hypersensitivity is linked to a switch in signaling pathways that mediate sensitization (Villarreal et al., 2009). For example, acute exposure to prostaglandin E2 (PGE2) produces hyperalgesia and an increase in the excitability of sensory neurons, which are both mediated by increases in cAMP and activation of protein kinase A (PKA) (Aley and Levine, 1999, England et al., 1996, Hingtgen et al., 1995, Lopshire and Nicol, 1998, Sachs et al., 2009). With inflammation, or when sensory neurons are maintained in the presence of the inflammatory mediator, nerve growth factor (NGF), the sensitization induced by subsequent administration of PGE2 shifts from using PKA as the primary effector to activation of Epacs (Eijkelkamp et al., 2013, Hucho et al., 2005, Vasko et al., 2014, Wang et al., 2007).