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  • br Physiological roles for EPAC isoforms vascular


    Physiological roles for EPAC isoforms: vascular function The effects of cAMP on limiting vascular endothelial cell (VEC) inflammation and vascular smooth muscle cell (VSMC) proliferation have been well documented 36, 37, 38. However, recent work has demonstrated that several key effects of cAMP in both cell types require EPAC1. One of the most important relates to the ability of cAMP to limit proinflammatory signalling from specific cytokines involved in propagating vascular inflammation, particularly interleukin-6 (IL-6). Sustained IL-6 production appears to drive chronic, low-level vascular inflammation that leads to neointimal thickening [39], vascular dysfunction [40], phosphocholine [41], and increased risk of myocardial infarction [42]. An early step in the development of the vascular dysfunction that ultimately leads to the formation of atherosclerotic plaques is the conversion of VECs from an anticoagulant/anti-inflammatory to a prothrombotic/proinflammatory phenotype. Ultimately plaques may become sufficiently large that they occlude vessels and block blood flow. Alternatively, if they are unstable, they may rupture and trigger the formation of thrombi responsible for myocardial infarction or ischaemic stroke. Surgical treatment for atherosclerosis typically involves percutaneous coronary intervention (PCI), a revascularisation procedure involving implantation of a stent into the narrowed coronary artery to physically open the previously narrowed blood vessel lumen and restore blood flow. However, it can also trigger neointimal hyperplasia (NH) characterised by localised inflammation and VSMC proliferation and migration (Figure 3), leading to in-stent restenosis and stent failure [43]. The increased inflammatory activity associated with atherosclerosis and in-stent restenosis is partially brought about by increased levels of proinflammatory cytokines, particularly IL-6 42, 44. IL-6 has been detected in atherosclerotic plaques [45] and increases in IL-6 affect VECs by triggering counterproductive angiogenesis through vascular endothelial growth factor (VEGF) production [46] and increasing the secretion of chemokines including monocyte chemoattractant protein 1 (MCP-1)/CCL2 [47], which recruit monocytes to the inflamed endothelium (Figure 4). Signalling by IL-6 occurs through an IL-6 receptor (IL-6R) complex comprising an IL-6-binding α chain (IL-6Rα) and gp130, which interacts with IL-6Rα [48] (Figure 4). IL-6 has been reported to exert both inflammatory and anti-inflammatory actions [49] and a single nucleotide polymorphism (SNP), Asp358Ala, has been identified in the IL-6R to reduce inflammation and the risk of developing coronary heart disease (CHD) 50, 51, although the mechanisms for this remain unclear [52]. It is IL-6 receptor ‘trans-signalling’ [53] that is thought to underlie the proinflammatory actions of IL-6 in various diseases, including atherosclerosis [54]. During trans-signalling, IL-6 binds to soluble forms of IL-6Rα (sIL-6Rα), allowing activation of gp130 in cells that do not normally express IL-6Rα such as VECs [53] (Figure 4). Consequently, binding of the sIL-6Rα/IL-6 complex to gp130 on VECs leads to receptor clustering and activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways. Activated Tyr705-phosphorylated STAT3 then homodimerises and translocates to the nucleus, where it acts as a transcription factor to induce multiple IL-6-responsive genes 47, 55 (Figure 4). An important mechanism for downregulating JAK–STAT signalling is via the suppressor of cytokine signalling (SOCS) family of proteins [56], which are directly induced by the same JAK–STAT pathway that they inhibit, forming a classical negative feedback loop [57] (Figure 4). For example, SOCS3 binds to JAK-phosphorylated receptors via the SOCS3 SH2 domain, thereby inhibiting JAK activity and activation of downstream signalling [58]. SOCS3 also targets multiple SH2-bound proteins for proteasomal degradation [58], with proteolytic targets including gp130 and JAK2 [59]. Consistent with its role as a negative regulator of inflammatory signalling, SOCS3 expression is localised to atherosclerotic plaques 60, 61 and SOCS3 knockdown in apoE−/− mice increases STAT activation and proinflammatory gene expression in aorta leading to enhanced atherogenesis [61]. Moreover, IL-6 has been reported to promote acute and chronic inflammatory disease in the absence of SOCS3 [62] and conditional deletion of SOCS3 in VECs results in pathological angiogenesis [63]. By contrast, either overexpression of SOCS3 or introduction of SOCS-derived peptides has been shown to suppress JAK–STAT signalling, acute inflammation, and the development of atherosclerosis and NH, illustrating the important protective role of SOCS3 64, 65, 66.