Therapeutic Targeting of Cyclic AMP Signalling to Combat Cardiovascular Disease

The suppressor of cytokine signalling 3 (SOCS3) protein is a potent inhibitor of pro-inflammatory pathways involved in atherogenesis and the development of neo-intimal hyperplasia (NIH), which contributes to the in-stent re-stenosis responsible for the failure of percutaneous coronary intervention (PCI) procedures. We have shown that cyclic AMP sensor EPAC1 triggers induction of the SOCS3 gene in vascular endothelial cells (VECs), thereby attenuating interleukin 6 (IL-6)-mediated pro-inflammatory signalling. We propose that EPAC1 localisation to the nuclear pore controls cyclic AMP-mediated activation of a transcription factor complex, leading to SOCS3 induction and suppression of pro-inflammatory signalling. We are now perusing an integrated program of work to examine the translational potential and wider significance of the EPAC1/SOCS3 pathway in controlling human VEC function and also developing putative therapeutics for the management of chronic inflammation in vascular settings.