Regulation of the inflammatory response of vascular endothelial cells by EPAC1

Parnell, E., Smith, B. O. , Palmer, T. M., Terrin, A., Zaccolo, M. and Yarwood, S. J. (2012) Regulation of the inflammatory response of vascular endothelial cells by EPAC1. British Journal of Pharmacology, 166(2), pp. 434-446. (doi: 10.1111/j.1476-5381.2011.01808.x)

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Life-threatening diseases of the cardiovascular system, like atherosclerosis, are exacerbated by unwanted inflammation within the structures of large blood vessels. This inflammation involves increased permeability of the vascular endothelial cells (VECs) that form the lining of blood vessels, leading to exaggerated extravasation of blood components and accumulation of fluid in the extravascular space. This results in tissue dysfunction and increased secretion of chemokines that attract leukocytes and monocytes to the inflamed endothelium. Cyclic AMP is synthesized in VECs in response to endogenous Gs-coupled receptors and is known to limit cytokine action and reduce endothelial hyperpermeability induced by multiple pro-inflammatory stimuli. The mechanisms underlying this anti-inflammatory action of cyclic AMP are now being elucidated and it is becoming clear that the cyclic AMP sensor, exchange protein activated by cyclic AMP (EPAC1), appears to play a key role in suppressing unwanted inflammation. EPAC1 mediates at least three anti-inflammatory pathways in VECs by down-regulating inflammatory signalling through the induction of the suppressors of cytokine signalling 3 (SOCS-3) gene, limiting integrin-dependent vascular permeability and enhancing endothelial barrier function through the stabilization of VE-cadherin junctions. Given that manipulation of cellular cyclic AMP levels currently forms the basis of many effective pharmaceuticals and that EPAC1 is involved in multiple anti-inflammatory protective processes in VECs, does this make EPAC1 an attractive target for the development of activators capable of eliciting a coordinated programme of ‘protection’ against the development of endothelial dysfunction? Here we discuss whether EPAC1 represents an attractive therapeutic target for limiting endothelial dysfunction associated with cardiovascular diseases like atherosclerosis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Zaccolo, Professor Manuela and Yarwood, Dr Stephen and Palmer, Dr Timothy and Smith, Dr Brian and Parnell, Mr Euan and Terrin, Ms Anna
Authors: Parnell, E., Smith, B. O., Palmer, T. M., Terrin, A., Zaccolo, M., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:British Journal of Pharmacology
ISSN (Online):1476-5381
Published Online:13 April 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
528251The Role of EPAC1-regulated Protein Kinase C Isoforms in Mediating C/EBPdelta -dependent, Anti-inflammatory Actions of Cyclic AMP in Vascular Endothelial CellsStephen YarwoodBritish Heart Foundation (BHF)PG/10/026/28303Institute of Molecular Cell and Systems Biology
498581EPAC1 and ERK-dependent activation of C/EBP transcription factors: a new cyclic AMP-activated anti-inflammatory gene expression module in vascular endothelial cellsTimothy PalmerBritish Heart Foundation (BHF)PG/08/125/26415Institute of Cardiovascular and Medical Sciences