Restenosis is a known complication following balloon angioplasty used in the treatment of atherosclerosis. It results in neointimal thickening which occurs in part via the proliferation of vascular smooth muscle (VSM) cells. Despite recent advances in revascularisation techniques, neointimal hyperplasia from increased VSM cells remains a significant clinical problem. Phosphoprotein enriched in astrocytes-15 (PEA-15) is an extracellular signal-regulated kinases 1/2 (ERK1/2) binding protein. It acts as a cytoplasmic “anchor” preventing ERK1/2 translocation to the nucleus and activation of proliferative pathways in VSM cells (1). The aim of this study was to determine the role of PEA-15 in murine and human models of neointima hyperplasia. Arterial injury was induced by wire denudation and ligation of the left carotid artery (LCA) in C57BL/6 mice. General anaesthesia was induced by inhalation of 3% isoflurane supplemented with oxygen and maintained at 1.5% isoflurane throughout the procedure. Saphenous veins were obtained from patients undergoing coronary artery bypass surgery and incubated ex vivo in 30% serum for 14 days to induce neointimal hyperplasia. Protein and mRNA levels were determined by immunoblotting and qPCR using Taqman gene expression assays respectively. Immunolocalisation was established using confocal microscopy. Values are mean ± S.E.M., expressed as a fold change and compared by ANOVA and unpaired t test. In comparison to uninjured right carotid arteries (RCA), PEA-15 protein levels were not altered 3 days after arterial injury in LCA of sham-operated mice (without the insertion of the wire) (0.91±0.11 vs. RCA, n=3) whereas there was a reduction in PEA-15 expression in injured LCA (0.34±0.17 vs. RCA, n=3, p<0.01). In contrast, PEA-15 protein levels were unchanged 7 days post-surgery in either sham-operated or injured LCA (1.36±0.23 and 1.22±0.17 vs. RCA respectively, n=3). Immunolocalisation revealed expression of PEA-15 within the medial layer and confirmed immunoblotting data (n=3). PEA-15 expression was also reduced in organ-cultured human saphenous veins compared to freshly isolated tissue (0.44±0.06 vs. control, n=5, p<0.05). Similarly, expression of the smooth muscle marker, calponin was significantly down regulated (0.18±0.05 vs. control, n=4, p<0.05) while a marker of proliferation (proliferating cell nuclear antigen) was increased (4.3±0.7 vs. control, n=4, p<0.05). In addition, qPCR revealed a significant decrease in PEA-15 gene expression compared to control saphenous veins (0.68±0.05 vs. control, n=6, p<0.05). In conclusion, we provide evidence for dysregulated PEA-15 expression in the development of neointima hyperplasia in both murine and human models which may regulate in part an increase in VSM cell proliferation. Targeting this pathway could be beneficial in the treatment of restenosis.