P412Ibuprofen-eluting stents: a novel therapeutic approach in the prevention of in-stent stenosis

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The re-occlusion of blood vessels following percutaneous coronary intervention with stenting (in-stent stenosis) is a major clinical problem; for example, 5-10% of patients receiving drug-eluting stents experience re-occlusion of the treated vessel and failure rates in patients receiving bare metal stents is even higher. Re-occlusion of the treated vessel occurs due to proliferation and migration of vascular smooth muscle cells (VSMCs), caused, at least in part, by damage to the treated vessel, inflammation and impaired healing of the endothelial cell layer. Novel drug eluting stents that reduce inflammation and promote endothelial repair whilst preventing detrimental VSMC proliferation and migration are required. We previously have shown that certain non-steroidal anti-inflammatory drugs (NSAIDs) show great promise for the prevention of in-stent stenosis as they prevent the proliferation of rodent VSMCs. In the present study, we have investigated whether ibuprofen has a differential effect on the proliferation and migration of human VSMCs and endothelial cells. Using direct cell counting, we have shown that higher doses of ibuprofen are required to inhibit human coronary VSMC proliferation (HCASMC; 0.62 ± 0.03mM) compared to doses required to inhibit the proliferation of human endothelial cells, such as human pulmonary endothelial cells (HPMECs; 1.5 ± 0.05mM). We also observed in that 0.41 ± 0.06mM ibuprofen was required to reduce HCASMC migration by 50% in cell migration assays whereas inhibition of migration of human endothelial cells was not observed at non-toxic drug concentrations (i.e. concentrations greater than 1.5mM). These data show that ibuprofen has differential effects on VSMC and endothelial cell proliferation and migration and, thus, might be a promising drug to deliver in a novel drug eluting stent platform to reduce coronary stent failure rates. Ongoing studies aim to establish why VSMCs and endothelial cells respond differently to ibuprofen as this might identify other drugs with the potential to prevent in-stent stenosis.

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