Novel strategies to inhibit smooth muscle cell hyperplasia and intimal thickening

Abstract

Coronary artery disease (CAD), underpinned by atherosclerosis, remains a leading cause of morbidity and mortality, particularly in the Western World. Although the advent of percutaneous transluminal coronary angioplasty (PTCA) has provided a fundamental change in the treatment of CAD and drug-eluting stents (DES) have brought about marked improvement, there still remain significant challenges such as restenosis and late stent thrombosis. Coronary artery bypass grafting (CABG) has been acknowledged as the most effective way to treat CAD. However saphenous vein graft failures still present a problem due to stenosis. Vascular smooth muscle cell (VSMC) proliferation and migration is the primary driver of restenosis after percutaneous coronary interventions (PCI) and vein graft failure after CABG. Endothelial dysfunction also plays an important role in both restenosis and late thrombosis following PCI. Therefore, key to the prevention of restenosis and late stent thrombosis is to suppress SMC proliferation and migration, and to enhance re-endothelialisation. The broad aim of work in this thesis is to seek more effective strategies to inhibit SMC hyperplasia and intimal thickening while promoting re-endothelialisation.

More specifically, the effects of three kinds of bio-molecules on prevention of restenosis are investigated in this thesis. Firstly, a novel “cocktail” consisting of a combination of VEGF-A, VEGF-D and cRGD, which has not been studied with SMC and EC in response to injury, is tested in a rat carotid balloon injury model. Secondly, the efficacy of the DNAzyme, Dz13, targeting c-Jun is tested in the rabbit autologous vein bypass graft model using the lipid-based transfection agent 1,2- dioleoyl-3-trimethylammonium propane (DOTAP) / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Lastly, the anti-restenotic potential of miR-191, a natural microRNA inhibitor of the immediate early gene Egr-1, is examined in the balloon-injured rat carotid artery model.

The data presented in this thesis demonstrates that localised delivery of Dz13, miR191 and a novel cocktail of VEGF-A, VEGF-D and cRGD can inhibit neointima formation in animal models. According to these studies, the cocktail, Dz13 and miR191 may be useful approaches for reducing in-stent restenosis and late thrombosis. The ability of these biomolecules to be delivered at a local level makes them ideal for inclusion in stent-based strategies.