Target Validation, Cardiovascular, Oxidative Stress, Cellular Signalling

Coronary Heart Disease is associated with narrowing of one or more of the coronary arteries and can be treated by permanent insertion of a tiny metal stent into the affected area. Current state of the art devices are drug-eluting stents (DES), and although they are commonly used, they are not suitable for all patient groups. Insertion of a stent causes severe injury to the artery wall, promoting an intense inflammatory reaction with accompanying oxidative stress and release of reactive oxygen species (ROS). This can impair patient progress following stent placement and unfortunately development of DES that release drugs to inhibit oxidative stress has largely failed to improve patient outcomes. An alternative novel approach is to use stents with coatings that provide inherent anti-oxidant activity that could protect the vascular endothelium by reducing oxidative stress and inflammation post-stent placement.

Preliminary work from our group has demonstrated the pivotal role that oxidation plays in contributing to endothelial dysfunction. We have identified a particular protein kinase, CaMKII, as a key transducer of pathophysiological effects in vascular endothelial cells. CaMKII can become hyper-active following oxidation and may therefore be an important candidate in producing endothelial damage post-stent placement.

This project aims to investigate the feasibility of using novel coatings for stents. This is with a view to determining which of these coatings produce sufficient anti-oxidant activity to reduce/ reverse the damaging effects mediated via ROS and inflammation following stent placement. The project will involve testing out how these novel coatings may affect primary adult endothelial cells that have been treated with stressors that mimic the damaging effects seen post-stent placement. Effects on endothelial cell growth and function will be studied in isolation and in association with smooth muscle cells to mimic the environment in the vascular wall. A possible role for targeting CaMKII in this context will also be explored. The project involves collaboration between departments at the University of Strathclyde. Dr Currie is based in Strathclyde Institute of Pharmacy & Biomedical Sciences (SIPBS) and Dr McCormick is based in the Biomedical Engineering department.

Vascular endothelial cell and smooth muscle cell isolation and culture, kinase assays, proliferation assays, cell imaging and immunofluorescence, immunoblotting, scanning electron microscopy, atomic force microscopy and UV-spectroscopy 

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McCluskey C. et al (2015) Pro-inflammatory signalling in vascular endothelium: a novel role for CaMKIId in ageing. Heart 101: A100-A101

Feng N. & Anderson M.E. (2017) CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J.Mol.Cell.Cardiol. 103: 102-109