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This project tests the hypothesis that pharmacological inhibition of the pro-inflammatory and oxidant-producing enzyme myeloperoxidase (MPO) stabilises ‘vulnerable’ lesions and hence may prevent a heart attack or stroke. MPO is expressed in certain white blood cells where it plays an important role in the innate immune system by producing hypochlorite (bleach) to kill bacteria and other pathogens. However, there is also evidence for MPO contributing to vascular disease by inducing endothelial dysfunction (Arterioscl Thromb Vasc Biol 2019;39:1448) and destabilising atherosclerotic plaque (Eur Heart J 2018;39:3301). The project is a collaboration with Professor Tony Kettle (University of Otago, Christchurch), Dr Alkystis Phinikaridou and Professor René Botnar (King’s College, London) and AstraZeneca. It makes use of a new class of molecules, ie, 2-thioxanthines, that effectively inhibit MPO. Using pre-clinical models, we are currently investigating how MPO inhibition stabilises existing unstable plaque, how this relates to intra- vs extra-cellular MPO in plaque, and for how long MPO needs to be inhibited for a lasting beneficial effect. Together with our collaborators at King’s College, we are also investigating whether MPO inhibition prevents plaque rupture in a model system.

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