The direct effect of statins on cardiovascular function

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Cardiovascular disease (CVD) is the leading cause of death in the western world. The incidence and prevalence of CVD is highest among the elderly due to the deleterious effects of advancing age on the heart and blood vessels1. Statins are a class of drugs which inhibit the enzyme HMG-CoA reductase leading to reduced cholesterol biosynthesis in the liver and a lowering of plasma LDL-cholesterol levels, ultimately reducing atherosclerosis in patients. In addition to their effects on cholesterol in the liver, statins are known to have positive pleiotropic effects on cardiovascular function. Previous work has shown that statins are potent activators of ERK5 kinase in cardiac endothelial cells, which regulates tight junction formation and vascular permeability2 and in cardiomyocytes, which may lead to improved mitochondrial function. Our hypothesis is that statin activation of ERK5 in both cardiomyocytes and cardiac endothelial cells improves cardiac function and ultimately protects against cardiac pathologies such as aging. This research could impact on the long-term management of cardiovascular aging in humans. We have developed a novel in vitro human multicellular cardiac microtissue amenable to long-term studies of cardiovascular function3. The project will utilise this model to analyse the long-term effect of statins on cardiac microtissue analysing functional parameters such as contractility (microelectrode array) and structural parameters such as cellular architecture (Zeiss light sheet microscopy). By comparing a range of different statins we will identify the most cardioselective statin and efficient dosing regimen to progress to an animal study. The second aim will be to use a C57Bl/6 mouse model to analyse cardiac and vascular performance following statin treatment. Cardiovascular physiology will be monitored by cardiac magnetic resonance imaging (MRI). Structural analysis on fixed cardiac tissue will be perform by using immunofluorescence and transmission electron microscopy (TEM).