Efthymiou, C.A.; (2005) The effect of atorvastatin on prosurvival mechanisms in myocardial ischaemia reperfusion injury. Doctoral thesis , University of London.

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Abstract

The treatment of acute myocardial infarction has long involved rapid reperfusion of the area at risk. Reperfusion of ischaemic myocardium, however, is not without hazard and can paradoxically result in myocyte death, in a process known as lethal reperfusion- induced injury. Attenuation of this reperfusion-induced injury has become a focus for the treatment of acute coronary artery disease in a clinical setting. In recent years the "Reperfusion Injury Salvage Kinase pathway" the so-called "RISK" pathway has been proposed as a key factor in ensuring myocardial survival. Several agents have been shown to attenuate lethal reperfusion induced injury via this mechanism, and the identification of clinically effective drugs that influence this pathway has taken on some urgency. Over the last two decades 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) reductase inhibitors called "statins" have revolutionised the treatment of hypercholesterolaemia. Meta-analysis of data from clinical trials investigating the effects of statins, however, have indicated that these drugs may have additional beneficial effects independent of their cholesterol-lowering properties. Amongst the pleiotropic effects which have not yet been fully investigated is their potential cardioprotective action. The aim of the present study was to investigate if atorvastatin reduces reperfusion induced injury by activation of the RISK pathway. Using an isolated perfused mouse heart model, the actions of atorvastatin given at reperfusion on infarct size and on the phosphorylation of the anti-apoptotic phosphatidylinositol-3-OH kinase (PI3K)-AKT, the P44/42 extra-cellular signal-regulated kinases (Erk 1/2), and the molecular chaperone Heat Shock Protein (HSP) 27 were studied. The data presented in this thesis indicate that atorvastatin, when administered at reperfusion, results in a significant reduction in infarct size and causes the phosphorylation of these prosurvival kinases. This reduction is sensitive to wortmannin and U0126, which are inhibitors of PBKinase and P44/42 respectively. In addition to the actions described atorvastatin also increased HSP25 phosphorylation (HSP25 is the murine equivalent of the human HSP27) an effect that was abrogated by the p38MAPK inhibitor SB203580, which prevents phosphorylation of p38 and its down stream target HSP25. In view of these findings the potential therapeutic role of human HSP27 was further investigated. Transgenic mice overexpressing HSP27, were found to be protected from lethal ischaemia compared to their HSP27 negative litter mates. In conclusion, this thesis provides evidence that atorvastatin attenuates lethal reperfusion induced injury in a process involving activation of the RISK pathway, and increase of HSP25 phosphorylation. In addition it is demonstrated that overexpression of HSP27 protects against lethal ischaemia.

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