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Title: Mechanisms underlying the cardioprotective effect of remote ischaemic preconditioning
Author: Abdul-Ghani , Safa
ISNI:       0000 0004 5922 5984
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality in the world. Intervention to treat the diseased heart includes cardiac surgery using cardiopulmonary bypass and cardioplegic ischaemic arrest. Blood supply restoration to the heali, at the end of ischaemic arrest, results in reperfusion injury and cardiac death by necrosis and apoptosis. Research in recent years has shown that the heart has endogenous mechanisms that can be used for protection (e.g. conditioning). Remote Ischaemic Preconditioning (RIPC) is a phenomenon where preconditioning of organs distant to the heart can protect the myocardium against index ischaemia and reperfusion (I/R) injury. However, translating this intervention to clinical practice has been delayed due to lack of understanding of the nature of the triggers and the mediators and more importantly the lack of understanding of cellular changes in myocardium prior to I1R. The overall aim of this study was to establish a mouse model of RIPC and to investigate the nature of the released trigger and the cellular changes in the myocardium associated with RIPC. In this work we characterized a mouse model of RIPC and investigated the cardioprotective effect of RIPC following I1R. In vivo and in vitro techniques (e.g. Tandem Mass Tags & mass spectrometric-based quantitative proteomics, western blotting, ELISA immunoassay, electrocardiography, Laser Doppler Flowmetry, High Performance Liquid Chromatography and Langendorffheart perfusion) were used to address the aim of this thesis. Our model of 4 cycles of hindlimb RIPC is cardioprotective as shown by reducing infarct size, creatine kinase release and improving functional recovery after (I/R) of Langendorff heati. RIPC was associated with an increase in heart rate as measured in isolated perfused heali. This effect was further confirmed in vivo and the ECG data was used to carry out heart rate variability analysis. This suggested that RIPC induces a sympathetic drive which can be α- or β-stimulation. Evidence for increased p-stimulation was shown by increased phosphorylation of proteins known to be activated by PKA (ryanodine receptor and myozenin). This stimulation appears to trigger cardiac ischaemic stress (elevated AMP/ A TP & ADP/ ATP ratios). RIPC was also associated with reduced microcirculatory blood flow (MBF) in the second uncuffed hindlimb which could be due to α-sympathetic stimulation causing vasoconstriction. RIPC induced phosphorylation of proteins linked to key signalling pathways and localized to the Z-disk of the sarcomere could be responsible for cardioprotection. Additionally, RIPC was found to cause significant accumulation of adenosine (associated with ischaemic stress) which is known to be cardioprotective. Interestingly, RIPC did not activate PKCα. or the RISK pathway proteins in tissue harvested immediately after the induction of RIPC. In conclusion, RIPC is associated with increased sympathetic drive which activates key Z-disk phosphoproteins, changes in MBF, ischaemically stress the myocardium and increases adenosine myocardial content. These changes confer protection against I/R.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available