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dc.contributor.authorKhan, Areeg Ismail Ahmed Abdulla
dc.identifier.citationKhan, A. 2014. Novel Translational Strategies to Treat Cardiac Injury and Dysfunction. Queen Mary University of Londonen_US
dc.description.abstractThere is ample evidence of the crucial role of PI3K/Akt dependent signalling in cardiac function, cellular growth and cell apoptosis. The PI3K/Akt pathway mediates cardioprotective effects in experimental models of cardiovascular disease. For example, activation of this pathway ameliorates the sepsis-induced cardiac dysfunction, whereas its activation in myocardial ischaemia/reperfusion (I/R) limits cardiac injury. This thesis investigates the role of two drugs, which activate the PI3K/Aktpathway, namely the haematopoietic cytokine erythropoietin and the anti-malarial drug artesunate, in a mouse animal model of experimental sepsis-induced cardiac dysfunction and in a rat model of regional myocardial I/R injury, respectively. Using a clinically relevant model of caecal ligation and puncture in mice, I demonstrated that aged (8 months) C57BL/6 mice (receiving fluid resuscitation and antibiotic therapy) developed significant cardiac dysfunction (within 24 h), while younger mice (2 months) did not. Erythropoietin attenuated the impaired systolic contractility (in vivo and ex vivo) caused by endotoxaemia (lipopolysacchride 9 mg kg-1; young mice) and sepsis (aged mice). These beneficial effects were associated with activation of Akt and endothelial nitric oxide synthase survival pathways and inhibition of the glycogen synthase kinase 3β, nuclear factor-κB and interleukin 1β pro-inflammatory pathways, secondary to activation of the β-common receptor. A single bolus administration of artesunate at the start of reperfusion in a rat model of myocardial I/R significantly attenuated the infarct size. This effect was mediated via activation of pro-survival pathways (PI3K/Akt and ERK 1/2 and STAT-3) and inhibition of the glycogen synthase kinase 3β and nuclear factor-κB pro-inflammatory pathways. Thus, in this thesis I have demonstrated that pharmacological activation of the PI3K/Akt pathway by erythropoietin and artesunate in sepsis and myocardial I/R, respectively, plays a vital role in the amelioration of cardiac dysfunction and injury.en_US
dc.description.sponsorshipMedical Research Councilen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectTranslational Medicine & Therapeuticsen_US
dc.titleNovel Translational Strategies to Treat Cardiac Injury and Dysfunctionen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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    Theses Awarded by Queen Mary University of London

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