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dc.contributor.authorKapoor, Amar
dc.description.abstractPeroxisome Proliferator-Activated Receptors (PPARs) are ligand activated transcription factors that belong to the nuclear hormone receptor family. In this thesis, I have investigated the anti-inflammatory role of PPAR-β/δ in animal models of regional myocardial ischaemia and reperfusion (I/R) injury and multiple organ injury/dysfunction associated with endotoxaemia and septic shock. Using a selective PPAR-β/δ agonist, GW0742, I have demonstrated that selective activation of PPAR-β/δ protects the rat heart against injury caused by regional I/R when administered, as late as, on reperfusion of the previously ischaemic myocardium. Additionally, I have demonstrated that genetic deletion of PPAR-β/δ greatly exacerbates the multiple organ injury/dysfunction caused by endotoxaemia in the mouse. Moreover, treatment of wild-type mice with GW0742 attenuated the multiple organ injury/dysfunction caused by endotoxaemia. Thus, activation of PPAR-β/δ affords a protective effect against multiple organ injury/dysfunction in endotoxic shock. I extended the above study by investigating the effect of PPAR-β/δ activation in a clinically relevant model of caecal ligation and puncture (CLP)-induced polymicrobial sepsis by evaluating survival in mice over 10 days. I demonstrated that treatment with GW0742, several hours after the induction of polymicrobial sepsis, improved survival. Furthermore, I have demonstrated this organ protective effect of PPAR-β/δ activation in a rat model of severe acute endotoxaemia. Finally, I have shown that the protective effects of PPAR-β/δ activation in animal models of acute regional myocardial I/R injury and endotoxic shock are secondary to an anti-inflammatory mechanism involving the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway, which leads to the inhibition of the activation of glycogen synthase kinase (GSK)-3β and nuclear factor (NF)-B activity, subsequently reducing the expression of NF-B-driven gene transcription of a number of pro-inflammatory mediators. Thus, in this thesis, I have demonstrated an anti-inflammatory protective role for PPAR-β/δ in models of regional myocardial I/R injury, septic shock and systemic inflammation.en_US
dc.titleRole of peroxisome proliferator-activated receptor-β/δ in acute myocardial infarction, septic shock and sepsisen_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 [2752]
    Theses Awarded by Queen Mary University of London

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