Role of peroxisome proliferator-activated receptor-β/δ in acute myocardial infarction, septic shock and sepsis

Abstract

Peroxisome 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.