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Role of 15-F2T-Isoprostane in the pathogenesis of myocardial ischemia-reperfusion injury : a novel therapeutic approach to cardioprotection with propofol Xia, Zhengyuan

Abstract

Myocardial ischemia-reperfusion injury (IRI) is a major pathophysiologic factor contributing to post-operative cardiac dysfunction in patients undergoing coronary artery bypass surgery utilizing cardiopulmonary bypass. Reactive oxygen species (ROS)- mediated lipid peroxidation plays a critical role in mediating myocardial IRI. This thesis reports the results of four studies designed to investigate the role of 15-F₂[sub t]-isoprostane, a reliable measure of lipid peroxidation that has bioactivity, in the pathogenesis of myocardial IRI and to explore the therapeutic potential of propofol. In the first study we demonstrated for the first time that significant in vivo lipid peroxidation occurs early during myocardial ischemia and continues during reperfusion rather than primarily only during reperfusion in patients undergoing cardiac surgery utilizing cardiopulmonary bypass. The plasma decay patterns of 15- F₂[sub t]-isoprostane during reperfusion parallel post-operative cardiac functional recovery. In an in vitro study, a unique therapeutic regimen of propofol was developed to best utilize its antioxidant properties in order to attenuate ROS generation during myocardial ischemia and early reperfusion in isolated rat hearts. Propofol provides better cardiac protection when applied at clinically achievable high concentration before ischemia and during global myocardial ischemia and continued during early reperfusion, followed by a relatively lower concentration during the later phase of reperfusion. Of particular relevance is our identification, using the isolated perfused rat hearts, that 15- F₂[sub t]-isoprostane is produced in situ during global myocardial ischemia. This finding provides evidence to support the use of antioxidant interventions during ischemia which would target the coronary endothelium and/or the cardiomyocytes. A third study investigated whether or not aging could be a factor that adversely affects the cardiac protective effect of propofol on myocardial IRI. The results showed that propofol equally preserved myocardial endogenous antioxidant capacity in the young and middle-aged rat hearts and, more significantly, enhanced post-ischemic myocardial functional recovery in the middle-aged rat hearts relative to that in the young rat hearts. This finding provides evidence to support the notion that drug(s) with antioxidant properties (such as propofol) could be more effective in attenuating myocardial IRI in populations suffering from insufficient or decreased endogenous antioxidant capacity, such as the elderly. In our study, we identified a strong inverse correlation between myocardial 15- F₂[sub t]-isoprostane levels and post-ischemic cardiac function in the isolated rat heart, suggesting 15- F₂[sub t]--isoprostane itself could be a factor mediating myocardial IRI. In the last study, we further explored whether 15- F₂[sub t]-isoprostane can directly mediate myocardial IRI and if 15- F₂[sub t]-isoprostane antagonism could be a potential adjunct therapy. We found that 15- F₂[sub t]-isoprostane exacerbated myocardial IRI as evidenced by an increased myocardial infarct size, cellular damage and reduced post-ischemic myocardial function. 15- F₂[sub t]-isoprostane antagonism abolished its deleterious effects. We also found evidence that 15- F₂[sub t]-isoprostane may mediate myocardial IRI, at least in part, by increasing ET-1 production during later reperfusion. It is hoped that the studies described in the thesis have enhanced knowledge concerning the role of 15- F₂[sub t]-isoprostane in the pathogenesis of myocardial IRI, from its mechanism(s) of action to its clinical relevance. It is hoped that our findings can aid in the development of novel and effective therapeutic interventions against myocardial ischemia-reperfusion injury.

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