Myocardial Antioxidant Enzyme Systems, Ischemia-Reperfusion Injury, and Selenium

Abstract

Coronary heart disease remains the greatest killer of Australian's, and given our ageing population, along with increasing risk factors, it is predicted to become an even more significant problem worldwide over the next 20 years. Reperfusion, without doubt is the most effective treatment for ischemic myocardium. However, this produces deleterious effects upon cells, and depending on the severity, may ultimately lead to cell death. While the pathogenesis of ischemia-reperfusion is not completely understood, there is considerable evidence implicating reactive oxygen species (ROS) as an initial cause of the injury. ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks, all potentially damaging to normal cellular function. ROS have been shown to be generated following routine clinical procedures such as coronary bypass surgery and thrombolysis, due to the unavoidable episode of ischemiareperfusion. Furthermore, they have been associated with poor cardiac recovery post-ischemia, with recent studies supporting a role for them in infarction, necrosis, apoptosis, arrhythmogenesis and endothelial dysfunction following ischemia-reperfusion. In normal physiological condition, ROS production is usually homeostatically controlled by endogenous free radical scavengers such as SOD, catalase, and the glutathione peroxidase and thioredoxin reductase systems. Targeting the generation of ROS with various antioxidants has been shown to reduce injury following oxidative stress, and improve recovery from ischemia-reperfusion injury. This thesis investigates the role of myocardial antioxidant enzymes in ischemiareperfusion injury, particularly the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) systems. GPX and TxnRed are selenocysteine dependent enzymes, and their activity is known to be dependent upon an adequate supply of dietary selenium and selenocysteine. In mammalian cells, the generation of selenocysteine occurs during amino acid biosynthesis and the degree of selenium (Se) incorporation into the cysteine residue is concentration dependent. Previous studies have found that up-regulation of these systems is cardioprotective and down-regulation is detrimental following ischemia-reperfusion. This thesis attempts to extend these observations by increasing not only our understanding of the roles of myocardial antioxidant enzymes in ischemia-reperfusion injury, but also the effect of dietary selenium on these systems. Furthermore, it investigates the effects of ischemia, reperfusion, and ageing on myocardial antioxidant enzymes.