Oxidative stress and myocardial injury in the diabetic heart

Abstract

Reactive oxygen or nitrogen species play an integral role in both myocardial injury and repair. This dichotomy is differentiated at the level of species type, amount and duration of free radical generated. Homeostatic mechanisms designed to prevent free radical generation in the first instance, scavenge, or enzymatically convert them to less toxic forms and water, playing crucial roles in the maintenance of cellular structure and function. The outcome between functional recovery and dysfunction is dependent upon the inherent ability of these homeostatic antioxidant defences to withstand acute free radical generation, in the order of seconds to minutes. Alternatively, pre-existent antioxidant capacity (from intracellular and extracellular sources) may regulate the degree of free radical generation. This converts reactive oxygen and nitrogen species to the role of second messenger involved in cell signalling. The adaptive capacity of the cell is altered by the balance between death or survival signal converging at the level of the mitochondria, with distinct pathophysiological consequences that extends the period of injury from hours to days and weeks. Hyperglycaemia, hyperlipidaemia and insulin resistance enhance oxidative stress in the diabetic myocardium that cannot adapt to ischaemia-reperfusion. Altered glucose flux, mitochondrial derangements and nitric oxide synthase uncoupling in the presence of decreased antioxidant defence and impaired prosurvival cell signalling may render the diabetic myocardium more vulnerable to injury, remodelling and heart failure.

Figure 1

Ischemia-reperfusion injury in the diabetic myocardium is multi-factorial and complex. a) Overexpression of phosphatase and tensin homologue on chromosome 10 (PTEN) in diabetes results in an inability to activate cellular protective pathways such as, PI3K/AKT and JAK2/STAT3 to prevent ischemia and reperfusion injury. b) Hexose biosynthase pathway (HBP) activation due to hyperglycemia results in glycosylation of proteins. Glycosylation of BAD, for example, leads to higher binding to and inactivation of anti-apoptotic BCL-2. This renders the cardiomyocyte more susceptible to mPTP. c) The multitude of effects of hyperglycemia and diabetes lead to uncoupling of the mitochondrial electron transport chains (ETC) and have a net effect of ROS overproduction and lower ATP production that renders the myocardium unable to ward off injury. d) Uncoupling of NOS enzymes and the resultant overproduction of peroxynitrite is a cyclical mode of cellular injury. This cycle is fed by overproduction of superoxide, which itself is formed from multiple sources during diabetes and ischemia and reperfusion. e) Release of divalent cations from metalloproteinases during ischemia and reperfusion promote production of OH^• radical from H₂O₂ through the fenton reaction. f) Activation of aldose reductase during ischemia and reperfusion depletes NADPH, the cofactor required for glutathione reductase (GR) activity. Decreased GR activity leads to lower levels of anti-oxidant glutathione (GSH), which also contributes to lower glutathione peroxidase (GPx) activity. Lower GPx activity decreases the amount of H₂O₂ neutralized and therefore contributes to higher oxidative stress and susceptibility to mPTP and resultant cardiac injury and remodeling.