Glutathione peroxidase in acute coronary syndromes

Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are among the primary antioxidant enzymes that scavenge reactive oxygen species in the blood (ROS), thereby protecting against high levels of oxidative stress. The consequences of oxidative stress include cellular injury and tissue damage. High levels of oxidative stress have been implicated in the pathogenesis of acute coronary syndromes (ACS), however large clinical trials involving dietary antioxidant supplements have not shown a reduction in the rate of major adverse cardiovascular events (MACE).  In a cohort of 262 ACS patients we examined the relationship between GPx activity, SOD activity and MACE. Patients with MACE were found to have significantly lower levels of GPx activity than those without MACE, whereas SOD activity did not differ between the groups. Furthermore, dividing the patients into quartiles corresponding to levels of GPx activity demonstrated significantly higher rates of MACE in the lower quartile of GPx activity compared to the highest quartile.  Previous studies have demonstrated that deficiencies in GPx activity are associated with vascular dysfunction and platelet-dependent thrombosis, leading to the hypothesis that low levels of GPx activity would be associated with increased levels of platelet reactivity. In 51 ACS patients we did not observe a significant relationship between these two parameters, however we did demonstrate that increasing levels of GPx activity was associated with lower levels of ROS. ROS measures were based on the response of the platelets to addition of exogenous nitric oxide. Such an inverse relationship between GPx activity and levels of ROS is consistent with the view that GPx activity may play an important role in an ACS by reducing ROS-mediated damage, thereby protecting against MACE.  We examined levels of GPx activity, protein concentration and mRNA expression across populations of ACS patients, stable coronary disease patients and healthy subjects. Cardiovascular risk factors thought to influence levels of GPx activity were controlled for in all three cohorts. These studies demonstrated that GPx activity, protein and mRNA levels were significantly elevated in the ACS patients compared to the stable coronary disease patients and healthy subjects. Oxidised low-density lipoprotein (oxLDL), a widely used marker of oxidative stress, was also significantly elevated in the ACS patients compared to the other two cohorts.  In a study examining the temporal changes in GPx activity in the acute phase of an ACS, GPx activity was found to be highly dynamic, with no consistent single time point that identified when peak activity occurred. In the majority of patients, levels of oxLDL were found to peak prior to, or at the same time, as peak GPx activity, suggesting that GPx activity was modulated by changes in oxidative stress.  In conclusion, the elevated levels of GPx activity observed in ACS patients were found to be highly dynamic throughout an ACS event. However those with lower levels of GPx activity have an increased risk of adverse clinical outcomes that may be due to an inadequate defence against levels of ROS. Whether these patients can be accurately identified and targeted with an appropriate therapeutic intervention warrants further investigation.