From Mice to Men

More than 1 million Americans experience new or recurrent myocardial infarction (MI) annually1 with clinical outcomes strongly related to infarct size and the deleterious effects of ventricular remodeling.2,3 Standard MI treatments are appropriately directed at early reperfusion, antiplatelet/lipid-lowering therapies, and the administration of β-blockers and angiotensin-converting enzyme inhibitors to help reduce adverse post-MI ventricular remodeling. However, there is strong evidence to suggest that inflammation and the generation of reactive oxygen species, such as the superoxide anion (O2−), contribute substantially to myocardial ischemia/reperfusion injury.4 Thus, there is great interest in developing novel therapies targeting postinfarct inflammatory processes, including oxidative stress.Article see p 478Attenuating the effects of O2− is an attractive potential therapy for MI. Not only does O2− directly damage tissue through the peroxidation of lipids and oxidation of sulfhydryl groups,5 but it also reacts with NO very rapidly, leading to the formation of another reactive oxidizing agent, peroxynitrate (ONOO−), and to decreased levels of NO, an extremely important cardioprotective regulator of cellular function and survival.6 Extracellular superoxide dismutase (EcSOD), a key enzyme that is secreted into the extracellular space and catalyzes the dismutation of O2− to hydrogen peroxide and molecular oxygen, has been shown to attenuate ischemia/reperfusion injury by limiting the direct effects of O2− and ONOO− as well as increasing NO bioavailability.7 To date, administration of antioxidant therapies after MI has been disappointing in patients with intravenous infusion of any of the 3 major superoxide dismutase enzymes, showing mixed results.8,9Because oxidative stress may last for weeks to months after MI, therapies need to be tailored to exert a sustained, localized antioxidant effect. As a result, parenteral …