Temporal Effects of Catalase Overexpression on Healing Following Myocardial Infarction Running Title: Pendergrass et al: Inducible Catalase Overexpression and Infarction

Background Reactive oxygen species, such as hydrogen peroxide (H2O2), contribute to progression of dysfunction following myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H2O2 scavenging on cardiac function after infarction using an inducible system. Methods and Results We developed a tamoxifen-inducible, cardiomyocyte-specific catalase overexpressing mouse. Catalase overexpression was induced either 5 days pre or post-MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H2O2 levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Pro-inflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase, despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days. Conclusions In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression prior to MI. Scavenging of H2O2 however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H2O2 levels, rather than acute levels immediately following MI, may be critical in directing remodeling and cardiac function at later time points.