Temporal effects of catalase overexpression on healing after myocardial infarction.
BACKGROUND
Reactive oxygen species, such as hydrogen peroxide (H(2)O(2)), contribute to progression of dysfunction after 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 H(2)O(2) scavenging on cardiac function after infarction using an inducible system.


RESULTS
We developed a tamoxifen-inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H(2)O(2) levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory 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 before MI. Scavenging of H(2)O(2), however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H(2)O(2) levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points.
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Karl D
KD
Pendergrass
Susan T
ST
Varghese
Kathryn
K
Maiellaro-Rafferty
Milton E
ME
Brown
W Robert
WR
Taylor
Michael E
ME
Davis
D000818:Animals; D002374:Catalase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
D024042:Collagen Type I; D024061:Collagen Type III; D013629:Tamoxifen; D006861:Hydrogen Peroxide; D002374:Catalase