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Temporal effects of catalase overexpression on healing after myocardial infarction
Karl D Pendergrass1, Susan T Varghese, Kathryn Maiellaro-Rafferty
1Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Insights
Sustained scavenging of hydrogen peroxide (H(2)O(2)) after myocardial infarction (MI) improved cardiac function and reduced scar formation. Acute H(2)O(2) reduction did not provide immediate functional benefits, suggesting a critical role for later time points.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Biomedical Science
Background:
- Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), exacerbate cardiac dysfunction post-myocardial infarction (MI).
- Conflicting results exist regarding the timing of intervention, with chronic overexpression studies differing from acute protein delivery findings.
Purpose of the Study:
- To investigate the temporal impact of cardiomyocyte-specific H(2)O(2) scavenging on cardiac function following MI.
- To utilize an inducible system to precisely control the timing of catalase overexpression.
Main Methods:
- Developed a tamoxifen-inducible, cardiomyocyte-specific catalase-overexpressing mouse model.
- Induced catalase overexpression either 5 days before or after MI induction.
- Measured cardiac catalase activity, H(2)O(2) levels, cardiac function, and gene expression (proinflammatory, fibrotic, collagen isoforms).
Main Results:
- Catalase overexpression significantly reduced cardiac H(2)O(2) levels at 7 and 21 days post-MI.
- Cardiac function improved at 21 days, but not acutely, when H(2)O(2) was scavenged.
- Overexpression abolished acute upregulation of proinflammatory and fibrotic genes, leading to reduced scar formation and altered collagen expression (decreased Collagen 1A, increased Collagen 3A).
Conclusions:
- Acute H(2)O(2) scavenging before MI did not yield immediate functional improvements.
- Sustained H(2)O(2) reduction post-MI mitigated inflammation and fibrosis, improving cardiac function at later time points.
- Sustained H(2)O(2) levels, rather than acute levels, are critical for cardiac remodeling and function post-MI.
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.
Methods And 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.
