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Temporal effects of catalase overexpression on healing after myocardial infarction.

ABSTRACT: 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.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.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.

SUBMITTER: Pendergrass KD

PROVIDER: S-EPMC3076122 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Temporal effects of catalase overexpression on healing after myocardial infarction.

Pendergrass Karl D KD Varghese Susan T ST Maiellaro-Rafferty Kathryn K Brown Milton E ME Taylor W Robert WR Davis Michael E ME

Circulation. Heart failure 20101022 1

<h4>Background</h4>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.<h4>Methods and results</h4>We developed a tamoxifen-inducible, cardiomyocyte-sp ...[more]

PMID: 20971939

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Project description:Both skin wound healing and the cardiac response to myocardial infarction (MI) progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3-mm skin wound using a disposable biopsy punch and the skin wound was imaged daily until closure. The same set of animals was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology was measured by echocardiography at baseline and MI days 3 and 7. Animals that survived until day 7 were grouped as survivors, and animals that died from MI were grouped as nonsurvivors. Survivors had faster skin wound healing than nonsurvivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). N-glycoproteome profiling of MI day 3 plasma revealed α2-macroglobulin and ELL-associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. To investigate the clinical relevance of α2-macroglobulin, we mapped the plasma glycoproteome in patients with MI 48 h after admission and in healthy controls. In patients, α2-macroglobulin was increased 48 h after MI. Apolipoprotein D, another plasma glycoprotein, detrimentally regulated both skin and cardiac wound healing in male but not female mice by promoting inflammation. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.NEW & NOTEWORTHY Faster skin wound healers had more efficient cardiac healing after myocardial infarction (MI). Two plasma proteins at D3 MI, EAF1 and A2M, predicted MI death in 66% of cases. ApoD regulated both skin and cardiac wound healing in male mice by promoting inflammation. The skin was a mirror to the heart and common pathways linked wound healing across organs.

Project description:Background The mitochondrial mRNA-binding protein FASTKD1 (Fas-activated serine/threonine [FAST] kinase domain-containing protein 1) protects myocytes from oxidative stress in vitro. However, the role of FASTKD1 in the myocardium in vivo is unknown. Therefore, we developed cardiac-specific FASTKD1 transgenic mice to test the effects of this protein on experimental myocardial infarction (MI). Methods and Results Transgenic mouse lines with cardiac myocyte-specific overexpression of FASTKD1 to varying degrees were generated. These mice displayed normal cardiac morphological features and function at the gross and microscopic levels. Isolated cardiac mitochondria from all transgenic mouse lines showed normal mitochondrial function, ATP levels, and permeability transition pore activity. Male nontransgenic and transgenic mice from the highest-expressing line were subjected to 8 weeks of permanent coronary ligation. Of nontransgenic mice, 40% underwent left ventricular free wall rupture within 7 days of MI compared with 0% of FASTKD1-overexpressing mice. At 3 days after MI, FASTKD1 overexpression did not alter infarct size. However, increased FASTKD1 resulted in decreased neutrophil and increased macrophage infiltration, elevated levels of the extracellular matrix component periostin, and enhanced antioxidant capacity compared with control mice. In contrast, markers of mitochondrial fusion/fission and apoptosis remained unaltered. Instead, transcriptomic analyses indicated activation of the integrated stress response in the FASTKD1 transgenic hearts. Conclusions Cardiac-specific overexpression of FASTKD1 results in viable mice displaying normal cardiac morphological features and function. However, these mice are resistant to MI-induced cardiac rupture and display altered inflammatory, extracellular matrix, and antioxidant responses following MI. Moreover, these protective effects were associated with enhanced activation of the integrated stress response.

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Temporal effects of catalase overexpression on healing after myocardial infarction.

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Temporal effects of catalase overexpression on healing after myocardial infarction.

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