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Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis
Sreesatya Raju Vulapalli1, Zhongyi Chen, Balvin H L Chua
1Cardiology Unit, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642, USA. raju_vulapalli@urmc.rochester.edu
Insights
Heme oxygenase-1 (HO-1) overexpression in the heart protects against ischemia-reperfusion injury. This cardioprotective effect in mice is linked to reduced cardiomyocyte apoptosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Physiology
Background:
- Heme oxygenase (HO)-1 is an enzyme involved in heme metabolism.
- Prior research suggests a cardioprotective role for HO-1 in heart failure.
- Investigating HO-1's role in preventing cardiomyocyte apoptosis and cardiac dysfunction is crucial.
Purpose of the Study:
- To determine if HO-1 prevents cardiomyocyte apoptosis and cardiac dysfunction following ischemia-reperfusion (I/R) injury.
- To assess the cardioprotective effects of HO-1 overexpression in the heart.
Main Methods:
- Generated transgenic mice with cardiac-specific HO-1 overexpression using the alpha-myosin heavy chain promoter.
- Utilized isolated heart preparations to evaluate functional recovery after ischemia-reperfusion.
- Assessed I/R injury in intact animals via coronary ligation and reperfusion.
- Quantified cardiomyocyte apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation.
Main Results:
- HO-1 transcript and protein levels were significantly elevated in the hearts of transgenic mice.
- Transgenic hearts demonstrated enhanced functional recovery during reperfusion compared to controls.
- HO-1 overexpression significantly reduced cardiac apoptosis in mice subjected to I/R injury.
- Fewer apoptotic myocytes were observed in HO-1 overexpressing hearts.
Conclusions:
- Cardioselective overexpression of HO-1 confers a protective effect against myocardial I/R injury in mice.
- The cardioprotective mechanism of HO-1 likely involves an antiapoptotic action.
- HO-1 plays a significant role in mitigating cardiac damage during ischemic events.
Abstract:
Heme oxygenase (HO)-1 converts heme to bilirubin, carbon monoxide, and iron. Our prior work has suggested a cardioprotective role for HO-1 in heart failure. To test whether HO-1 (heat shock protein 32) prevents cardiomyocyte apoptosis and cardiac dysfunction after ischemia-reperfusion (I/R), we generated transgenic mice overexpressing HO-1 in the heart under the control of the alpha-myosin heavy chain promoter. HO-1 transcript and protein increased markedly in the heart only. In an isolated heart preparation, we observed an enhanced functional recovery during reperfusion after ischemia in the transgenic hearts compared with nontransgenic controls. I/R injury was also performed in intact animals by coronary ligation and reperfusion to assess the protective role of HO-1 overexpression on heart apoptosis. HO-1 overexpression reduced cardiac apoptosis, as evidenced by fewer terminal deoxynucleodidyl transferase-mediated dUTP nick-end labeling-positive or in situ oligo ligation-positive myocytes, compared with nontransgenic mice. Our results indicate that cardioselective overexpression of HO-1 exerts a cardioprotective effect after myocardial I/R in mice, and this effect is probably mediated via an antiapoptotic action of HO-1.