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Hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes
1Department of Pharmacology, University of Arizona, Skaggs Pharmaceutical Science Building, 1703 East Mabel Street, Tucson, Arizona, 85721, USA. chen@pharmacy.arizona.edu
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Hydrogen peroxide (H2O2) can induce both cell death and hypertrophy in cardiomyocytes. Surviving heart cells exposed to H2O2 undergo significant enlargement, indicating a hypertrophic response.
Area of Science:
- Cardiovascular Biology
- Cellular Pathology
- Oxidative Stress Research
Background:
- Cardiomyocyte hypertrophy and cell death are hallmarks of advanced heart failure.
- The specific triggers for these cellular changes in pathological conditions remain largely unknown.
- Oxidants, such as hydrogen peroxide (H2O2), are generated during aerobic metabolism and increase with ischemic reperfusion injury.
Purpose of the Study:
- To investigate the cellular effects of hydrogen peroxide (H2O2) on cardiomyocytes.
- To determine if H2O2 can induce cardiomyocyte hypertrophy or cell death.
- To elucidate the mechanisms underlying H2O2-induced cellular responses in heart cells.
Main Methods:
- Utilized H9C2 cells and primary cultured neonatal rat cardiomyocytes.
- Administered short-term pulse treatments with varying concentrations of H2O2.
- Assessed caspase activation, cell viability, nuclear morphology, cell size, volume, protein content, and cytoskeletal/myofibrillar structure.
Main Results:
- H2O2 treatment (≤250 microM) activated DEVD-sequence specific caspases, with peak activity at 200 microM H2O2 after 24 hours.
- A fraction of cardiomyocytes underwent apoptosis (nuclear condensation, detachment), but the majority (>55%) survived.
- Surviving cells exhibited significant hypertrophy, with increased surface area, volume (up to sixfold), and protein content (up to threefold) after 5 days, showing altered actin stress fibers and disrupted myofibrils.
Conclusions:
- Hydrogen peroxide (H2O2) can induce both apoptosis and hypertrophy in cardiomyocytes.
- While lethal doses of H2O2 cause cell death, lower doses promote significant cardiomyocyte hypertrophy.
- These findings suggest a dual role for oxidants in the cellular remodeling observed in heart failure progression.
Abstract:
Cardiomyocyte hypertrophy and cell death are often observed in the end stages of heart failure. The triggers of these two cellular processes are not known under most pathological conditions. Oxidants are by-products of aerobic metabolism. The level of oxidants increases as a result of ischemic reperfusion. Using H9C2 and primary cultured neonatal rat cardiomyocytes, we found that a 2-h pulse treatment with H(2)O(2) at 250 microM or lower caused activation of DEVD sequence specific caspases. The activity of DEVD-ase peaked with 200 microM H(2)O(2) at 24 h. While a fraction of the cells detached and showed nuclear condensation, the majority of the cells (>55%) survived the treatment and appeared to enlarge when cultured for 5 days. These cells showed increases in cell surface area, cell volume, and protein content. With 200 microM H(2)O(2), treated cells appeared to be six times bigger in volume and contained three times more protein per cell than untreated cells. The enlarged cells showed enhanced actin stress fibers and disrupted myofibrils. Our data indicate that while H(2)O(2) can cause cell death, the surviving cardiomyocytes undergo hypertrophy.