Inhibition of Copper-Zinc Superoxide Dismutase Induces Cell Growth, Hypertrophic Phenotype, and Apoptosis in Neonatal Rat Cardiac Myocytes In Vitro
| Autor: | Krishna Singh, Wilson S. Colucci, David R. Pimental, Deborah A. Siwik, John D. Tzortzis, Patrick J. Pagano, Douglas B. Sawyer, Donny L.F. Chang |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Programmed cell death
medicine.medical_specialty Physiology Muscle Fibers Skeletal Apoptosis Cardiomegaly In Vitro Techniques DNA laddering medicine.disease_cause Gene Expression Regulation Enzymologic Superoxide dismutase chemistry.chemical_compound Superoxides Internal medicine In Situ Nick-End Labeling medicine Animals Xanthine oxidase Cells Cultured Chelating Agents TUNEL assay biology Superoxide Dismutase Superoxide Myocardium Cell Membrane Hypertrophy Molecular biology Rats Oxidative Stress Phenotype Endocrinology Animals Newborn chemistry biology.protein Ditiocarb Cardiology and Cardiovascular Medicine Cell Division Oxidative stress Intracellular |
| Zdroj: | Circulation Research. 85:147-153 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/01.res.85.2.147 |
| Popis: | Abstract —Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac myocytes. Neonatal rat ventricular myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 μmol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro–atrial natriuretic peptide, and c- fos mRNAs and decreased sarcoplasmic reticulum Ca 2+ ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 μmol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl transferase–mediated nick end-labeling (TUNEL), and increased bax mRNA expression. DDC-stimulated apoptosis was inhibited by the SOD/catalase mimetic EUK-8. The growth and apoptotic effects of DDC were mimicked by superoxide generation with xanthine plus xanthine oxidase. Thus, increased intracellular superoxide resulting from inhibition of SOD causes activation of a growth program and apoptosis in cardiac myocytes. These findings support a role for oxidative stress in the pathogenesis of myocardial remodeling and failure. |
| Databáze: | OpenAIRE |
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