Selective inhibition of muscle gene expression by oxidative stress in cardiac cells.
Reactive oxygen species have been suggested to play an important role in damage to cardiac tissue following ischemia and reperfusion. Oxygen radicals may also contribute to the cardiotoxicity of the anthracycline antibiotics, such as doxorubicin. We tested whether a selective inhibition of muscle gene expression, previously observed in cardiocytes treated with doxorubicin, might be reflective of a more generalized response evoked by oxidative stress in cardiac tissue. Cardiocytes in culture were exposed to hydrogen peroxide or glucose oxidase, and the effects on muscle gene expression were measured. Exposure to these agents led to a reduction in the levels of mRNA for the muscle-specific genes cardiac alpha-actin, troponin I, myosin light chain 2 (slow), and M isoform of creatine kinase, without affecting levels of the non-muscle genes pyruvate kinase and beta-actin. The magnitude of this effect was similar to that observed with doxorubicin. Although the hydrogen peroxide scavenging enzyme catalase and the intracellular radical scavengers N-acetylcysteine and 1,3-dimethyl-2-thiourea were without effect on doxorubicin-dependent reduction in gene expression, they inhibited the reduction in muscle gene expression mediated by hydrogen peroxide. These observations suggest that oxygen free radicals modulate muscle gene expression in cardiocytes by a pathway distinct from that utilized by doxorubicin.
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
S V
SV
Torti
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H
Akimoto
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K
Lin
M E
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Billingham
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Torti
D000818:Animals; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005949:Glucose Oxidase / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D018384:Oxidative Stress / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016166:Free Radical Scavengers; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D002374:Catalase