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Selective inhibition of muscle gene expression by oxidative stress in cardiac cells
1Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Abstract:
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.
Insights
Oxidative stress, caused by oxygen free radicals, reduces muscle gene expression in heart cells. This effect is distinct from doxorubicin-induced gene changes, suggesting different cellular pathways are involved.
Area of Science:
- Cardiology
- Molecular Biology
- Toxicology
Background:
- Reactive oxygen species (ROS) are implicated in cardiac tissue damage after ischemia/reperfusion.
- Oxygen radicals may contribute to cardiotoxicity from anthracycline antibiotics like doxorubicin.
Purpose of the Study:
- To investigate if oxidative stress generally inhibits muscle gene expression in cardiac cells.
- To determine if doxorubicin's effect on muscle gene expression is mediated by oxidative stress.
Main Methods:
- Cultured cardiocytes were exposed to hydrogen peroxide or glucose oxidase.
- Muscle-specific (cardiac alpha-actin, troponin I, MLC-2, CK-M) and non-muscle (pyruvate kinase, beta-actin) gene expression was measured via mRNA levels.
Main Results:
- Hydrogen peroxide and glucose oxidase reduced mRNA levels of muscle-specific genes, similar to doxorubicin.
- Non-muscle gene expression remained unaffected.
- Catalase and radical scavengers blocked peroxide-induced but not doxorubicin-induced gene expression changes.
Conclusions:
- Oxidative stress selectively reduces muscle gene expression in cardiocytes.
- The pathway for oxidative stress-mediated gene modulation differs from that of doxorubicin.