Torti S V, Akimoto H, Lin K, Billingham M E, Torti F M
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
J Mol Cell Cardiol. 1998 Jun;30(6):1173-80. doi: 10.1006/jmcc.1998.0681.
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.
有研究表明，活性氧物质在心肌缺血再灌注后的损伤过程中发挥重要作用。氧自由基也可能导致蒽环类抗生素（如阿霉素）的心脏毒性。我们测试了先前在用阿霉素处理的心肌细胞中观察到的对肌肉基因表达的选择性抑制，是否可能反映了心脏组织中氧化应激引发的更普遍的反应。将培养的心肌细胞暴露于过氧化氢或葡萄糖氧化酶中，并测量其对肌肉基因表达的影响。暴露于这些试剂导致肌肉特异性基因心脏α-肌动蛋白、肌钙蛋白I、肌球蛋白轻链2（慢型）和肌酸激酶M亚型的mRNA水平降低，而不影响非肌肉基因丙酮酸激酶和β-肌动蛋白的水平。这种效应的程度与阿霉素观察到的相似。尽管过氧化氢清除酶过氧化氢酶以及细胞内自由基清除剂N-乙酰半胱氨酸和1,3-二甲基-2-硫脲对阿霉素依赖性基因表达降低没有影响，但它们抑制了过氧化氢介导的肌肉基因表达降低。这些观察结果表明，氧自由基通过一条不同于阿霉素所利用的途径调节心肌细胞中的肌肉基因表达。
