Effects of probucol on changes of antioxidant enzymes in adriamycin-induced cardiomyopathy in rats.
OBJECTIVE
The clinical usefulness of doxorubicin (adriamycin, ADR) is restricted by the risk of developing congestive heart failure. Probucol has been reported to completely prevent ADR cardiomyopathy without interfering with its antitumor effects. The current study investigated the effects of ADR and probucol on antioxidant enzyme gene expression during adriamycin-induced cardiomyopathy in a rat model.


METHODS
The mRNA abundance by Northern and immunoreactive protein levels by Western blotting of myocardial antioxidant enzymes, glutathione peroxidase (GSHPx), manganese superoxide dismutase (MnSOD) and catalase (CAT) were examined in relation to the enzyme activities in hemodynamically assessed control and treated animals.


RESULTS
At 3 weeks post-treatment duration, ADR caused heart failure which was prevented by probucol. MnSOD mRNA abundance as well as protein levels were depressed by ADR treatment by 45% and 20%, respectively, and this change was prevented by probucol. However, the mRNA and protein levels of GSHPx and CAT were not significantly changed by ADR or probucol. ADR had no effect on SOD activity but this enzyme activity was increased by probucol and probucol plus ADR. GSHPx enzyme activity was decreased and oxidative stress as indicated by TBARS was increased by ADR and these changes were also modulated by probucol.


CONCLUSIONS
An increase in oxidative stress, GSHPx inactivation and MnSOD downregulation during ADR cardiomyopathy were prevented by probucol treatment.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
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Danelisen
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Belló-Klein
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D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents; D000975:Antioxidants / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002374:Catalase / Q000235:genetics; D004317:Doxorubicin; D005979:Glutathione Peroxidase / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced* / Q000517:prevention & control*; D015227:Lipid Peroxidation; D008297:Male; D011341:Probucol / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D011341:Probucol