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atio, thus failing to protect against adriamycin-induced changes in Bax/Bcl-xl ratio and
apoptosis.
The treatment with adriamycin was also found to cause an increase in the
expression of PPAR ô. Adriamycin treatment resulted in an increased expression of
PPAR ô, both in vivo and in vitro, which was prevented by the administration of
probucol, trolox and low doses of retinoic acid. The treatment with high doses of retinoic
acid did not result in a decrease of PPAR ô levels. Our gene chip anay studies also
showed that the administration of adriamycin resulted in an increased expression of
PPAR y and PPAR ô genes, which was prevented by the administration of probucol. The
administration of adriamycin also resulted in the decreased expression of cellular retinol
binding protein and cellular retinoic acid binding protein II which indicates the
disturbances in retinoic acid metabolism and signaling and this was prevented by the
administration of probucol.
It is concluded that adriamycin induced oxidative stress disrupts retinoic acid
signaling processes resulting in an increase in RAR/RXR ratio. The changes in
RAR/RXR receptor ratio correlated with the upregulation of pro-apoptotic proteins
leading to apoptosis. This apoptosis may play a significant role in the pathogenesis of
adriamycin-induced heart failure. The administration of antioxidants (probucol and
trolox) and low doses of retinoic acid result in a decrease in oxidative stress, the
RAR/RXR receptor ratio and offer protection against adriamycin-induced apoptosis.
High doses of retinoic acid, although acting as antioxidant, do not affect the changes in
RAR/RXR receptor ratio, thus failing to protect against adriamycin-induced apoptosis.