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Modulation of doxorubicin‐ induced oxidative stress and apoptosis through the phosphorylation of Akt/Ask1ser83 in rat cardiomyocytes
Author(s) -
Sharma Anita K.,
Ludke Ana,
AlShudiefat Abd AlRahman,
Bagchi Ashim K.,
Singal Pawan K.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.831.2
The clinical use of doxorubicin (DOX) against human malignancies is limited by its side effects of cardiomyopathy and heart failure. The underlying mechanism of DOX‐induced cardiotoxicity is still unclear. This study is investigating the role of Akt/Ask1 and the effect of trolox in DOX‐induced cardiotoxicity. Rat cardiomyocytes were exposed to DOX (5μM) for 24h without or with trolox (20μM) pretreatment for 4h. In a time course study , Akt activity decreased after 10 min of exposure to DOX until 24h. p38 showed a biphasic change with an up‐regulation up to 30 min and then another peak at 24h. JNK activity showed a steady increase up to 6h and was consistent up to 24h. p53 activity showed a steady rise until 24h. Activation of Ask1 was not observed up to 6h, however, it was up‐regulated at 24h. Activation of PARP, Caspase and Bax/Bcl‐xl also showed a time dependent increase up to 24h. Trolox pretreatment down‐regulated the DOX ‐induced increase in oxidative stress (OS) and promoted activity of Akt and Ask1 ser83 . Trolox attenuated above mentioned DOX‐induced cell signaling changes as well as apoptosis. Inhibition of Akt using wortmannin up‐ regulated phospho levels of Ask Thr845 and Bax/Bcl‐xl and down regulated Ask1 ser83 suggesting the role of Ask1 ser83 in trolox‐ modulation of DOX‐ induced OS and apoptosis. Thus, trolox could be used to modulate DOX –induced OS and apoptosis. (Supported by Manitoba Heart & Stroke Foundation)