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Cardiovascular Research 2002 53(4):936-943; doi:10.1016/S0008-6363(01)00506-5
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation

Keita Kunisada*,1, Eiroh Tone1, Shinji Negoro, Yoshikazu Nakaoka, Yuichi Oshima, Tomoaki Osugi, Masanobu Funamoto, Masahiro Izumi, Yasushi Fujio, Hisao Hirota and Keiko Yamauchi-Takihara

Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

keita.kunisada{at}ma5.seikyou.ne.jp

* Corresponding author. Tel.: +81-6-6879-3835; fax: +81-6-6879-3839

Objective: We recently reported that doxorubicin (Dox), an effective anti-cancer drug, induces apoptosis in cardiac myocytes in association with reduction of Bcl-xl expression. In the present study, we further examined whether overexpression of Bcl-xl ameliorates Dox-induced cardiac myocyte damage. Methods and results: Overexpression of the Bcl-xl gene by adenovirus vector resulted in an 11-fold increase in Bcl-xl protein in neonatal rat cardiac myocytes (BCL) compared to that in cells with β-galactosidase gene transfection (CTL). Although Dox treatment generated similar amounts of reactive oxygen species (ROS) in BCL and CTL, cell viability was maintained and the number of apoptotic cardiac myocytes was significantly decreased in BCL. Cytochrome c release and enhanced caspase-3 activity after Dox treatment were significantly suppressed and Bax expression level was decreased in BCL. Cardiac-specific gene expression is known to be inhibited by Dox. The expression of cardiac {alpha}-actin and sarcoplasmic reticulum Ca2+-ATPase 2a mRNA was equally inhibited in BCL and CTL after Dox treatment. Conclusions: Overexpression of Bcl-xl in cardiac myocytes failed to regulate Dox-induced ROS generation and cardiac-specific gene downregulation but inhibited apoptosis accompanied by reduction of Bax protein.

KEYWORDS Apoptosis; Free radicals; Gene therapy; Heart failure; Mitochondria

1 These authors contributed equally to this study.


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