title: Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation.
abstract: 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.
  
  
  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 beta-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 Ca(2+)-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.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. keita.kunisada@ma5.seikyiou.ne.jp
authors.forename: Keita
authors.initials: K
authors.lastname: Kunisada
authors.forename: Eiroh
authors.initials: E
authors.lastname: Tone
authors.forename: Shinji
authors.initials: S
authors.lastname: Negoro
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Osugi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Funamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Izumi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Hisao
authors.initials: H
authors.lastname: Hirota
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004317:Doxorubicin / Q000633:toxicity*; D015316:Genetic Therapy / Q000379:methods; D006321:Heart / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D009206:Myocardium / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004317:Doxorubicin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases