Myocardial expression of baculoviral p35 alleviates doxorubicin-induced cardiomyopathy in rats.
The clinical use of doxorubicin, one of the most effective antitumor drugs, is limited by its cardiotoxicity, which results in irreversible cardiomyopathy and congestive heart failure. This study aimed to evaluate a gene therapy approach using adenovirus-mediated expression of p35, a baculoviral antiapoptotic gene, for alleviating doxorubicin-induced cardiomyopathy. In cultured neonatal rat cardiomyocytes, transduction with a recombinant adenoviral vector expressing p35 (Ad2/CMVp35) but not a control adenoviral vector expressing no transgene (Ad2/CMVEV) significantly inhibited doxorubicin-induced increase in cellular reactive oxygen species (ROS), the activity of caspases 8 and 3, cytochrome c release, and apoptosis. Direct injection of Ad2/CMVp35 into the left ventricular wall inhibited myocardial caspase 3 activity and apoptosis and improved left ventricular performance in rats treated with doxorubicin, whereas the same dose of Ad2/CMV beta gal encoding beta-galactosidase had no effect. These results suggest that adenovirus-mediated expression of p35 protects cardiomyocytes against doxorubicin cardiotoxicity, possibly by inhibiting caspase activity and by reducing cellular ROS levels. Localized delivery of gene transfer vectors expressing an antiapoptotic protein such as p35 to the myocardium may represent a therapeutic approach to alleviate doxorubicin-induced cardiomyopathy.
Date
Taro
T
Genzyme Corporation, Framingham, MA 01701, USA.
Luo
Zhengyu
Z
Yamakawa
Midori
M
Belanger
Adam J
AJ
Scaria
Abraham
A
Cheng
Seng H
SH
Gregory
Richard J
RJ
Mochizuki
Seibu
S
Jiang
Canwen
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity*; D015316:Genetic Therapy; D005822:Genetic Vectors; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D004317:Doxorubicin; D020169:Caspases