Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo.
Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.
Ueno
Michihiko
M
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki, Japan.
Kakinuma
Yoshihiko
Y
Yuhki
Koh-ichi
K
Murakoshi
Nobuyuki
N
Iemitsu
Motoyuki
M
Miyauchi
Takashi
T
Yamaguchi
Iwao
I
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004452:Echocardiography; D019332:Endothelin-1 / Q000378:metabolism; D004789:Enzyme Activation; D006352:Heart Ventricles / Q000166:cytology*; D007275:Injections, Intravenous; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D012333:RNA, Messenger; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases