Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo

Full Papers

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Japan">Michihiko Ueno, Department of Cardiovascular Control, Kochi Medical School, Japan
Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Japan">Yoshihiko Kakinuma, Department of Pharmacology, Asahikawa Medical College, Japan">Koh-ichi Yuhki, Nobuyuki Murakoshi, Motoyuki Iemitsu, Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Japan">Takashi Miyauchi, Iwao Yamaguchi

Author information

Michihiko Ueno
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Japan
Yoshihiko Kakinuma
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Department of Cardiovascular Control, Kochi Medical School, Japan
Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Japan
Koh-ichi Yuhki
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Department of Pharmacology, Asahikawa Medical College, Japan
Nobuyuki Murakoshi
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Motoyuki Iemitsu
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Takashi Miyauchi
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan
Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Japan
Iwao Yamaguchi
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Japan

Keywords: doxorubicin, apoptosis, cardiomyopathy, caspase, mitochondria

JOURNAL FREE ACCESS

2006 Volume 101 Issue 2 Pages 151-158

DOI https://doi.org/10.1254/jphs.FP0050980

View "Advance Publication" version (June 10, 2006).

Details

Abstract

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.

Corresponding author

Register with J-STAGE for free!