Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo
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...
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doaj-9f02df55a0bf4e549aef65817164b3172020-11-25T02:06:07ZengElsevierJournal of Pharmacological Sciences1347-86132006-01-011012151158Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In VivoUeno Michihiko0Kakinuma Yoshihiko1Yuhki Koh-ichi2Murakoshi Nobuyuki3Iemitsu Motoyuki4Miyauchi Takashi5Yamaguchi Iwao6Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, Japan; Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, JapanCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, Japan; Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi 783-8505, Japan; Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Corresponding author (affiliation #3). kakinuma@med.kochi-u.ac.jpCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, Japan; Department of Pharmacology, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, JapanCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, JapanCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, JapanCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, Japan; Center for TARA (Tsukuba Advanced Research Alliance), University of Tsukuba, Tsukuba, Ibaraki 305-8575, JapanCardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Tsukaba, Ibaraki 305-8575, JapanAbstract.: 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. Keywords:: doxorubicin, apoptosis, cardiomyopathy, caspase, mitochondriahttp://www.sciencedirect.com/science/article/pii/S1347861319344603 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ueno Michihiko Kakinuma Yoshihiko Yuhki Koh-ichi Murakoshi Nobuyuki Iemitsu Motoyuki Miyauchi Takashi Yamaguchi Iwao |
spellingShingle |
Ueno Michihiko Kakinuma Yoshihiko Yuhki Koh-ichi Murakoshi Nobuyuki Iemitsu Motoyuki Miyauchi Takashi Yamaguchi Iwao Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo Journal of Pharmacological Sciences |
author_facet |
Ueno Michihiko Kakinuma Yoshihiko Yuhki Koh-ichi Murakoshi Nobuyuki Iemitsu Motoyuki Miyauchi Takashi Yamaguchi Iwao |
author_sort |
Ueno Michihiko |
title |
Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo |
title_short |
Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo |
title_full |
Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo |
title_fullStr |
Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo |
title_full_unstemmed |
Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo |
title_sort |
doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2006-01-01 |
description |
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. Keywords:: doxorubicin, apoptosis, cardiomyopathy, caspase, mitochondria |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319344603 |
work_keys_str_mv |
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