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Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression

  • Organ Toxicity and Mechanisms
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Abstract

Azole antifungals such as ketoconazole are generally known to induce a variety of heart function side effects, e.g., long-QT syndrome and ventricular arrhythmias. However, a clear mechanism for the action of ketoconazole in heart cells has not been reported. In the present study, we assessed the correlation between ketoconazole-induced apoptosis and the alteration of genes in response to ketoconazole in rat cardiomyocytes. Cardiomyocyte viability was significantly inhibited by treatment with ketoconazole. Ketoconazole also stimulated H2O2 generation and TUNEL-positive apoptosis in a dose-dependent manner. DNA microarray technology revealed that 10,571 genes were differentially expressed by more than threefold in ketoconazole-exposed cardiomyocytes compared with untreated controls. Among these genes, parkin, which encodes a component of the multiprotein E3 ubiquitin ligase complex, was predominantly overexpressed among those classified as apoptosis- and reactive oxygen species (ROS)-related genes. The expression of parkin was also elevated in cardiomyocytes treated with exogenous H2O2. Moreover, cell viability and apoptosis in response to ketoconazole were inhibited in cardiomyocytes treated with ROS inhibitors and transfected with parkin siRNA. From the present findings, we concluded that ketoconazole may increase the expression of parkin via the ROS-mediated pathway, which consequently results in the apoptosis and decreased viability of cardiomyocytes.

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Acknowledgments

This research was supported by a Grant (08172KFDA508) from Korea Food & Drug Administration in 2008 and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF 2010-0013344).

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The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea

      Kyung Jong Won, Kang Pa Lee, Suyeol Yu, Donghyen Lee, Dong-Youb Lee, Seung Hyo Jung, Suji Baek & Bokyung Kim

    2. Department of Cosmetic Science, College of Natural Sciences, Hoseo University, Asan, 336-795, Korea

      Hwan Myung Lee

    3. Department of Physical Therapy, College of Public Health and Welfare, Yongin University, Yongin, 449-714, Korea

      Junghwan Kim

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    1. Kyung Jong Won
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    Correspondence to Bokyung Kim.

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    Kyung Jong Won and Kang Pa Lee have contributed equally to this work.

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    Won, K.J., Lee, K.P., Yu, S. et al. Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression. Arch Toxicol 89, 1871–1880 (2015). https://doi.org/10.1007/s00204-015-1502-0

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