title: Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression.
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.
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Kyung Jong
authors: KJ
authors: Won
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Kang Pa
authors: KP
authors: Lee
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Suyeol
authors: S
authors: Yu
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Donghyen
authors: D
authors: Lee
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Dong-Youb
authors: DY
authors: Lee
authors: Department of Cosmetic Science, College of Natural Sciences, Hoseo University, Asan, 336-795, Korea.
authors: Hwan Myung
authors: HM
authors: Lee
authors: Department of Physical Therapy, College of Public Health and Welfare, Yongin University, Yongin, 449-714, Korea.
authors: Junghwan
authors: J
authors: Kim
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Seung Hyo
authors: SH
authors: Jung
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
authors: Suji
authors: S
authors: Baek
authors: Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea. bkkim2@kku.ac.kr.
authors: Bokyung
authors: B
authors: Kim
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007654:Ketoconazole / Q000633:toxicity*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000935:Antifungal Agents; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D007654:Ketoconazole
keywords: Apoptosis; Cardiomyocytes; DNA array; Ketoconazole; Parkin protein