title: The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes.
abstract: Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression.
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.|Department of Medicine, Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Ho
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Yen
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.|Department of Medical Research, Cathay General Hospital, New Taipei City 221, Taiwan, Republic of China.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan, Republic of China.
authors.forename: Wei-Shiang
authors.initials: WS
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.|Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: James Yi-Hsin
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D020746:Calcium Channels, L-Type; D035683:MicroRNAs; C503803:Myog protein, rat; D018008:Myogenin; D004317:Doxorubicin
keywords: cardio-toxicity; doxorubicin; gene regulation; mRNA expression profile; myogenin