Role of oxidative stress in clofazimine-induced cardiac dysfunction in a zebrafish model.

Autor: Ng PCI; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China., Chan JYW; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China., Leung RKK; School of Public Health, University of Hong Kong, Hong Kong, China; Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China., Li J; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China., Ren Z; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China., Chan AWH; Department of Anatomical & Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China., Xu Y; Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China., Lee SS; Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China., Wang R; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China., Ji X; Faculty of Health Sciences, University of Macau, Macao, China., Zheng J; Faculty of Health Sciences, University of Macau, Macao, China., Chan DPC; Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China. Electronic address: denisechan@cuhk.edu.hk., Yew WW; Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China. Electronic address: yewww@cuhk.edu.hk., Lee SMY; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: simonlee@um.edu.mo.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2020 Dec; Vol. 132, pp. 110749. Date of Electronic Publication: 2020 Oct 02.
DOI: 10.1016/j.biopha.2020.110749
Abstrakt: Background: Clofazimine (CFZ), a riminophenazine, is now commonly used in the treatment of multidrug-resistant tuberculosis. However, its use may be potentially associated with cardiac dysfunction in some individuals. In this study, the zebrafish heart, by merit of its developmental and genetic characteristics being in homology with that of human, was chosen as an animal model for evaluation of such dysfunction.
Methods: Morphological and physiological parameters were used to assess cardiac dysfunction. Transcriptome analysis was performed, followed by validation with real-time quantitative PCR, for delineation of the relevant genomics.
Results: Exposure of 2 dpf zebrafish to 4 mg/L CFZ for 2 days, adversely affected cardiac functions including significant decreases in HR, SV, CO, and FS, with observable pathophysiological developments of pericardial effusion and blood accumulation in the heart, in comparison with the control group. In addition, genes which respond to xenobiotic stimulus, related to oxygen transport, glutathione metabolism and extracellular matrix -receptor interactions, were significantly enriched among the differentially up-regulated genes. Antioxidant response element motif was enriched in the 5000 base pair upstream regions of the differentially expressed genes. Co-administration of N-acetylcysteine was shown to protect zebrafish against the development of CFZ-induced cardiac dysfunction.
Conclusions: This study suggests an important role of oxidative stress as a major pathogenetic mechanism of riminophenazine-induced cardiac dysfunction.
(Copyright © 2020. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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