Amiodarone, an Anti-arrhythmia Drug, Inhibits Epithelial to Mesenchymal Transformation and Causes Cardiac Valve Defect during Zebrafish Embryogenesis
Date Issued
2008
Date
2008
Author(s)
Chen, Ta-Yuan
Abstract
Amiodarone, a type Ⅲ anti-arrhythmia drug, is commonly used to treat arrhythmia, including pregnant women. In order to develop an animal model for studying the effect of Amiodarone on embryonic development, we used zebrafish due to its transparent embryo which makes dynamical observation be possible. When zebrafish embryos were treated with 15 μM Amiodarone from 10 hour post-fertilization (hpf) to 72 hpf, blood regurgitation between ventricle and atrium was found. Whole mount in situ hybridization showed that versican and has2, molecular markers for cardiac valves were over-expressed ectopically at 72 hpf, suggesting that Amiodarone causes embryos to have cardiac valve defect. Moreover, VE-cadherin (cdh5), a marker downregulate during epithelial to mesenchymal transformation (EMT) which is an important process during cardiac valve formation at cardiac valve was also overexpression at cardiac valves, indicating that EMT during cardiac valve development was inhibited by treating Amiodarone. After knockdown of versican by injecting 16 ng versican-morpholino (MO), the expression of cdh5 was downregulated at 72 hpf, suggesting that versican modulates the cdh5 expression. Using harmonic optical microscopy and two-photon fluorescence microscopy, we observed in vivo that valves were not formed in the Amiodarone-treated embryos derived from zebrafish transgenic line Tg(cmlc2:HcRFP), whose RFP reporter was driven by heart-specific promoter cmlc2. Histochemical examination of embryos also strengthened the evidence that cardiac valve was defective due to Amiodarone treatment. Taken together, our findings conclude that Amiodarone overexpress versican to inhibit cardiac valve formation due to repression of EMT during embryonic cardiac valve development.
Subjects
zebrafish
valve
EMT
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