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ToxSci Advance Access originally published online on September 6, 2007
Toxicological Sciences 2007 100(2):486-494; doi:10.1093/toxsci/kfm235
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aristolochic Acid Induces Heart Failure in Zebrafish Embryos That is Mediated by Inflammation

Cheng-chen Huang*,1, Peng-Chi Chen*,{dagger}, Chin-Wei Huang* and John Yu*,{dagger}

* Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan {dagger} Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan

1 To whom correspondence should be addressed at Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan. Fax: 886-2-2789-9503. E-mail: huangcc{at}gate.sinica.edu.tw.

Correspondence may also be addressed to John Yu. E-mail: johnyu{at}gate.sinica.edu.tw.

Received July 9, 2007; accepted August 29, 2007


  Abstract

Aristolochic Acid (AA) is a component of Chinese herbs that has been found to be toxic to multiple organs in adults. Its toxicity to developing embryos has not been reported. Here, we describe that AA specifically causes heart defects in developing zebrafish embryos in a dosage-dependent manner. The treated embryos are able to develop their hearts normally up to 24 h postfertilization, when cardiac contraction initiates, but begin to show deformation and reduction of the hearts followed by gradual contractility loss and eventually lethality, suggesting that AA is primarily affecting cardiac physiology rather than cardiogenesis. Histological analyses reveal that the AA-treated hearts develop hypertrophy and disorganization of cardiomyocytes and loss of endocardium. By transmission electron microscopy, we observed broken and disorganized cardiac fibers in the AA-treated hearts. AA induces the expression of proinflammation genes, including cox-2, IL-1ß, and others. The AA-induced cardiac defects can be attenuated by the cox-2 antagonist NS398 via reducing the expression of the inflammatory genes. This attenuation could be further enhanced by known heart failure drugs, such as angiotensin-converting enzyme inhibitor and ß-adrenergic receptor antagonist. In contrast, the heart defects are enhanced by a ß-adrenergic receptor agonist. In summary, AA causes profound toxicity to zebrafish embryos that exhibit pathophysiological and pharmacological features resembling those of heart failure in humans and other model organisms, and thus, zebrafish could be a new model for studies on heart failure.

Key Words: aristolochic acid; zebrafish; heart failure; inflammation; cox-2.


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