Aristolochic Acid induces heart failure in zebrafish embryos that is mediated by inflammation.
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-1beta, 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 beta-adrenergic receptor antagonist. In contrast, the heart defects are enhanced by a beta-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.
Huang
Cheng-Chen
CC
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan. huangcc@gate.sinica.edu.tw
Chen
Peng-Chi
PC
Huang
Chin-Wei
CW
Yu
John
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D004357:Drug Synergism; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000503:physiopathology; D004699:Endocardium / Q000187:drug effects / Q000196:embryology / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D006333:Heart Failure / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D009153:Mutagens / Q000633:toxicity*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015027:Zebrafish