Impaired Cardiovascular Function Caused by Different Stressors Elicits a Common Pathological and Transcriptional Response in Zebrafish Embryos
- Authors
- Chen, J.
- ID
- ZDB-PUB-130712-11
- Date
- 2013
- Source
- Zebrafish 10(3): 389-400 (Journal)
- Registered Authors
- Chen, Jing
- Keywords
- none
- MeSH Terms
-
- Animals
- Carbaryl
- Cell Proliferation
- Disease Models, Animal
- Edema, Cardiac/chemically induced
- Embryo, Nonmammalian
- Gene Expression
- Genes, cdc
- Heart/embryology*
- Heart Failure/chemically induced*
- Heart Failure/pathology
- Morpholinos
- Myocardial Contraction
- Myocardium/pathology
- Phenotype
- Tretinoin
- Valproic Acid
- Zebrafish
- PubMed
- 23837677 Full text @ Zebrafish
Zebrafish embryos have been widely used to study the genes and processes needed for normal vertebrate heart development. We recently observed that exposure to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) or retinoic acid (RA) produces very similar signs of heart failure in developing zebrafish via divergent molecular pathways. The fact that diverse stressors and mutations cause severe pericardial edema and circulatory collapse in developing zebrafish has been largely unexplored. We hypothesized that unrelated chemicals can trigger a common pathological response leading to the same end-stage heart failure. To test this hypothesis, we compared the effects of TCDD, RA, carbaryl, valproic acid, and morpholino oligonucleotide (MO) knockdown of TBX5 on the developing heart in zebrafish embryos. These model stressors have all been previously reported to affect zebrafish heart development, and elicited very similar signs of embryonic heart failure. Microarray analysis showed that one cluster of 92 transcripts affected by these different treatments was significantly downregulated by all treatments. This gene cluster is composed of transcripts required for chromosome assembly, DNA replication, and cell cycle progression. We refer to this cluster as the cell cycle gene cluster (CCGC). Immunohistochemistry revealed that downregulation of the CCGC precedes a halt in cardiomyocyte proliferation in the hearts of zebrafish exposed to any of the treatments. Previous work has shown that the initial response to TCDD is a decrease in cardiac output. Since this precedes the signs of edema, heart failure, and fall in CCGC expression, we postulated that any factor that decreases cardiac output will produce the same syndrome of heart failure responses. To test this, we used MO knockdown of cardiac troponin T2 (TNNT2) to specifically block contractility. The TNNT2-MO produced exactly the same signs of cardiotoxicity as the other treatments, including downregulation of the signature CCGC. Our results indicate that agents altering cardiac output can have amplified consequences during specific periods in development.