Zebrafish Cardiomyopathy Models

Cardiomyopathy (CM) manifests as myocardial defects with impaired systolic function. CMs can be ischemic or non-ischemic. Nonischemic CM can be broadly classified into hypertrophic, restrictive, and dilated (HCM, RCM, and DCM, respectively). The classification system is primarily built on the phenotypic tools available in human patients and enhanced by studies in animal models.

Zebrafish have a proven track record in uncovering the molecular mechanisms of human cardiovascular disease (CVD), including common forms of cardiomyopathy - dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). It was observed that some mutants generated from the forward genetic screen exhibited lack of blood circulation as well as pericardial edema. Through high-speed video imaging of the embryonic heart, a standard non-invasive assessment of cardiac performance was performed and revealed impaired cardiac contractility, fractional shortening, stroke volume, and/or cardiac output. In conclusion, the zebrafish has emerged as a new animal model to help study the genetic basis of human CMs.

Fig.1 Assessment of sarcomere function in the zebrafish heart.

Our Zebrafish Cardiomyopathy Models

Creative Biogene offers doxorubicin-induced CM, diabetes-induced CM, diphtheria toxin A-induced myocarditis, and genetic models of CM. In adult zebrafish we induced a single intraperitoneal bolus of doxorubicin to induce CM, a phenotype showing global cardiac damage suggested by reduced myocardial and endocardial volume. We cultured adult fish for 32 weeks in a solution containing glucose to mimic diabetic CM, and zebrafish hearts exhibited hypertrophy, apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmias.

We have established several CM transgenic models, such as transgenic 2057del2 zebrafish, adult transgenic zebrafish mutated in the sodium channel gene scn5a, transgenic erbb2 zebrafish, and transgenic gatad1 zebrafish, among others. Among them, the transgenic 2057del2 zebrafish, as a model of arrhythmogenic CM, exhibited enlarged heart, decreased myocardial sodium and potassium transmembrane currents, and prolonged action potentials. An adult transgenic zebrafish model with mutations in the sodium channel gene scn5a also displays arrhythmogenic CM. Transgenic erbb2 zebrafish hearts exhibited signs of a DCM phenotype, such as enlarged ventricles and reduced trabeculae. Transgenic fish harboring a DCM pathogenic mutation in gatad1 exhibited enlarged hearts.

Creative Biogene can easily generate a large number of knock-out/knock-in models through CRISPR/Cas9 technology. We aim to provide new insights into the molecular pathways that orchestrate cardiac development through facile genetic manipulation of forward and reverse genetic approaches combined with noninvasive, high-resolution imaging, and phenotype-based screening.

Advantages

• Non-invasive imaging tracks entire stages of embryonic development
• Cell biology in intact organisms
• Visualization of Pathogenesis
• Examine multiple functions of genes in different mutants
• High-throughput genetic and drug screening

References

1. Dvornikov AV, de Tombe PP, Xu X. Phenotyping cardiomyopathy in adult zebrafish. Prog Biophys Mol Biol. 2018, 138:116-125.
2. Giardoglou P, Beis D. On Zebrafish Disease Models and Matters of the Heart. Biomedicines. 2019, 7(1):15.
3. Poon KL, Brand T. The zebrafish model system in cardiovascular research: A tiny fish with mighty prospects. Glob Cardiol Sci Pract. 2013, 2013(1):9-28.

For research use only. Not intended for any clinical use.