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Generation and Application of the Zebrafish heg1 Mutant as a Cardiovascular Disease Model
Shuxian Lu1, Mengyan Hu1, Zhihao Wang1
1Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an 710069, China.
Insights
Researchers developed a new zebrafish model for studying cardiovascular disease (CVD) and dilated cardiomyopathy (DCM). This model effectively screens Traditional Chinese Medicine for potential CVD treatments.
Area of Science:
- Cardiovascular research
- Zebrafish as a model organism
- Genetics and molecular biology
Background:
- Cardiovascular disease (CVD) is a leading global cause of mortality.
- Animal models are crucial for understanding CVD pathogenesis and developing therapies.
- HEG1 protein is vital for cardiovascular development; its loss causes dilated cardiomyopathy (DCM).
Purpose of the Study:
- To generate and characterize a zebrafish model of DCM and thrombosis.
- To validate the utility of this model for cardiovascular drug screening.
- To identify potential therapeutic effects of Traditional Chinese Medicine (TCM) on DCM and thrombosis.
Main Methods:
- CRISPR/Cas9 technology was used to create a heg1-specific knockout zebrafish line.
- Phenotypic analysis of cardiovascular malformations, heart rate, and blood flow in heg1 mutants.
- Treatment of mutants with TCM herbs and Chinese herbal monomers, followed by efficacy evaluation.
Main Results:
- The heg1 mutant zebrafish exhibited severe cardiovascular defects, including enlarged chambers, slowed heart rate, and thrombosis, mimicking human heart failure.
- Abnormal expression of cardiac and vascular markers was observed in the mutants.
- TCM interventions showed therapeutic effects on DCM and thrombosis phenotypes in the zebrafish model.
Conclusions:
- A novel zebrafish model for DCM and thrombosis has been established.
- This model is suitable for rapid and cost-effective screening of cardiovascular drugs.
- The study offers an alternative to traditional in vitro screening methods and identifies potential clinical candidates from TCM.
Abstract:
Cardiovascular disease (CVD) is the leading cause of global mortality, which has caused a huge burden on the quality of human life. Therefore, experimental animal models of CVD have become essential tools for analyzing the pathogenesis, developing drug screening, and testing potential therapeutic strategies. In recent decades, zebrafish has entered the field of CVD as an important model organism. HEG1, a heart development protein with EGF like domains 1, plays important roles in the development of vertebrate cardiovascular system. Loss of HEG1 will affect the stabilization of vascular endothelial cell connection and eventually lead to dilated cardiomyopathy (DCM). Here, we generated a heg1-specific knockout zebrafish line using CRISPR/Cas9 technology. Zebrafish heg1 mutant demonstrated severe cardiovascular malformations, including atrial ventricular enlargement, heart rate slowing, venous thrombosis and slow blood flow, which were similar to human heart failure and thrombosis phenotype. In addition, the expression of zebrafish cardiac and vascular markers was abnormal in heg1 mutants. In order to apply zebrafish heg1 mutant in cardiovascular drug screening, four Traditional Chinese Medicine (TCM) herbs and three Chinese herbal monomers were used to treat heg1 mutant. The pericardial area, the distance between sinus venosus and bulbus arteriosus (SV-BA), heart rate, red blood cells (RBCs) accumulation in posterior cardinal vein (PCV), and blood circulation in the tail vein were measured to evaluate the therapeutic effects of those drugs on DCM and thrombosis. Here, a new zebrafish model of DCM and thrombosis was established, which was verified to be suitable for drug screening of cardiovascular diseases. It provided an alternative method for traditional in vitro screening, and produced potential clinical related drugs in a rapid and cost-effective way.
