PUBLICATION
Zebrafish VCAP1X2 regulates cardiac contractility and proliferation of cardiomyocytes and epicardial cells
- Authors
- Hsieh, F.C., Lu, Y.F., Liau, I., Chen, C.C., Cheng, C.M., Hsiao, C.D., Hwang, S.L.
- ID
- ZDB-PUB-180520-2
- Date
- 2018
- Source
- Scientific Reports 8: 7856 (Journal)
- Registered Authors
- Hsiao, Chung-Der, Hwang, Sheng-Ping L.
- Keywords
- none
- MeSH Terms
-
- Animals
- Calcium/metabolism
- Cell Proliferation
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Heart Ventricles/metabolism
- Mutagenesis
- Myocardial Contraction
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/metabolism
- Myofibrils/metabolism
- Myosin Heavy Chains/genetics
- Myosin Heavy Chains/metabolism
- Phosphorylation
- Protein Isoforms/chemistry
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Sarcomeres/chemistry
- Sarcomeres/physiology
- Sodium-Calcium Exchanger/genetics
- Sodium-Calcium Exchanger/metabolism
- Vascular Cell Adhesion Molecule-1/chemistry
- Vascular Cell Adhesion Molecule-1/genetics
- Vascular Cell Adhesion Molecule-1/metabolism*
- Zebrafish/metabolism*
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 29777134 Full text @ Sci. Rep.
Citation
Hsieh, F.C., Lu, Y.F., Liau, I., Chen, C.C., Cheng, C.M., Hsiao, C.D., Hwang, S.L. (2018) Zebrafish VCAP1X2 regulates cardiac contractility and proliferation of cardiomyocytes and epicardial cells. Scientific Reports. 8:7856.
Abstract
Sarcomeric signaling complexes are important to sustain proper sarcomere structure and function, however, the mechanisms underlying these processes are not fully elucidated. In a gene trap experiment, we found that vascular cell adhesion protein 1 isoform X2 (VCAP1X2) mutant embryos displayed a dilated cardiomyopathy phenotype, including reduced cardiac contractility, enlarged ventricular chamber and thinned ventricular compact layer. Cardiomyocyte and epicardial cell proliferation was decreased in the mutant heart ventricle, as was the expression of pAKT and pERK. Contractile dysfunction in the mutant was caused by sarcomeric disorganization, including sparse myofilament, blurred Z-disc, and decreased gene expression for sarcomere modulators (smyd1b, mypn and fhl2a), sarcomeric proteins (myh6, myh7, vmhcl and tnnt2a) and calcium regulators (ryr2b and slc8a1a). Treatment of PI3K activator restored Z-disc alignment while injection of smyd1b mRNA restored Z-disc alignment, contractile function and cardiomyocyte proliferation in ventricles of VCAP1X2 mutant embryos. Furthermore, injection of VCAP1X2 variant mRNA rescued all phenotypes, so long as two cytosolic tyrosines were left intact. Our results reveal two tyrosine residues located in the VCAP1X2 cytoplasmic domain are essential to regulate cardiac contractility and the proliferation of ventricular cardiomyocytes and epicardial cells through modulating pAKT and pERK expression levels.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping