Cardiac Na+-Ca2+ exchanger 1 (ncx1h) is critical for the ventricular cardiomyocyte formation via regulating the expression levels of gata4 and hand2 in zebrafish

Ca 2+ signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca 2+ transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca 2+ efflux in cardiomyocytes. It is involved in cardiogenesis, while the m...

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Bibliographic Details
Published in:Science China. Life sciences 2021-02, Vol.64 (2), p.255-268
Main Authors: Chu, Liming, Yin, Huimin, Gao, Lei, Gao, Li, Xia, Yu, Zhang, Chiyuan, Chen, Yi, Liu, Tingxi, Huang, Jijun, Boheler, Kenneth R., Zhou, Yong, Yang, Huang-Tian
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Calcium (mitochondrial)
Calcium efflux
Calcium signalling
Calcium transport
Cardiac muscle
Cardiomyocytes
Contraction
Danio rerio
Genetic screening
Heart rate
Leucine
Life Sciences
Mitochondria
Myocytes
Na+/Ca2+ exchanger
NCX1 protein
Protein transport
Research Paper
Transcription factors
Ventricle
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Summary:Ca 2+ signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca 2+ transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca 2+ efflux in cardiomyocytes. It is involved in cardiogenesis, while the mechanism is unclear. Here, using the forward genetic screening in zebrafish, we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene (mutant LDD353 / ncx1h L154P ) that led to smaller hearts with reduced heart rate and weak contraction. Mechanistically, the number of ventricular but not atrial cardiomyocytes was reduced in ncx1h L154P zebrafish. These defects were mimicked by knockdown or knockout of ncx1h . Moreover, ncx1h L154P had cytosolic and mitochondrial Ca 2+ overloading and Ca 2+ transient suppression in cardiomyocytes. Furthermore, ncx1h L154P and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions, while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes. These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish, and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2 .
ISSN:1674-7305
1869-1889
DOI:10.1007/s11427-019-1706-1