Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model
Author | Da’as, Sahar Isa |
Author | Hasan, Waseem |
Author | Salem, Rola |
Author | Younes, Nadine |
Author | Abdelrahman, Doua |
Author | Mohamed, Iman A. |
Author | Aldaalis, Arwa |
Author | Temanni, Ramzi |
Author | Mathew, Lisa Sara |
Author | Lorenz, Stephan |
Author | Yacoub, Magdi |
Author | Nomikos, Michail |
Author | Nasrallah, Gheyath K. |
Author | Fakhro, Khalid A. |
Available date | 2023-09-28T05:03:08Z |
Publication Date | 2022-08-01 |
Publication Name | International Journal of Molecular Sciences |
Identifier | http://dx.doi.org/10.3390/ijms23168840 |
Citation | Da’as, S.I.; Hasan, W.; Salem, R.; Younes, N.; Abdelrahman, D.; Mohamed, I.A.; Aldaalis, A.; Temanni, R.; Mathew, L.S.; Lorenz, S.; et al. Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model. Int. J. Mol. Sci. 2022, 23, 8840. https://doi.org/10.3390/ijms23168840 |
ISSN | 16616596 |
Abstract | Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart’s contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant’s total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model. |
Sponsor | This research was supported by the Qatar Foundation, Qatar Cardiovascular Research Center and was funded by the Sidra Medicine, Research and Development Fund of the Zebrafish Functional Genomics Core Facility. Institutional Review Board Statement The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of Qatar University (QU-IACUC 2-9/2019-1). |
Language | en |
Publisher | MDPI |
Subject | actin c-MYBPC3 HCM hypertrophic cardiomyopathy RNA seq zebrafish knockout |
Type | Article |
Issue Number | 16 |
Volume Number | 23 |
ESSN | 1422-0067 |
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