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Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy
S. Raj Murthi, A. Petry, B. Shashikadze, JB. Stöckl, M. Schmid, G. Santamaria, K. Klingel, D. Kračun, X. Chen, S. Bauer, JP. Schmitt, F. Flenkenthaler, J. Gorham, CN. Toepfer, D. Potěšil, P. Hruška, Z. Zdráhal, Z. Mayer, M. Klop, L. Lehmann, Y....
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
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- MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit * metabolism genetics MeSH
- Fibrosis MeSH
- Cardiomyopathy, Hypertrophic * metabolism genetics pathology MeSH
- Myocytes, Cardiac * metabolism pathology MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Sarcomeres * metabolism MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.
Cardiovascular Medicine Radcliffe Department of Medicine University of Oxford Oxford UK
Department of Genetics Harvard Medical School Boston USA
DZHK Partner Site Munich Heart Alliance Munich Germany
Laboratory for Functional Genome Analysis LAFUGA Gene Center LMU Munich Munich Germany
School of Medicine and Health Technical University of Munich Munich Germany
Wellcome Centre for Human Genetics University of Oxford Oxford UK
References provided by Crossref.org
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- $a Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.
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