Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

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-MHC<sup>719/+</sup> 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-MHC<sup>719/+</sup> 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-MHC<sup>719/+</sup> 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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Publication Details

Journal
Scientific Reports
Published
2025-01-16
DOI
https://doi.org/10.1038/s41598-025-85187-9
Citations
2
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
2.78

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article

Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

Christine E. Seidman, Thomas Fröhlich, Jonathan G. Seidman, Andreas Petry et al.
2 citations
Scientific Reports
Cardiomyopathy and Myosin Studies
2.78
article

Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

Christine E. Seidman, Thomas Fröhlich, Jonathan G. Seidman, Andreas Petry, Cordula M. Wolf, Bachuki Shashikadze, Sarala Raj Murthi, Gianluca Santamaria, Stefan Holdenrieder, Josh Gorham, Florian Flenkenthaler, Luisa Lehmann, Karin Klingel, Mathieu Klop, Alessandra Moretti, Jan B. Stöckl, Yishi Qin, Damir Kračun, Christopher N. Toepfer, Joachim P. Schmitt, Nadine Spielmann, David Potěšil, Pavel Hruška, Xinpei Chen, Sabine Bauer, Peter Ewert, Agnes Görlach, Zsuzsanna Mayer, Zbyněk Zdráhal, Manuel Schmid, Laura Papanakli
article en
2 citations

Abstract

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-MHC<sup>719/+</sup> 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-MHC<sup>719/+</sup> 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-MHC<sup>719/+</sup> 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.

Scientific ReportsVol. 15(1)
Central European Institute of Technology (CZ), Centre for Human Genetics (GB), Harvard University (US), University of Zurich (CH), TUM Klinikum (DE), Helmholtz Zentrum München (DE), Magna Graecia University (IT), University of Oxford (GB), Düsseldorf University Hospital (DE), Central European Institute of Technology – Masaryk University (CZ), Institute for Biomedical Engineering (CH), University Hospital of Zurich (CH), Universitätsklinik Balgrist (CH), University Children's Hospital Tübingen (DE), German Centre for Cardiovascular Research (DE), Deutsches Herzzentrum München (DE), Heinrich Heine University Düsseldorf (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE)
Deutsches Zentrum für Herz-Kreislaufforschung, Deutsche Forschungsgemeinschaft, Ministerstvo Školství, Mládeže a Tělovýchovy, Technische Universität München, Central European Institute of Technology, European Regional Development Fund
Good health and well-being
Openalex Percentile: Top 12%
Cardiomyopathy and Myosin Studies
2.78
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