Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy
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 facto...
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2025-01-01
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| author | Sarala Raj Murthi Andreas Petry Bachuki Shashikadze Jan B. Stöckl Manuel Schmid Gianluca Santamaria Karin Klingel Damir Kračun Xinpei Chen Sabine Bauer Joachim P. Schmitt Florian Flenkenthaler Josh Gorham Christopher N. Toepfer David Potěšil Pavel Hruška Zbyněk Zdráhal Zsuzsanna Mayer Mathieu Klop Luisa Lehmann Yishi Qin Laura Papanakli Nadine Spielmann Alessandra Moretti Thomas Fröhlich Peter Ewert Stefan Holdenrieder Jonathan G. Seidman Christine E. Seidman Agnes Görlach Cordula M. Wolf |
| author_facet | Sarala Raj Murthi Andreas Petry Bachuki Shashikadze Jan B. Stöckl Manuel Schmid Gianluca Santamaria Karin Klingel Damir Kračun Xinpei Chen Sabine Bauer Joachim P. Schmitt Florian Flenkenthaler Josh Gorham Christopher N. Toepfer David Potěšil Pavel Hruška Zbyněk Zdráhal Zsuzsanna Mayer Mathieu Klop Luisa Lehmann Yishi Qin Laura Papanakli Nadine Spielmann Alessandra Moretti Thomas Fröhlich Peter Ewert Stefan Holdenrieder Jonathan G. Seidman Christine E. Seidman Agnes Görlach Cordula M. Wolf |
| author_sort | Sarala Raj Murthi |
| collection | DOAJ |
| description | 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-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. |
| format | Article |
| id | doaj-art-5ab111998b9c495ba8aef15d8a0845b9 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-5ab111998b9c495ba8aef15d8a0845b92025-01-19T12:24:34ZengNature PortfolioScientific Reports2045-23222025-01-0115112210.1038/s41598-025-85187-9Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathySarala Raj Murthi0Andreas Petry1Bachuki Shashikadze2Jan B. Stöckl3Manuel Schmid4Gianluca Santamaria5Karin Klingel6Damir Kračun7Xinpei Chen8Sabine Bauer9Joachim P. Schmitt10Florian Flenkenthaler11Josh Gorham12Christopher N. Toepfer13David Potěšil14Pavel Hruška15Zbyněk Zdráhal16Zsuzsanna Mayer17Mathieu Klop18Luisa Lehmann19Yishi Qin20Laura Papanakli21Nadine Spielmann22Alessandra Moretti23Thomas Fröhlich24Peter Ewert25Stefan Holdenrieder26Jonathan G. Seidman27Christine E. Seidman28Agnes Görlach29Cordula M. Wolf30Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichLaboratory for Functional Genome Analysis LAFUGA Gene Center, LMU MunichLaboratory for Functional Genome Analysis LAFUGA Gene Center, LMU MunichDepartment of Genetics, Harvard Medical SchoolFirst Department of Medicine and Regenerative Medicine in Cardiovascular Diseases, Klinikum rechts der Isar, School of Medicine & Health, Technical University of MunichCardiopathology, Institute for Pathology and Neuropathology, University Hospital of TübingenExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental Cardiology, Department of Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichInstitute of Pharmacology, University Hospital Düsseldorf and Cardiovascular Research Institute Düsseldorf (CARID), Heinrich-Heine-UniversityLaboratory for Functional Genome Analysis LAFUGA Gene Center, LMU MunichDepartment of Genetics, Harvard Medical SchoolDepartment of Genetics, Harvard Medical SchoolMendel Centre for Plant Genomics and Proteomics, Central European Institute of Technology, Masaryk UniversityMendel Centre for Plant Genomics and Proteomics, Central European Institute of Technology, Masaryk UniversityMendel Centre for Plant Genomics and Proteomics, Central European Institute of Technology, Masaryk UniversityInstitute for Laboratory Medicine, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichDepartment of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichInstitute of Experimental Genetics and German Mouse Clinic, Helmholtz Center Munich, German Research Center for Environmental HealthFirst Department of Medicine and Regenerative Medicine in Cardiovascular Diseases, Klinikum rechts der Isar, School of Medicine & Health, Technical University of MunichLaboratory for Functional Genome Analysis LAFUGA Gene Center, LMU MunichDepartment of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichInstitute for Laboratory Medicine, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichDepartment of Genetics, Harvard Medical SchoolDepartment of Genetics, Harvard Medical SchoolExperimental and Molecular Pediatric Cardiology, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichDepartment of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, TUM University Hospital, School of Medicine & Health, Technical University of MunichAbstract 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.https://doi.org/10.1038/s41598-025-85187-9Hypertrophic cardiomyopathyHypoxiaHIF1AHypertrophyMyocardial fibrosis |
| spellingShingle | Sarala Raj Murthi Andreas Petry Bachuki Shashikadze Jan B. Stöckl Manuel Schmid Gianluca Santamaria Karin Klingel Damir Kračun Xinpei Chen Sabine Bauer Joachim P. Schmitt Florian Flenkenthaler Josh Gorham Christopher N. Toepfer David Potěšil Pavel Hruška Zbyněk Zdráhal Zsuzsanna Mayer Mathieu Klop Luisa Lehmann Yishi Qin Laura Papanakli Nadine Spielmann Alessandra Moretti Thomas Fröhlich Peter Ewert Stefan Holdenrieder Jonathan G. Seidman Christine E. Seidman Agnes Görlach Cordula M. Wolf Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy Scientific Reports Hypertrophic cardiomyopathy Hypoxia HIF1A Hypertrophy Myocardial fibrosis |
| title | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| title_full | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| title_fullStr | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| title_full_unstemmed | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| title_short | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| title_sort | contribution of hypoxia inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| topic | Hypertrophic cardiomyopathy Hypoxia HIF1A Hypertrophy Myocardial fibrosis |
| url | https://doi.org/10.1038/s41598-025-85187-9 |
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