Academic Journal
Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy
| العنوان: | Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
|---|---|
| المؤلفون: | 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 |
| المصدر: | Scientific Reports, Vol 15, Iss 1, Pp 1-22 (2025) |
| بيانات النشر: | Nature Portfolio, 2025. |
| سنة النشر: | 2025 |
| المجموعة: | LCC:Medicine LCC:Science |
| مصطلحات موضوعية: | Hypertrophic cardiomyopathy, Hypoxia, HIF1A, Hypertrophy, Myocardial fibrosis, Medicine, Science |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-025-85187-9 |
| URL الوصول: | https://doaj.org/article/5ab111998b9c495ba8aef15d8a0845b9 |
| رقم الانضمام: | edsdoj.5ab111998b9c495ba8aef15d8a0845b9 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20452322 |
|---|---|
| DOI: | 10.1038/s41598-025-85187-9 |