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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2025
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| _version_ | 1824458945762164736 |
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| author | Raj Murthi, S Petry, A Shashikadze, B Stöckl, JB Schmid, M Santamaria, G Klingel, K Kračun, D Chen, X Bauer, S Schmitt, JP Flenkenthaler, F Gorham, J Toepfer, CN Potěšil, D Hruška, P Zdráhal, Z Mayer, Z Klop, M Lehmann, L Qin, Y Papanakli, L Spielmann, N Moretti, A |
| author_facet | Raj Murthi, S Petry, A Shashikadze, B Stöckl, JB Schmid, M Santamaria, G Klingel, K Kračun, D Chen, X Bauer, S Schmitt, JP Flenkenthaler, F Gorham, J Toepfer, CN Potěšil, D Hruška, P Zdráhal, Z Mayer, Z Klop, M Lehmann, L Qin, Y Papanakli, L Spielmann, N Moretti, A |
| author_sort | Raj Murthi, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2025-02-19T04:33:57Z |
| format | Journal article |
| id | oxford-uuid:ec3075e9-5d47-4623-a152-2140aad3314f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:33:57Z |
| publishDate | 2025 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:ec3075e9-5d47-4623-a152-2140aad3314f2025-01-16T20:09:33ZContribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ec3075e9-5d47-4623-a152-2140aad3314fEnglishJisc Publications RouterNature Research2025Raj Murthi, SPetry, AShashikadze, BStöckl, JBSchmid, MSantamaria, GKlingel, KKračun, DChen, XBauer, SSchmitt, JPFlenkenthaler, FGorham, JToepfer, CNPotěšil, DHruška, PZdráhal, ZMayer, ZKlop, MLehmann, LQin, YPapanakli, LSpielmann, NMoretti, AHypertrophic 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. |
| spellingShingle | Raj Murthi, S Petry, A Shashikadze, B Stöckl, JB Schmid, M Santamaria, G Klingel, K Kračun, D Chen, X Bauer, S Schmitt, JP Flenkenthaler, F Gorham, J Toepfer, CN Potěšil, D Hruška, P Zdráhal, Z Mayer, Z Klop, M Lehmann, L Qin, Y Papanakli, L Spielmann, N Moretti, A Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy |
| 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 |
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