Journal Article

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

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

2025

Overview

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 719/+ 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 719/+ 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 719/+ 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/1647 / 631/208 / 631/337 / 631/45 / 692/308 / 692/4019 / 692/53 / Animals / Cardiomyocytes / Cardiomyopathy / Cardiomyopathy, Hypertrophic - genetics / Cardiomyopathy, Hypertrophic - metabolism / Cardiomyopathy, Hypertrophic - pathology / Cardiovascular diseases / Disease Models, Animal / Disease progression / Fibrosis / Heart diseases / HIF1A / Humanities and Social Sciences / Humans / Hypertrophic cardiomyopathy / Hypertrophy / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Male / Mice / Mice, Knockout / multidisciplinary / Myocardial fibrosis / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Pathogenesis / Phenotypes / Proteomics / Sarcomeres - metabolism / Sarcomeres - pathology / Science / Science (multidisciplinary) / Transcription factors / Transcriptomes / Ventricle