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.

1st Department of Medicine and Regenerative Medicine in Cardiovascular Diseases Klinikum rechts der Isar School of Medicine and Health Technical University of Munich Munich Germany

Cardiopathology Institute for Pathology and Neuropathology University Hospital of Tübingen Tübingen Germany

Cardiovascular Medicine Radcliffe Department of Medicine University of Oxford Oxford UK

Department of Congenital Heart Defects and Pediatric Cardiology German Heart Center Munich TUM University Hospital School of Medicine and Health Technical University of Munich Munich Germany

Department of Experimental and Clinical Medicine Magna Graecia University of Catanzaro Catanzaro Italy

Department of Genetics Harvard Medical School Boston USA

DZHK Partner Site Munich Heart Alliance Munich Germany

Experimental and Molecular Pediatric Cardiology Department of Congenital Heart Defects and Pediatric Cardiology German Heart Center Munich TUM University Hospital School of Medicine and Health Technical University of Munich Munich Germany

Experimental Cardiology Department of Cardiology German Heart Center Munich TUM University Hospital School of Medicine and Health Technical University of Munich Munich Germany

Institute for Laboratory Medicine German Heart Center Munich TUM University Hospital School of Medicine and Health Technical University of Munich Munich Germany

Institute of Experimental Genetics and German Mouse Clinic Helmholtz Center Munich German Research Center for Environmental Health Neuherberg Germany

Institute of Pharmacology University Hospital Düsseldorf and Cardiovascular Research Institute Düsseldorf Heinrich Heine University Düsseldorf Germany

Laboratory for Functional Genome Analysis LAFUGA Gene Center LMU Munich Munich Germany

Mendel Centre for Plant Genomics and Proteomics Central European Institute of Technology Masaryk University Brno Czech Republic

School of Medicine and Health Technical University of Munich Munich Germany

University Hospital Balgrist University of Zurich and Institute for Biomechanics ETH Zurich Zurich Switzerland

Wellcome Centre for Human Genetics University of Oxford Oxford UK

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