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Raj Murthi, S.* ; Petry, A.* ; Shashikadze, B.* ; Stöckl, J.B.* ; Schmid, M.* ; Santamaria, G.* ; Klingel, K.* ; Kračun, D.* ; Chen, X.* ; Bauer, S.* ; Schmitt, J.P.* ; Flenkenthaler, F.* ; Gorham, J.M.* ; Toepfer, C.N.* ; Potěšil, D.* ; Hruška, P.* ; Zdráhal, Z.* ; Mayer, Z.* ; Klop, M.* ; Lehmann, L.* ; Qin, Y.* ; Papanakli, L.* ; Spielmann, N. ; Moretti, A.* ; Fröhlich, T.* ; Ewert, P.* ; Holdenrieder, S.* ; Seidman, J.G.* ; Seidman, C.E.* ; Görlach, A.* ; Wolf, C.M.*

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

Sci. Rep. 15:2132 (2025)

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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.

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