Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy

• Published in: Molecular biology reports Vol. 49; no. 12; pp. 11795 - 11809
• Main Authors: Lunde, Ida G., Aronsen, J. Magnus, Melleby, A. Olav, Strand, Mari E., Skogestad, Jonas, Bendiksen, Bård A., Ahmed, M. Shakil, Sjaastad, Ivar, Attramadal, Håvard, Carlson, Cathrine R., Christensen, Geir
• Format: Journal Article
• Language: English; Norwegian
• Published: Dordrecht Springer Netherlands 01.12.2022; Springer Nature B.V; Kluwer Academic/Plenum Publishers
• Subjects: Animal Anatomy; Animal Biochemistry; Animals; Aortic stenosis; Biomedical and Life Sciences; Calcineurin; Calcineurin - metabolism; Calcium signalling; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomyocytes; Cells, Cultured; Cross-breeding; Extracellular Matrix Biology; Heparan sulfate; Histology; Hypertrophy; Immunoprecipitation; Life Sciences; Mice; Morphology; Myocardium; Myocytes, Cardiac - metabolism; Neonates; NF-AT protein; NFATC Transcription Factors - metabolism; Original; Original Article; Proteoglycans; Rats; Signal transduction; Signal Transduction - physiology; Syndecan; Syndecan-4 - genetics; Syndecan-4 - metabolism; Ventricle; Heart failure; Proteoglycan; Inflammation; Matrix; Calcium; Fibrosis
• ISSN: 0301-4851; 1573-4978; 1573-4978
• DOI: 10.1007/s11033-022-07985-y

Background Cardiomyocyte hypertrophy is a hallmark of cardiac dysfunction in patients with aortic stenosis (AS), and can be triggered by left ventricular (LV) pressure overload in mice by aortic banding (AB). Syndecan-4 is a transmembrane heparan sulphate proteoglycan which is found increased in the myocardium of AS patients and AB mice. The role of syndecan-4 in cardiomyocyte hypertrophy is not well understood. Purpose of the study We developed mice with cardiomyocyte-specific overexpression of syndecan-4 ( Sdc4-Tg ) and subjected these to AB to examine the role of syndecan-4 in hypertrophy and activation of the pro-hypertrophic calcineurin-NFAT signalling pathway. Methods and results Sdc4-Tg mice showed exacerbated cardiac remodelling upon AB compared to wild type (WT). At 2–6 weeks post-AB, Sdc4-Tg and WT mice showed similar hypertrophic growth, while at 20 weeks post-AB, exacerbated hypertrophy and dysfunction were evident in Sdc4-Tg mice. After cross-breeding of Sdc4-Tg mice with NFAT-luciferase reporter mice, we found increased NFAT activation in Sdc4-Tg hearts after AB. Immunoprecipitation showed that calcineurin bound to syndecan-4 in Sdc4-Tg hearts. Isolated cardiomyocytes from Sdc4-Tg mice showed alterations in Ca 2+ fluxes, suggesting that syndecan-4 regulated Ca 2+ levels, and thereby, activating the syndecan-4-calcineurin complex resulting in NFAT activation and hypertrophic growth. Similarly, primary cardiomyocyte cultures from neonatal rats showed increased calcineurin-NFAT-dependent hypertrophic growth upon viral Sdc4 overexpression. Conclusion Our study of mice with cardiomyocyte-specific overexpression of Sdc4 have revealed that syndecan-4 is important for activation of the Ca 2+ -dependent calcineurin-NFAT signalling pathway, hypertrophic remodelling and dysfunction in cardiomyocytes in response to pressure overload.