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Calcineurin-NFAT dynamics corresponds to cardiac remodeling during aortic banding and debanding, mimicking aortic valve replacement

Ida G. Lunde, Biljana Skrbic, Ivar Sjaastad, Geir Christensen, Cathrine R. Carlson, Theis Tønnessen

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Aortic valve stenosis (AS) is a major health problem. Extensive myocardial remodeling increases operative risk and might lead to incomplete reverse remodeling with persistent symptoms after aortic valve replacement (AVR); this makes the optimal timing of AVR a clinical challenge. The pathogenesis behind incomplete reverse remodeling is unclear. Central among signaling pathways in the remodeling heart is the pro-hypertrophic Ca2+-activated calcineurin and its downstream nuclear factor of activated T-cell (NFATc1-c4) transcription factors.

We investigated calcineurin-NFATc dynamics in patient and mouse hearts during remodeling and reverse remodeling. Myocardial biopsies were obtained from AS patients during AVR and left ventricles harvested from mice subjected to aortic banding (AB) and debanding (DB). The transcript and protein of the NFATc-responsive gene regulator of calcineurin 1-4 (RCAN1-4) and luciferase activity in NFAT-luciferase mice were used as read-outs for calcineurin-NFATc activity. Calcineurin-NFATc activation was sustained through AB 24 h to 18 weeks and elevated in AS patients. All four NFATc isoforms were elevated in AS, while NFATc4 was persistently elevated during chronic remodeling after AB in mice. NFAT activation remained reversible when 1 week’s AB was followed by 1 week’s DB and accompanied functional improvement. However, when DB for 1 week followed AB for 4 weeks, NFAT activation was not reversed. In conclusion, calcineurin-NFAT dynamics correspond with cardiac remodeling and reverse remodeling during experimental AB and DB. Our data suggest that calcineurin-NFATc attenuation is important for reverse remodeling and outcomes after AVR for AS

Front Mol Med, Sec. Molecular Medicine for Cardiology doi: 10.3389/fmmed.2022.980717

 

Ida Gjervold Lunde

Researcher

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Theis Tønnessen

Group Leader & Professor & Senior Consultant

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Institute for Experimental Medical Research

Oslo University Hospital, Ullevål

PB 4956 Nydalen

NO-0424 Oslo

Norway

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