LncRNA Bigheart stimulates Regulator of calcineurin 1 (Rcan1) expression in an auto-amplification loop that stimulates calcineurin-NFAT signalling in heart failure

Abstract Background Cardiac hypertrophy precedes many heart diseases and understanding its molecular basis remains one of the greatest challenges in cardiovascular medicine. Recent studies highlighted sporadic involvement long noncoding RNAs (lncRNAs) cardiac development disease but our lncRNAs failure is still limited. Results Expression profiling failing mouse hearts revealed dysregulation “Bigheart”, a novel lncRNA that evolutionary conserved. Bigheart overexpressed using serotype 9 adeno-associated virus (AAV) neonatal rat cardiomyocytes (NRCMs) induced spontaneous hypertrophy, while silencing this with specific siRNAs blunted hypertrophic response agonist-stimulated cardiomyocytes. GapmeR-mediated prevented transverse aortic constriction (TAC)-induced pathological remodeling vivo. Mechanistically, analysis genomic locus several binding sites for transcription factor nuclear activated T-cells (NFAT), downstream pro-hypertrophic calcineurin-NFAT signaling cascade. The sensitivity transcriptional induction signalling was further demonstrated by luciferase assays promoter-luciferase construct. Finally, RNA-sequencing Gapmer-silenced chromatin isolation RNA purification (ChIRP) coupled to mass spectrometry (MS), interacts heterogeneous ribonucleoproteins (hnRNPs) High Mobility Group Box 1 (HMGB1) acts trans stimulate Regulator calcineurin (Rcan1), facilitator signaling. Conclusions These results indicate constitutes positive feedforward loop promising target attenuate maladaptive Funding Acknowledgement Type funding sources: Public Institution(s). Main source(s): Maastricht university