The long non-coding RNA NRON promotes the development of cardiac hypertrophy in the murine heart

Jeannine Hoepfner, Julia Leonardy, Dongchao Lu, Kevin Schmidt, Hannah J. Hunkler, Sinje Biß, Ariana Foinquinos, Ke Xiao, Kumarswamy Regalla, Deepak Ramanujam, Stefan Engelhardt, Christian Bär, Thomas Thum

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Physiological and pathological cardiovascular processes are tightly regulated by several cellular mechanisms. Non-coding RNAs, including long non-coding RNAs (lncRNAs), represent one important class of molecules involved in regulatory processes within the cell. The lncRNA non-coding repressor of NFAT (NRON) was described as a repressor of the nuclear factor of activated T cells (NFAT) in different in vitro studies. Although the calcineurin/NFAT-signaling pathway is one of the most important pathways in pathological cardiac hypertrophy, a potential regulation of hypertrophy by NRON in vivo has remained unclear. Applying subcellular fractionation and RNA fluorescence in situ hybridization (RNA-FISH), we found that, unlike what is known from T cells, in cardiomyocytes, NRON predominantly localizes to the nucleus. Hypertrophic stimulation in neonatal mouse cardiomyocytes led to a downregulation of NRON, while NRON overexpression led to an increase in expression of hypertrophic markers. To functionally investigate NRON in vivo, we used a mouse model of transverse aortic constriction (TAC)-induced hypertrophy and performed NRON gain- and loss-of-function experiments. Cardiomyocyte-specific NRON overexpression in vivo exacerbated TAC-induced hypertrophy, whereas cardiomyocyte-specific NRON deletion attenuated cardiac hypertrophy in mice. Heart weight, cardiomyocyte cell size, hypertrophic marker gene expression, and left ventricular mass showed a NRON-dependent regulation upon TAC-induced hypertrophy. In line with this, transcriptome profiling revealed an enrichment of anti-hypertrophic signaling pathways upon NRON-knockout during TAC-induced hypertrophy. This set of data refutes the hypothesized anti-hypertrophic role of NRON derived from in vitro studies in non-cardiac cells and suggests a novel regulatory function of NRON in the heart in vivo.

Original languageEnglish
Pages (from-to)1265-1274
Number of pages10
JournalMolecular Therapy
Volume30
Issue number3
DOIs
StatePublished - 2 Mar 2022

Keywords

  • NFAT signaling
  • NRON
  • cardiac hypertrophy
  • heart failure
  • non-coding RNA

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