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.      «

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 path...     »