AIMS: The expression of the sodium/calcium exchanger NCX1 increases during cardiac hypertrophy and heart failure, playing an important role in Ca(2+) extrusion. This increase is presumed to result from stress signalling induced changes in the interplay between transcriptional and post-transcriptional regulations. We aimed to determine the impact of the SRF transcription factor known to regulate the NCX1 promoter and microRNA genes, on the expression of NCX1 mRNA and protein and annexin A5 (AnxA5), a Ca(2+)-binding protein interacting with NCX1 and increased during HF. METHODS AND RESULTS: NCX1 mRNA was decreased while the protein was increased in the failing heart of the cardiomyocyte-restricted SRF knock-out mice (SRF(HKO)). The induction of NCX1 mRNA by the pro-hypertrophic drug phenylephrine observed in control mice was abolished in the SRF(HKO) though the protein was strongly increased. AnxA5 protein expression profile paralleled the expression of NCX1 protein in the SRF(HKO). MiR-1, a microRNA regulated by SRF, was decreased in the SRF(HKO) and repressed by phenylephrine. In vitro and in vivo manipulation of miR-1 levels and site-directed mutagenesis showed that NCX1 and AnxA5 mRNAs are targets of miR-1. AnxA5 overexpression slowed down Ca(2+) extrusion during caffeine application in adult rat cardiomyocytes. CONCLUSION: Our study reveals the existence of a complex regulatory loop where SRF regulates the transcription of NCX1 and miR-1, which in turn functions as a rheostat limiting the translation of NCX1 and AnxA5 proteins. The decrease of miR-1 and increase of AnxA5 appear as important modulators of NCX1 expression and activity during heart failure.
AIMS: The expression of the sodium/calcium exchanger NCX1 increases during cardiac hypertrophy and heart failure, playing an important role in Ca(2+) extrusion. This increase is presumed to result from stress signalling induced changes in the interplay between transcriptional and post-transcriptional regulations. We aimed to determine the impact of the SRF transcription factor known to regulate the NCX1 promoter and microRNA genes, on the expression of NCX1 mRNA and protein and annexin A5 (AnxA5), a Ca(2+)-binding protein interacting with NCX1 and increased during HF. METHODS AND RESULTS:NCX1 mRNA was decreased while the protein was increased in the failing heart of the cardiomyocyte-restricted SRF knock-out mice (SRF(HKO)). The induction of NCX1 mRNA by the pro-hypertrophic drug phenylephrine observed in control mice was abolished in the SRF(HKO) though the protein was strongly increased. AnxA5 protein expression profile paralleled the expression of NCX1 protein in the SRF(HKO). MiR-1, a microRNA regulated by SRF, was decreased in the SRF(HKO) and repressed by phenylephrine. In vitro and in vivo manipulation of miR-1 levels and site-directed mutagenesis showed that NCX1 and AnxA5 mRNAs are targets of miR-1. AnxA5 overexpression slowed down Ca(2+) extrusion during caffeine application in adult rat cardiomyocytes. CONCLUSION: Our study reveals the existence of a complex regulatory loop where SRF regulates the transcription of NCX1 and miR-1, which in turn functions as a rheostat limiting the translation of NCX1 and AnxA5 proteins. The decrease of miR-1 and increase of AnxA5 appear as important modulators of NCX1 expression and activity during heart failure.
Authors: Antonio Vinciguerra; Luigi Formisano; Pierpaolo Cerullo; Natascia Guida; Ornella Cuomo; Alba Esposito; Gianfranco Di Renzo; Lucio Annunziato; Giuseppe Pignataro Journal: Mol Ther Date: 2014-06-23 Impact factor: 11.454
Authors: Nicolas Diguet; Samuel A J Trammell; Cynthia Tannous; Robin Deloux; Jérôme Piquereau; Nathalie Mougenot; Anne Gouge; Mélanie Gressette; Boris Manoury; Jocelyne Blanc; Marie Breton; Jean-François Decaux; Gareth G Lavery; István Baczkó; Joffrey Zoll; Anne Garnier; Zhenlin Li; Charles Brenner; Mathias Mericskay Journal: Circulation Date: 2017-12-07 Impact factor: 29.690
Authors: Tania Zaglia; Paola Ceriotti; Antonio Campo; Giulia Borile; Andrea Armani; Pierluigi Carullo; Valentina Prando; Raffaele Coppini; Vladimiro Vida; Tomas O Stølen; Wisløff Ulrik; Elisabetta Cerbai; Giovanni Stellin; Giuseppe Faggian; Diego De Stefani; Marco Sandri; Rosario Rizzuto; Fabio Di Lisa; Tullio Pozzan; Daniele Catalucci; Marco Mongillo Journal: Proc Natl Acad Sci U S A Date: 2017-10-09 Impact factor: 11.205