An SRF/miR-1 axis regulates NCX1 and Annexin A5 protein levels in the normal and failing heart

Eva Tritsch, Youssef Mallat, Florence Lefebvre, Nicolas Diguet, Brigitte Escoubet, Jocelyne Blanc, Leon J. De Windt, Daniele Catalucci, Gregoire Vandecasteele, Zhenlin Li, Mathias Mericskay*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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. NCX1 mRNA was decreased while the protein was increased in the failing heart of the cardiomyocyte-restricted SRF knock-out mice (SRFHKO). The induction of NCX1 mRNA by the pro-hypertrophic drug phenylephrine observed in control mice was abolished in the SRFHKO though the protein was strongly increased. AnxA5 protein expression profile paralleled the expression of NCX1 protein in the SRFHKO. MiR-1, a microRNA regulated by SRF, was decreased in the SRFHKO 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. 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.
Original languageEnglish
Pages (from-to)372-380
JournalCardiovascular Research
Issue number3
Publication statusPublished - 1 Jun 2013


  • Annexin
  • Cardiomyopathy
  • microRNA
  • NCX1
  • SRF

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