title: An SRF/miR-1 axis regulates NCX1 and annexin A5 protein levels in the normal and failing heart.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Aging, Stress and Inflammation , UPMC Univ Paris 6, 7, quai Saint Bernard - BP 256, Paris 75005, France.
authors: Eva
authors: E
authors: Tritsch
authors: Youssef
authors: Y
authors: Mallat
authors: Florence
authors: F
authors: Lefebvre
authors: Nicolas
authors: N
authors: Diguet
authors: Brigitte
authors: B
authors: Escoubet
authors: Jocelyne
authors: J
authors: Blanc
authors: Leon J
authors: LJ
authors: De Windt
authors: Daniele
authors: D
authors: Catalucci
authors: Grégoire
authors: G
authors: Vandecasteele
authors: Zhenlin
authors: Z
authors: Li
authors: Mathias
authors: M
authors: Mericskay
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D017304:Annexin A5; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C499849:NCX1 protein, mouse; D012333:RNA, Messenger; D026362:Serum Response Factor; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D010656:Phenylephrine; D002110:Caffeine; D002118:Calcium
keywords: Annexin; Cardiomyopathy; NCX1; SRF; microRNA