title: Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line.
abstract: Cardiac hypertrophy (CH) generally occurs as the result of the sustained mechanical stress caused by elevated systemic arterial blood pressure (BP). However, in animal models, elevated salt intake is associated with CH even in the absence of significant increases in BP. We hypothesize that CH is not exclusively the consequence of mechanical stress but also of other factors associated with elevated BP such as abnormal cell sodium homeostasis. We examined the effect of small increases in intracellular sodium concentration ([Na(+)](i)) on transcription factors and genes associated with CH in a cardiac cell line. Increases in [Na(+)](i) led to a time-dependent increase in the expression levels of mRNA for natriuretic peptide and myosin heavy chain genes and also increased myocyte enhancer factor (MEF)2/nuclear factor of activated T cell (NFAT) transcriptional activity. Increases in [Na(+)](i) are associated with activation of salt-inducible kinase 1 (snflk-1, SIK1), a kinase known to be critical for cardiac development. Moreover, increases in [Na(+)](i) resulted in increased SIK1 expression. Sodium did not increase MEF2/NFAT activity or gene expression in cells expressing a SIK1 that lacked kinase activity. The mechanism by which SIK1 activated MEF2 involved phosphorylation of HDAC5. Increases in [Na(+)](i) activate SIK1 and MEF2 via a parallel increase in intracellular calcium through the reverse mode of Na(+)/Ca(2+)-exchanger and activation of CaMK1. These data obtained in a cardiac cell line suggest that increases in intracellular sodium could influence myocardial growth by controlling transcriptional activation and gene expression throughout the activation of the SIK1 network.
authors.affiliation: Membrane Signaling Networks, Atherosclerosis Research Unit, Department of Medicine, CMM, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Sergej
authors.initials: S
authors.lastname: Popov
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Venetsanou
authors.forename: P Jorge
authors.initials: PJ
authors.lastname: Chedrese
authors.forename: Vanda
authors.initials: V
authors.lastname: Pinto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
mesh_terms: D001706:Biopsy; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D006325:Heart Atria / Q000166:cytology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008985:Monensin / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012964:Sodium / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
chemical_list: D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D014157:Transcription Factors; D012313:RNA; D008985:Monensin; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases