TY - JOUR
T1 - Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line
AU - Popov, Sergej
AU - Venetsanou, Kyriaki
AU - Chedrese, P Jorge
AU - Pinto, Vanda
AU - Takemori, Hiroshi
AU - Franco-Cereceda, Anders
AU - Eriksson, Per
AU - Mochizuki, Naoki
AU - Soares-da-Silva, Patricio
AU - Bertorello, Alejandro M
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
KW - Biopsy
KW - Cardiomegaly
KW - Cell Line
KW - Gene Expression
KW - Heart Atria
KW - Histone Deacetylases
KW - Humans
KW - Hydrogen-Ion Concentration
KW - MADS Domain Proteins
KW - MEF2 Transcription Factors
KW - Monensin
KW - Myocytes, Cardiac
KW - Myogenic Regulatory Factors
KW - NFATC Transcription Factors
KW - Phosphorylation
KW - Plasmids
KW - Protein-Serine-Threonine Kinases
KW - RNA
KW - Sodium
KW - Transcription Factors
KW - Transcription, Genetic
KW - Transfection
U2 - 10.1152/ajpheart.00512.2011
DO - 10.1152/ajpheart.00512.2011
M3 - Article (Academic Journal)
C2 - 22467310
SN - 0363-6135
VL - 303
SP - H57-65
JO - AJP - Heart and Circulatory Physiology
JF - AJP - Heart and Circulatory Physiology
IS - 1
ER -