Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line

Abstract

Popov S, Venetsanou K, Chedrese PJ, Pinto V, Takemori H, Franco-Cereceda A, Eriksson P, Mochizuki N, Soares-da-Silva P, Bertorello AM. Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line. Am J Physiol Heart Circ Physiol 303: H57-H65, 2012. First published March 30, 2012 doi:10.1152/ajpheart.00512.2011.-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 ϩ ]i) on transcription factors and genes associated with CH in a cardiac cell line. Increases in [Na ϩ ]i led to a timedependent 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 ϩ ]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 ϩ ]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 ϩ ]i activate SIK1 and MEF2 via a parallel increase in intracellular calcium through the reverse mode of Na ϩ /Ca 2ϩ -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.hypertension; cardiac hypertrophy; Na ϩ ,K ϩ -ATPase; ion gradients CARDIAC HYPERTROPHY IS CONSIDERED to be the heart's response to sustained mechanical stress caused by either obstruction of cardiac outflow (valve stenosis) or elevated systemic arterial blood pressure. At the molecular level, its development involves the activation of numerous genes and transcription factors (9, 18, 30) that ultimately lead to abnormal myocardial growth. Hypertension is presently one of the major causes of cardiac hypertrophy. Although systemic hypertension has multiple causes, it ultimately results from the kidney's inability to maintain sodium homeostasis after normal or excessive sodium intake (1, 16). Whereas a sustained increase in systemic blood pressure is likely to influence the development of cardiac hypertrophy, it has also been demonstrated that high salt intake is associated with left ventricle hypertrophy even without significant increases in systemic blood pr...

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

“…SIK1 was initially discovered in adrenal glands of rats fed with a HS diet and it has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. 4,6 In agreement with previous literature, we observed that the regulatory action of SIK1 on blood pressure levels is exerted specifically during abnormal salt intake. Furthermore, our results showed that within the vasculature SIK1 was induced in the VSMCs layer of the wild-type mice aorta in response to the chronic HS intake.…”

“…3 In addition, SIK1 regulates active sodium transport in renal and lung epithelia by increasing sodium-potassium ATPase (Na + ,K + -ATPase) activity and mediates gene expression activation in cardiac myocytes on increase in intracellular sodium. [4][5][6] SIK1 is also present in the vasculature and its activity in endothelial and vascular smooth muscle cells (VSMCs) seems to be relevant for controlling the vascular tone and arterial blood pressure by regulating Na + ,K + -ATPase activity in VSMCs. 7 A polymorphism in SIK1 gene resulting in 1 amino acid change ( 15 Gly→Ser) in the protein enhances the kinase activity and is associated with lower blood pressure and reduced left ventricle (LV) mass index in humans.…”

Lack of Salt-Inducible Kinase 2 (SIK2) Prevents the Development of Cardiac Hypertrophy in Response to Chronic High-Salt Intake

“…Although ubiquitous, this effect is particularly relevant in the renal epithelia [15], and in cardiac myocytes [33]. In cardiac myocytes, SIK1 mediates the increases in MEF2C, NFAT5c and genes associated with CH in response to increases in intracellular sodium [33].…”

Post-translational Modifications Regulate Class IIa Histone Deacetylase (HDAC) Function in Health and Disease

“…PKC-related kinases 1 and 2 (PRK1 and PRK2) also target T292 (68), highlighting the PKC signaling pathway as an important determinant of HDAC5 phosphorylation status. Other enzymes that target both S259 and S498 are AMP-activated protein kinase (69,70), G protein-coupled receptor kinase-5 (GRK5) (71), whereas salt-inducible kinase 1 (SIK1) phosphorylates only S259 (72).…”

“…Independently of blood pressure, high salt intake has also been known to be associated with left ventricle hypertrophy (128,144). More recently, this mechanism was shown to be phosphorylation-dependent, as increased sodium levels activate the critical cardiac kinase SIK1, leading to HDAC5 phosphorylation and enhanced MEF2 and NFAT transcriptional activity (72). Interestingly, a recent study examined the mechanisms through which clinically relevant neurohormonal stimuli regulate HDAC phosphorylation in adult cardiomyocytes (62).…”