Abstract 204: Sodium Sensing Network in Hypertension-Induced Cardiac Hypertrophy

Abstract

Hypertension is related to alterations of sodium homeostasis that promote abnormal accumulation of water in the intravascular compartment leading to blood pressure elevation. This process can been associated with increased heart mass resulting in cardiac hypertrophy. At cellular level, the concentration and active transport of Na+ is regulated by Na+,K+-ATPase enzyme (NK). In vitro studies have shown a correlation between high blood pressure, NK and SIK activities. Increases in intracellular Na+ are paralleled by elevations in intracellular Ca2+ via NCX1, leading to the activation of SIK1 by a Ca2+/calmodulin-dependent kinase. Activation of SIK1 results in the dephosphorylation of the NK α-subunit and an increase in its catalytic activity. Accordingly, the aim of the present study was to evaluate the cardiac Na+ sensing network changes associated with hypertension in aging hypertensive rats. Systolic and diastolic blood pressures, determined by the tail-cuff method, were significantly higher in 3, 13 and 21-month old SHR than in age-matched WKY. In the SHR, ageing was associated with increases in cardiac mass, gene expression of hypertrophic (α-skeletal muscle actin and β-myosin heavy chain) markers as well as inflammatory cytokine (IL-6). The decreased expression of heart SIK isoforms, SIK1 and SIK3, was associated with downregulation of transcription factors Snail2, Zeb1, MFAT5c and KLF4, in 13 and 21-month old SHR. Cardiac α2-isoform of NK was found to be decreased in 21 month old SHR. Whereas, NKα1, NHE3 and NCX1 showed no differences between age-matched SHR and WKY. Na+-dependent ASCT2 and Na+-independent LAT1 amino acid transporter transcript levels of were significantly higher in 21 month old SHR than in WKY. In the aged SHR, cardiac hypertrophy was associated with dysregulation of several elements of the intracellular Na+ sensing network. Downregulation of SIK1 and transcription factors is correlated with expression of NKα2, suggesting impaired sodium handling. It is proposed that, cardiac hypertrophy is not exclusively the consequence of mechanical stress but also of other factors associated with elevated blood pressure such as abnormal cell sodium homeostasis.Supported by grant PIC/IC/83204/2007.