Salt-induced Na+/K+-ATPase-α/β expression involves soluble adenylyl cyclase in endothelial cells

Abstract

High dietary salt intake may lead to vascular stiffness, which predicts cardiovascular diseases such as heart failure, and myocardial and cerebral infarctions as well as renal impairment. The vascular endothelium is a primary target for deleterious salt effects leading to dysfunction and endothelial stiffness. We hypothesize that the Ca- and bicarbonate-activated soluble adenylyl cyclase (sAC) contributes to Na/K-ATPase expression regulation in vascular endothelial cells and is an important regulator of endothelial stiffness. In vitro stimulation of vascular endothelial cells with high sodium (150 mM Na)-induced Na/K-ATPase-α and Na/K-ATPase-β protein expression determined by western blot. Promoter analyses revealed increased cAMP response element (CRE)-mediated Na/K-ATPase-α transcriptional activity under high sodium concentrations. Inhibition of sAC by the specific inhibitor KH7 or siRNA reduced the sodium effects. Flame photometry revealed increased intracellular sodium concentrations in response to high sodium stimulations, which were paralleled by elevated ATP levels. Using atomic force microscopy, a nano-technique that measures cellular stiffness and deformability, we detected significant endothelial stiffening under increased sodium concentrations, which was prevented by inhibition of sAC using KH7 and Na/K-ATPase using ouabain. Furthermore, analysis of primary aortic endothelial cells in an in vitro aging model revealed an impaired Na/K-ATPase-α sodium response and elevated intracellular sodium levels with cellular aging. We conclude that sAC mediates sodium-induced Na/K-ATPase expression in vascular endothelium and is an important regulator of endothelial stiffness. The reactivity of Na/K-ATPase-α expression regulation in response to high sodium seems to be impaired in aging endothelial cells and might be a component of endothelial dysfunction.

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

“…In the vascular endothelium, the role that the sAC-cAMP axis plays in Na + /K + -ATPase regulation has been demonstrated, as the inhibition of sAC (KH7 and interfering RNA) significantly decreases the mRNA and protein levels of Na + /K + -ATPase [ 84 ]. A recent study confirmed that the sAC-dependent regulation of Na + /K + -ATPase in the vascular endothelium plays an important role in endothelial stiffness [ 83 ].…”

“…sAC, in a PKA-dependent manner, is especially involved in corticotropin-releasing hormone-mediated CREB phosphorylation and c-fos (endogenous CREB target) induction in hippocampal neuronal cells [ 82 ]. A recent study demonstrated that sAC contributes to the regulation of CREB-mediated Na + /K + -ATPase expression in the vascular endothelium and is an important regulator of endothelial stiffness [ 83 , 84 ]. Besides promoting CREB activity, sAC also regulates several other transcription factors.…”

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease

“…The consumption of salt amounts that exceed the buffer capacity of the glycocalyx is a factor that contributes to its destruction and to the movement of sodium from the vascular bed into the intercellular space [9,10]. It was shown that the expression of Na + /K + -ATPase and the related endothelial stiffness increase under a high salt load [15]. The use of erythrocyte models to estimate individual salt sensitivity based on the sodium buffer capacity of the glycocalyx and of osmotic fragility based on the activity of sodium transporters is justified by the similarity between the endothelium and erythrocytes in relation to sodium transporters [27] and by the functional similarity of their glycocalyces [16,17].…”

“…Furthermore, Na + /K + -ATPase expression in the vascular endothelium is an important regulator of endothelial stiffness under an excessive salt load [15].…”

A three-step approach identifies novel shear stress-sensitive endothelial microRNAs involved in vasculoprotective effects of high-intensity interval training (HIIT)

“…It has also been noted that the vascular endothelium is an important ‘mechano-sensor’ transducing hemodynamic signals which may result in flow-induced conversion of endothelial cells into an elongated arterial phenotype as well as in functional and structural changes of the overall arterial wall [20, 23]. Of note, vascular maladaptations including endothelial cell stiffening, disturbed endothelial barrier function and reduced nitric oxide (NO) production [24, 25] as well as the development of atherosclerotic lesions and plaque formation is mainly found in regions with disturbed flow which increases the secretion of pro-inflammatory molecules and most likely alters miRNA expression [26, 27]. By contrast, these deleterious changes are mostly absent from regions with constant laminar flow [26].…”