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 Ca2+- 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.

中文翻译：

---

盐诱导的Na + / K +-ATPase-α/β表达涉及内皮细胞中的可溶性腺苷酸环化酶。

高盐饮食可能导致血管僵硬，从而预测心血管疾病，例如心力衰竭，心肌和脑梗塞以及肾功能不全。血管内皮是导致功能障碍和内皮僵硬的有害盐效应的主要靶标。我们假设，Ca2 +和碳酸氢盐激活的可溶性腺苷酸环化酶（sAC）有助于血管内皮细胞中Na + / K + -ATPase表达的调节，并且是内皮硬度的重要调节剂。Western blot测定高钠（150 mM Na +）诱导的Na + / K +-ATPase-α和Na + / K +-ATPase-β蛋白表达对血管内皮细胞的体外刺激。启动子分析显示，在高钠浓度下，cAMP反应元件（CRE）介导的Na + / K +-ATPase-α转录活性增加。特异性抑制剂KH7或siRNA对sAC的抑制作用会降低钠的作用。火焰光度法显示，在高钠刺激下，细胞内钠浓度增加，这与ATP水平升高平行。使用原子力显微镜，一种测量细胞硬度和可变形性的纳米技术，我们在钠浓度增加的情况下检测到明显的内皮硬化，这可以通过使用KH7抑制sAC以及使用哇巴因抑制Na + / K + -ATPase来防止。此外，在体外衰老模型中对主动脉内皮细胞的分析显示，随着细胞衰老，Na + / K +-ATPase-α钠反应受损，细胞内钠水平升高。我们得出的结论是，sAC介导钠诱导的Na + / K + -ATPase在血管内皮中的表达，并且是内皮硬度的重要调节剂。Na + / K +-ATPase-α表达调节对高钠的反应性似乎在衰老的内皮细胞中受损，并且可能是内皮功能障碍的一部分。