Hyperosmolality-induced damage to cells

高凝状态会增加血栓形成的风险，从而导致心血管事件。我们确定血浆钠浓度是通过影响血管性血友病因子（vWF）（凝血级联反应的关键启动子）的产生来调节血液凝固性的一个因素。我们发现，从血液中正常值的下限到严重高钠血症水平的范围内，盐的升高可逆地增加了培养的内皮细胞中vWF mRNA的表达和vWF分泌的速率。高盐可增加张力调节转录因子NFAT 5的表达及其与vWF基因启动子的结合，提示高渗信号参与了vWF的上调。为了提高体内的NaCl，我们模拟了轻度脱水，通过给小鼠喂食含有30%水的凝胶食物使小鼠受到水分限制（WR）。这种WR将血钠从145.1 ± 0.5 mmol/L升高至150.2 ± 1.3 mmol/L，并激活高渗信号传导，这从组织中NFAT 5的表达增加得到证明。WR使肝、肺vWF mRNA表达增加，血vWF蛋白表达升高。肝脏免疫组化染色显示内皮细胞vWF蛋白的产生增加，毛细血管内微血栓的数量增加。WR还增加血液中D-二聚体的水平，表明正在进行的凝血和溶栓。社区动脉粥样硬化风险研究的临床数据的多变量回归分析表明，血清钠显著有助于预测血浆vWF和卒中风险。结果表明，在生理范围内细胞外钠的升高使vWF充分升高，从而增加凝血能力和血栓形成的风险。

Hypercoagulability increases risk of thrombi that cause cardiovascular events. We identified plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 0.5 to 150.2 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis.