Hyperosmolality-induced damage to cells

高凝性增加了引起心血管事件的血栓的风险。我们发现血浆钠浓度是通过影响血管性血友病因子（vWF）的产生来调节血液凝固性的一个因素，vWF是凝血级联的一个关键发起者。我们发现，从血液正常水平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内皮细胞中的vWF mRNA和vWF分泌的速度。高盐胁迫增加了强直调节转录因子NFAT5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NaCl的含量，我们建立了轻度脱水模型，给小鼠喂食含30%水的凝胶食物进行限水（WR）。这种WR使血钠从145.1 0.5升高到150.2 1.3 mmol/L，并激活高渗信号，这可以从组织中NFAT5表达的增加中得到证明。白藜芦醇可使肝、肺vWF mRNA升高，使血液vWF蛋白升高。肝脏免疫染色显示内皮细胞产生vWF蛋白增加，毛细血管内微血栓数量增加。WR也增加血d -二聚体水平，表明正在进行凝血和溶栓。社区动脉粥样硬化风险研究临床数据的多因素回归分析表明，血清钠对预测血浆vWF和卒中风险有显著作用。结果表明，细胞外钠在生理范围内的升高足以提高vWF，从而增加凝血性和血栓形成的风险。

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.