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.
| Dmitrieva, Natalia I; Burg, Maurice B (2014) Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis. Proc Natl Acad Sci U S A 111:6485-90 |
| Zhou, Xiaoming; Burg, Maurice B; Ferraris, Joan D (2012) Water restriction increases renal inner medullary manganese superoxide dismutase (MnSOD). Am J Physiol Renal Physiol 303:F674-80 |
| Dmitrieva, Natalia I; Malide, Daniela; Burg, Maurice B (2011) Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA. Am J Physiol Regul Integr Comp Physiol 301:R632-40 |
| Dmitrieva, Natalia I; Burg, Maurice B (2011) Increased insensible water loss contributes to aging related dehydration. PLoS One 6:e20691 |
| Dmitrieva, Natalia I; Cui, Kairong; Kitchaev, Daniil A et al. (2011) DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts. Proc Natl Acad Sci U S A 108:20796-801 |
