Endogenous cardiotonic steroids and vascular fibrosis in preeclampsia

Abstract

Background. Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis.Objective.We hypothesized that in human and rat PE, elevated MBG level is associated with development of fibrosis of umbilical arteries and rat thoracic aortae.Design and methods.Twelve patients with PE (mean blood pressure (BP) 118 ± 4 mmHg; mean age 28 ± 2 years; mean gestation age 36 ± 1 weeks) and 12 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; mean age 26 ± 1 years; mean gestation age 37 ± 1 weeks) were enrolled in the clinical study. We tested 16 pregnant Sprague-Dawley rats. Hypertension was provoked in 8 rats by 1,8 % Na supplementation.Results.PE in humans and rats was associated with the higher plasma MBG level and was associated with five-fold decrease in Fli-1 level and four-fold increase in collagen-1 level in the PE umbilical arteries vs. those from the normal subjects (p < 0,01). Isolated rings of umbilical arteries from the subjects with PE exhibited impaired response to the relaxant effect of sodium nitroprusside vs. control vessels (EC50 = 141 nmol/L vs. EC50 = 0,9 nmol/L; p < 0,001). Similar results were obtained for thoracic aorta of rats with experimental PE.Conclusions. These results demonstrate that elevated MBG level is implicated in the development of fibrosis umbilical arteries in PE.