Abstract
Background: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Objectives and Methods: We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study. Results: PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. Conclusion: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.
Highlights
Preeclampsia (PE) represents one of the most serious complications of pregnancy, leading to maternal and fetal morbidity and mortality
That in patients with PE, elevation of arterial blood pressure (BP) is associated with markedly increased plasma levels of MBG, which are significantly higher than in normal pregnancy [5,8,9], and lower Na/K-ATPase activity in erythrocytes from PE patients compared to non-complicated pregnancy [8,9,10,11]
In the patients with PE, elevated levels of MBG were associated with a substantial inhibition of Na/K-ATPase in the erythrocytes, as compared to that in subjects with uncomplicated pregnancies (Table 1)
Summary
Preeclampsia (PE) represents one of the most serious complications of pregnancy, leading to maternal and fetal morbidity and mortality. That in patients with PE, elevation of arterial blood pressure (BP) is associated with markedly increased plasma levels of MBG, which are significantly higher than in normal pregnancy [5,8,9], and lower Na/K-ATPase activity in erythrocytes from PE patients compared to non-complicated pregnancy [8,9,10,11]. Results: PE was associated with a higher placental (0.04 ± 0.01 vs 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs 1.5 ± 0.2 μmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs control.
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