Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia

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.

Preeclampsia: Сardiotonic Steroids, Fibrosis and a Hint to Cancerogenesis

“…In the nucleus, phosphorylated PKCδ phosphorylates Fli1, which withdraws Fli1-induced inhibition of the collagen-1 promoter and increases in procollagen expression and collagen production [32] (Figure 1). The mechanism of vascular fibrosis induced by various vascular factors including CS is also implicated in remodeling of spiral uterine arteries, associated with the development of PE [32,37]. Interestingly, the same mechanism of synthesis of collagen-1, Fli1-dependent fibrosis, was found in myocardium of rats with renal failure [38].…”

Endogenous Bufadienolides, Fibrosis and Preeclampsia

“…In this model, in vivo immunoneutralization of MBG with poly-and monoclonal antibodies produced antihypertensive effect associated with the increase in vascular NKA activity [33,42]. Considering that, (i) MBG stimulates synthesis of collagen, (ii) fibrosis in placenta and umbilical arteries in PE patients is accompanied by elevated placental MBG and a dramatic decrease in Fli-1 level [43], and (iii) PE is associated with vascular stiffening [44,45]; it has been showed that MBG is one of the factors, implicated in pathogenesis of PE via induction of vasoconstriction and vascular fibrosis [41]. In the recent study, it has been shown that the placental levels of Fli-1 were dramatically lower, while collagen-1 levels were higher in both placenta and umbilical arteries in PreE samples compared to the tissues from control noncomplicated pregnancy.…”

“…In the recent study, it has been shown that the placental levels of Fli-1 were dramatically lower, while collagen-1 levels were higher in both placenta and umbilical arteries in PreE samples compared to the tissues from control noncomplicated pregnancy. e subsequent treatment of the umbilical artery explants from PE patients with anti-MBG mAb was accompanied by a significant decrease in collagen-1 abundance [43].…”

Pathogenetic features of formation of experimental preeclampsia-like condition

“…После эвтаназии оценивали количество плодов и их среднюю массу, измеряли вес плаценты, оценивали уровень эндоглина в плаценте, sFlt1 в плаценте и кольцах грудной аорты, а также измеряли количество Fli1, коллагена-1, трансформирующего фактора роста бета (ТФР-бета), коллагена-4 в кольцах грудной аорты. Подготовку образцов тканей плаценты, а также колец грудной аорты проводили по ранее отработанной методике [7]. Для оценки содержания МБГ в плазме крови использовали моноклональные анти-МБГ антитела 4G4.…”