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Int. J. Mol. Sci. 2018, 19(8), 2377; https://doi.org/10.3390/ijms19082377

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

1
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA
2
Institute of Neonatology, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg 197431, Russia
3
Department of Obstetrics and Gynecology, School of Pediatric Medicine, St. Petersburg 194353, Russia
4
Institute of Highly Pure Biopreparations, St. Petersburg 197110, Russia
5
Sechenov Institute of Evolutionary Physiology and Biochemistry, 44 Torez Prospect, St. Petersburg 194223, Russia
6
DO Ott Institute of Obstetrics and Gynecology, St. Petersburg 199034, Russia
7
Department of Obstetrics and Gynecology, University of Tennessee, Chattanooga, TN 37403, USA
*
Author to whom correspondence should be addressed.
Received: 12 July 2018 / Revised: 4 August 2018 / Accepted: 7 August 2018 / Published: 13 August 2018
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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. View Full-Text
Keywords: preeclampsia; Na/K-ATPase; cardiotonic steroids; digitalis-like factors; marinobufagenin; immunotherapy; fibrosis; collagen; Fli-1 preeclampsia; Na/K-ATPase; cardiotonic steroids; digitalis-like factors; marinobufagenin; immunotherapy; fibrosis; collagen; Fli-1
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Fedorova, O.V.; Ishkaraeva, V.V.; Grigorova, Y.N.; Reznik, V.A.; Kolodkin, N.I.; Zazerskaya, I.E.; Zernetkina, V.; Agalakova, N.I.; Tapilskaya, N.I.; Adair, C.D.; Lakatta, E.G.; Bagrov, A.Y. Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia. Int. J. Mol. Sci. 2018, 19, 2377.

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