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Int. J. Mol. Sci. 2018, 19(8), 2377;

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

Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA
Institute of Neonatology, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg 197431, Russia
Department of Obstetrics and Gynecology, School of Pediatric Medicine, St. Petersburg 194353, Russia
Institute of Highly Pure Biopreparations, St. Petersburg 197110, Russia
Sechenov Institute of Evolutionary Physiology and Biochemistry, 44 Torez Prospect, St. Petersburg 194223, Russia
DO Ott Institute of Obstetrics and Gynecology, St. Petersburg 199034, Russia
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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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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