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Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 Aug 13; Vol. 19 (8). Date of Electronic Publication: 2018 Aug 13. - Publication Year :
- 2018
-
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.<br />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.<br />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.<br />Conclusion: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.
- Subjects :
- Adult
Animals
Antibodies immunology
Blood Pressure
Bufanolides blood
Case-Control Studies
Collagen Type I metabolism
Erythrocytes enzymology
Female
Fibrosis
Gestational Age
Humans
Immunotherapy
Microfilament Proteins antagonists & inhibitors
Microfilament Proteins metabolism
Pre-Eclampsia immunology
Pre-Eclampsia pathology
Pregnancy
Rats
Receptors, Cytoplasmic and Nuclear antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear metabolism
Sodium-Potassium-Exchanging ATPase metabolism
Trans-Activators
Umbilical Arteries pathology
Antibodies therapeutic use
Bufanolides immunology
Placenta metabolism
Pre-Eclampsia drug therapy
Umbilical Arteries metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30104471
- Full Text :
- https://doi.org/10.3390/ijms19082377