Abstract

We studied 16 patients with PE (mean BP = 1232 mmHg;282 years, 36 weeks gest. age) and 14 gestational age-matched normal pregnant subjects (mean BP = 922 mmHg). PE was associated with a rise in plasma and placental levels of MBG. In PE umbilical arteries, the expression of Fli-1, a transcription factor and a negative regulator of fibrosis, was significantly reduced (P<0.001), while procollagen-1 expression was increased (P<0.01). As compared to control vessels, isolated rings of umbilical arteries from subjects with PE demonstrated unaltered responsiveness to endothelin-1 (EC50 = 2.2 and 3.2 nmol/L, respectively), but exhibited an impaired response to the relaxant effect of sodium nitroprusside (EC50= 1.5 vs. 32.4 nmol/L P<.001) following endothelin-1-induced constriction. Ex vivo treatment of normal umbilical arteries explants with 1 and 10 nmol/L MBG mimicked the effects of PE, specifically suppressed Fli-1 and increased collagen-1 expression while impairing vasorelaxation. Our results indicate that in PE, elevated levels of MBG induce vascular fibrosis via a Fli-1-dependent mechanism which leads to an impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy of this syndrome.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000869-04
Application #
8335946
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$377,262
Indirect Cost

  Institution

Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Fedorova, Olga V; Ishkaraeva, Valentina V; Grigorova, Yulia N et al. (2018) Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia. Int J Mol Sci 19:
Strauss, Michél; Smith, Wayne; Wei, Wen et al. (2018) Marinobufagenin is related to elevated central and 24-h systolic blood pressures in young black women: the African-PREDICT Study. Hypertens Res 41:183-192
AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V et al. (2017) The Pressure of Aging. Med Clin North Am 101:81-101
Gable, Marjorie E; Ellis, Linda; Fedorova, Olga V et al. (2017) Comparison of Digitalis Sensitivities of Na(+)/K(+)-ATPases from Human and Pig Kidneys. ACS Omega 2:3610-3615
Haller, Steven T; Yan, Yanling; Drummond, Christopher A et al. (2016) Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling. J Am Heart Assoc 5:
Fedorova, Olga V; Zernetkina, Valentina I; Shilova, Victoria Y et al. (2015) Synthesis of an Endogenous Steroidal Na Pump Inhibitor Marinobufagenin, Implicated in Human Cardiovascular Diseases, Is Initiated by CYP27A1 via Bile Acid Pathway. Circ Cardiovasc Genet 8:736-45
Fedorova, Olga V; Lakatta, Edward G; Bagrov, Alexei Y et al. (2015) Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the salt-sensitivity in men. J Hypertens 33:534-41; discussion 541
Kennedy, David J; Shrestha, Kevin; Sheehey, Brendan et al. (2015) Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure. Circ Heart Fail 8:1068-76
Fedorova, Olga V; Emelianov, Igor V; Bagrov, Konstantin A et al. (2015) Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists. J Hypertens 33:1602-10
Grigorova, Yulia N; Juhasz, Ondrej; Zernetkina, Valentina et al. (2015) Aortic Fibrosis, Induced by High Salt Intake in the Absence of Hypertensive Response, Is Reduced by a Monoclonal Antibody to Marinobufagenin. Am J Hypertens :

Showing the most recent 10 out of 18 publications