Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

Abstract

Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia that is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by the deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with the restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer; as Fli1 is a proto-oncogene, a hypothesis on the suppression of Fli1 by cardiotonic steroids as a potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia that is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable of impairing marinobufagenin-Na/K-ATPase interactions.

Endogenous Digitalis-like Factors as a Key Molecule in the Pathophysiology of Pregnancy-Induced Hypertension and a Potential Therapeutic Target in Preeclampsia

“…As normal pregnancy is associated with fluid and sodium retention [ 51 ], the attention around the possible role of EDLF in pregnancy arose after their discovery [ 52 ]. In 1984, two research teams found an endogenous factor that cross-reacted with digoxin antibodies in the serum of pregnant women, and increased levels of this factor were associated with hypertensive disorders of pregnancy [ 53 , 54 ].…”

Preeclampsia subtypes: Clinical aspects regarding pathogenesis, signs, and management with special attention to diuretic administration

“…Na/K-ATPase (Na + pump) inhibitors, including digitalis-like cardiotonic steroid marinobufagenin (MBG), have been recognized as one of the classic agents seen in elevating blood pressure in response to sodium loads [53]. The potent endogen steroid MBG, also produced by the placenta, is included in the pathogenesis in reference to PE [54].…”

Canrenone Restores Vasorelaxation Impaired by Marinobufagenin in Human Preeclampsia

“…As a result, in PE, due to elevated MBG, umbilical arteries lose their capacity to relax although their contractile response remains unchanged [ 5 ]. Therefore, in PE patients, heightened MBG plasma levels represent a potential target for therapy and for the immunoneutralization of MBG [ 14 ]. We developed an anti-MBG monoclonal antibody that possesses a remarkable capacity to reduce blood pressure and cardiac fibrosis in rats with renal failure [ 11 , 15 ].…”