In preeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries

Abstract

Background-Marinobufagenin (MBG), a bufadienolide cardiotonic steroid, induces cardiovascular fibrosis. Because levels of MBG in preeclampsia are increased, and anti-MBG monoclonal antibody reduces blood pressure (BP) in a rat model of preeclampsia, we hypothesized that in preeclampsia, elevated MBG levels would be associated with the development of fibrosis in feto-placental circulation and with impairment of vascular relaxation.

Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

“…Decrease of Fli-1, a nuclear transcription factor and a member of ETS family is implicated in MBG-induced fibrosis [11,12,18]. Fli-1 acts as a negative regulator of collagen-1 synthesis and it competes with another transcription factor, ETS-1, to maintain a balance between stimulation and repression of Col1a2 gene [26,27].…”

“…Previously, in partially nephrectomized rats we demonstrated that development of cardiac fibrosis in the presence of elevated MBG levels was associated with decrease of Fli-1 [12]. In preeclampsia, which is also associated with elevated levels of MBG, fibrosis of umbilical arteries was accompanied by a dramatic reduction in the levels of Fli-1 [18]. In uremic rats a single administration of monoclonal anti-MBG antibody markedly reduced cardiac levels of collagen-1 in parallel with an increase in the levels of Fli-1, suggesting a causative relationship between MBG and Fli-1 [12].…”

“…In uremic rats a single administration of monoclonal anti-MBG antibody markedly reduced cardiac levels of collagen-1 in parallel with an increase in the levels of Fli-1, suggesting a causative relationship between MBG and Fli-1 [12]. Accordingly, MBG downregulated Fli-1, and stimulated synthesis of collagen in rat renal and cardiac fibroblasts [11], and in the explants of human umbilical arteries [18]. Our present results support these previous observations, and for first time demonstrate that MBG-induced decrease of Fli-1 followed by initiation of the pro-fibrotic signaling in vascular tissues is reversed by mineralocorticoid antagonists.…”

“…Following the 24-hr preincubation of aortic explants with MBG, canrenone and combination of both compounds, segments of thoracic aortae were homogenized in lysis RIPA buffer (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and Western Blot analysis was performed as previously reported [18]. Solubilized proteins from aortic sarcolemma was separated by 10% Tris-Glycine polyacrylamide gel (Life Technologies) electrophoresis and transferred to a nitrocellulose membrane.…”

“…Notably, in this study MBG exhibited pro-fibrotic effect in the absence of changes in aldosterone levels [7]. Importantly, high levels of MBG were associated with hypertension [17], stiffening of umbilical vessels and elevated vascular level collagen-1 in preeclamptic patients, and in vitro incubation of the healthy blood vessels in the presence of low MBG concentration produced similar phenotype [18]. We hypothesized that aldosterone antagonists can also reverse MBG-induced vascular fibrosis.…”