Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Recently, we demonstrated that (i) MBG induces fibrosis in rat tissues via a mechanism involving Fli1, a negative regulator of collagen-1 synthesis, and (ii) MBG sensitive Na/K-ATPase inhibition is reversed by mineralocorticoid antagonists. We hypothesized that in human PE elevated MBG level is associated with the development of fibrosis of the umbilical arteries and that this fibrosis can be attenuated by canrenone. Fifteen patients with PE (mean BP = 118 ± 4 mmHg; 34 ± 2 years; 38 ± 0.3 weeks gest. age) and twelve gestational age-matched normal pregnant subjects (mean BP = 92 ± 2 mmHg; 34 ± 1 years; 39 ± 0.2 weeks gest. age) were enrolled in the study. PE was associated with a higher plasma MBG level, with a four-fold decrease in Fli1 level and a three-fold increase in collagen-1 level in the PE umbilical arteries vs. those from the normal subjects (p < 0.01). Isolated rings of umbilical arteries from the subjects with PE exhibited impaired responses to the relaxant effect of sodium nitroprusside vs. control vessels (EC50 = 141 nmol/L vs. EC50 = 0.9 nmol/L; p < 0.001). The effects of PE on Fli1 and collagen-1 were blocked by the in vitro treatment of umbilical arteries by 10 μmol/L canrenone. Similar results were obtained for umbilical arteries pretreated with MBG. These data demonstrate that elevated MBG level is implicated in the development of the fibrosis of umbilical arteries in PE, and that this could be blocked by mineralocorticoid antagonists.
BACKGROUND Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6–19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.
Rationale Previously we demonstrated that in patients with preeclampsia elevated levels of endogenous Na/K-ATPase inhibitor, marinobufagenin, cause inhibition of Friend leukemia virus integration 1 (Fli1), a negative regulator of collagen-1 synthesis. Objective We hypothesized that in vitro silencing of Fli1 in healthy human umbilical arteries would be associated with an increase in collagen-1 output, similar to the effect of preeclampsia. Methods The isolated segments of healthy human umbilical arteries were tested for sensitivity to MBG and Fli1 silencing with Fli1 siRNA or control siRNA. Results Following 24-h incubation of arteries with nanomolar concentrations of marinobufagenin, Fli1 expression was inhibited 5 fold (p < 0.001), and synthesis of collagen-1 increased 3 times (p < 0.01). 24-hour incubation of umbilical artery fragments with Fli1 siRNA caused a dramatic decrease of Fli1 (7-fold; p<0.001) and cytoplasmic PKCδ (4-fold; p<0.001) expression in comparison to control siRNA or untreated control, followed by elevation in procollagen (3-fold; p<0.001) and collagen-1 (3-fold; p<0.001) levels in vascular tissue. Conclusions Our results show that after silencing the Fli1 gene in healthy human umbilical arteries a new phenotype emerges which is typical for preeclampsia and is associated with vascular fibrosis.
Background: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Objectives and Methods: We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/mL) for 4 hours. Results: PE was associated with higher blood pressure (117 ± 2 vs 107 ± 2 mmHg; p < 0.01), plasma MBG levels (1.54 ± 0.34 vs 0.49 ± 0.11 nmol/L; p < 0.01), protein excretion (26 vs 12 mg/24 hours), sFlt-1 (4-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all p < 0.01). In 12 rats was treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mmHg) and Fli1 was decreased much less (2-fold; p < 0.01 vs nontreated rats). Conclusion: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1. Supported by Russian Scientific Foundation grant № 18-15-00222.
Objective. Establish the relationship between the action of antiangiogenic factors sFLT-1 and endoglin, as well as marinobufagenin in the formation of symptoms of preeclampsia in the clinic and experiment. Materials and methods. In the first experimental phase, preeclampsia-like state was simulated in pregnant rats, the changes in the content of substances reflected in the target tissues were studied, as well as the effect on their concentrations of anti-marinobufagenin antibodies. In the second (clinical) phase, changes in the content of sFlt-1 and endoglin-1 in placental tissues, as well as marinobufagenin in blood plasma and activity of Na+/K+-ATPase of erythrocytes in pregnant women with preeclampsia were studied. Results. In rats, an increase in systolic blood pressure, and marinobufagenin plasma levels was observed during the formation of a preeclampsia-like condition. Administration of antibodies to marinobufagenin caused a decrease in blood pressure. Found that during the formation of a preeclampsia-like condition, there is an increase in the content of sFlt-1 in the placenta and thoracic aorta and endoglin in the placenta. In patients with preeclampsia, it was found that the increase in blood pressure occurs against the background of an increase in the content of marinobufagenin in blood plasma, as well as a decrease in the activity of Na+/K+-ATPase of erythrocytes. The formation of preeclampsia is accompanied by a significant increase in the level of antiangiogenic factors endoglin and sFlt-1 in the placenta. Summary. In patients with preeclampsia, the development of clinical symptoms is accompanied by an increase in the placental tissues of the content of antiangiogenic factors endoglin and sFlt-1 and the content of marinobufagenin in blood plasma. The obtained data are confirmed by the results of an experiment performed on pregnant rats with modeling of preeclampsia-like condition.
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