Development of a therapeutic anti-marinobufagenin antibody

内源性强心类固醇MBG的血浆和胎盘水平在PE中升高。在体外，低浓度的MBG通过激活蛋白激酶C-δ和抑制Fli 1（一种核转录因子和胶原蛋白-1合成的负调节因子）来刺激胶原蛋白合成。由于PE中MBG水平显著增加，并且MBG发挥促纤维化作用，我们假设在PE中，胎盘MBG水平升高与胎儿-胎盘循环中纤维化的发展和血管舒张受损相关。我们研究了18例PE患者（平均血压，1232 mmHg; 292岁，35周gest。年龄）和12名胎龄匹配的正常妊娠受试者。与对照组相比，PE患者胎盘MBG水平升高（48.6 ± 7.0 vs. 13.6 ± 2.5 nmol/g; P<0.01），红细胞Na/K-ATP酶活性降低2倍，Fli-1水平降低4倍，脐动脉中1型前胶原和1型胶原水平升高2倍。与对照血管相比，在对内皮素-1的反应性不变（EC 50 = 20和33 nmol/L）的情况下，PE患者的离体脐环在内皮素-1诱导的收缩后对硝普钠的舒张作用表现出明显受损的反应（EC 50 = 141 vs. 0.9 nmol/L P<0.001）。来自对照受试者的脐动脉外植体与1-10 nmol/L MBG的离体孵育降低了Fli-1的水平，增加了胶原蛋白-1的水平，并降低了血管环对硝普钠松弛作用的敏感性，模拟了PE的作用。这些结果表明，在PE中，MBG水平升高与血管纤维化和血管舒张受损有关。

Plasma and placental levels of an endogenous cardiotonic steroid MBG are elevated in PE. In vitro low concentrations of MBG stimulate collagen synthesis via activation of protein kinase C-delta and suppression of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Because levels of MBG in PE are markedly increased, and MBG exerts pro-fibrotic effects, we hypothesized that in PE, elevated placental MBG levels would be associated with development of fibrosis in feto-placental circulation and with impairment of vascular relaxation. We studied 18 patients with PE (mean blood pressure, 1232 mmHg; 292 years, 35 wks gest. age) and 12 gestational age-matched normal pregnant subjects. PE was associated with a rise in the levels of MBG in placentae (48.67.0 vs. 13.62.5 nmol/g; P<.01), a 2-fold reduction of erythrocyte Na/K-ATPase activity, a 4-fold decrease in the level of Fli-1 and a 2-fold increase in the levels of procollagen-1 and collagen-1 in the umbilical arteries vs. those in control subjects. As compared to control vessels, isolated rings of umbilical from PE patients, in the presence of unaltered responsiveness to endothelin-1 (EC50 = 20 and 33 nmol/L), exhibited markedly impaired response to the relaxant effect of sodium nitroprusside (EC50= 141 vs. 0.9 nmol/L P<.001) following endothelin-1-induced constriction. Ex vivo incubation of umbilical arteries explants from control subjects with 1-10 nmol/L MBG reduced levels of Fli-1, increased levels of collagen-1, and reduced sensitivity of vascular rings to the relaxant effect of sodium nitroprusside, mimicking the effect of PE. These results demonstrate that in PE, elevated levels of MBG are implicated in vascular fibrosis and impairment of vasorelaxation.