Development of a therapeutic anti-marinobufagenin antibody

PE患者血浆和胎盘内源性强心类固醇MBG水平升高。在体外，低浓度的MBG通过激活蛋白激酶C-Delta和抑制核转录因子和胶原-1合成的负调控因子FLI1来刺激胶原的合成。由于胎盘MBG水平在PE中显著升高，且MBG具有促纤维化作用，我们推测在PE中胎盘MBG水平升高可能与胎儿胎盘循环纤维化的发生和血管松弛功能受损有关。我们研究了18例PE患者(平均血压1232毫米汞柱；292岁，最短35周)。年龄)和12名胎龄匹配的正常孕妇。与对照组相比，PE组胎盘组织中MBG水平升高(48.67.0nmol/g比13.62.5nmol/g；P<0.01)，红细胞Na/K-ATPase活性降低2倍，脐动脉组织中Fli-1水平降低4倍，前胶原-1和胶原-1水平增加2倍。与对照血管相比，PE患者的脐带离体环对ET-1的反应性不变(EC_(50)=20和33nmol/L)，对硝普钠引起的收缩反应明显减弱(EC_(50)=141vs.0.9nmol/L P&lt；.001)。对照组脐动脉外植体与1~10nmol/L微球共同孵育，可降低血管环中Fli-1的水平，增加胶原-1的水平，降低血管环对硝普钠松弛作用的敏感性，类似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松弛障碍有关。

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.