Development of a therapeutic anti-marinobufagenin antibody

我们研究了16例PE患者(平均血压=1232 mm Hg；282岁，最短36周)。年龄)和14例胎龄匹配的正常孕妇(平均血压=922毫米汞柱)。PE与血浆和胎盘MBG水平升高有关。在PE脐动脉中，转录因子和纤维化负调控因子Fli-1的表达显著降低(P&lt；0.001)，而前胶原-1的表达显著增加(P&lt；0.01)。与对照血管相比，PE患者的脐动脉离体环对ET-1的反应性没有改变(EC_(50)分别为2.2和3.2nmol/L)，但对硝普钠的收缩反应减弱(EC_(50)=1.5vs.32.4nmol/L P&lt；.001)。1和10nmol/L的MBG体外作用与PE相似，特异性地抑制Fli-1和增加胶原-1的表达，同时损害血管的松弛。我们的结果表明，在PE中，MBG水平升高通过依赖Fli-1的机制诱导血管纤维化，导致血管松弛功能受损，提示MBG是治疗这种综合征的潜在靶点。

We studied 16 patients with PE (mean BP = 1232 mmHg; 282 years, 36 weeks gest. age) and 14 gestational age-matched normal pregnant subjects (mean BP = 922 mmHg). PE was associated with a rise in plasma and placental levels of MBG. In PE umbilical arteries, the expression of Fli-1, a transcription factor and a negative regulator of fibrosis, was significantly reduced (P<0.001), while procollagen-1 expression was increased (P<0.01). As compared to control vessels, isolated rings of umbilical arteries from subjects with PE demonstrated unaltered responsiveness to endothelin-1 (EC50 = 2.2 and 3.2 nmol/L, respectively), but exhibited an impaired response to the relaxant effect of sodium nitroprusside (EC50= 1.5 vs. 32.4 nmol/L P<.001) following endothelin-1-induced constriction. Ex vivo treatment of normal umbilical arteries explants with 1 and 10 nmol/L MBG mimicked the effects of PE, specifically suppressed Fli-1 and increased collagen-1 expression while impairing vasorelaxation. Our results indicate that in PE, elevated levels of MBG induce vascular fibrosis via a Fli-1-dependent mechanism which leads to an impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy of this syndrome.