Development of a therapeutic anti-marinobufagenin antibody

我们研究了16例PE患者（平均BP = 1232 mmHg; 282岁，36周gest。年龄）和14例胎龄匹配的正常妊娠受试者（平均BP = 922 mmHg）。PE与血浆和胎盘MBG水平升高相关。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<0.001），而前胶原-1的表达增加（P<0.01）。与对照血管相比，PE受试者的脐动脉环对内皮素-1的反应性未发生改变（EC 50分别为2.2和3.2 nmol/L），但对内皮素-1诱导的收缩后硝普钠的舒张作用的反应性受损（EC 50 = 1.5 vs. 32.4 nmol/L P<0.001）。用1和10 nmol/L MBG离体处理正常脐动脉外植体模拟PE的作用，特异性抑制Fli-1并增加胶原-1表达，同时损害血管舒张。我们的研究结果表明，在PE中，MBG水平升高通过Fli-1依赖性机制诱导血管纤维化，导致血管舒张受损，并表明MBG代表了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.