Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Institute of Neonatology, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg 197431, Russia.
Int J Mol Sci. 2018 Aug 13;19(8):2377. doi: 10.3390/ijms19082377.
Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis.
We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study.
PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae ( < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo ( < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo.
These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.
先前的研究表明，包括 Na/K-ATPase 抑制剂 marinobufagenin（MBG）在内的强心甾体在子痫前期（PE）的发病机制中起作用。用 Digibind（一种洋地黄抗体）免疫中和升高的 MBG，可降低 PE 患者的血压（BP），抗-MBG 单克隆抗体可降低 PE 大鼠模型的 BP。最近，我们证明 MBG 通过抑制核转录因子 Fli-1 诱导心血管组织纤维化，Fli-1 是胶原-1 合成的负调节剂。
我们假设，在 PE 中，升高的胎盘 MBG 水平与脐动脉纤维化的发展有关。11 名 PE 患者（平均 BP 为 124 ± 4 mmHg；年龄 29 ± 2 岁；39 周孕龄）和 10 名年龄匹配的正常妊娠孕妇（平均 BP 为 92 ± 2 mmHg；对照组）参加了临床研究。
PE 与胎盘（0.04 ± 0.01 与 0.49 ± 0.11 pmol/g；<0.01）和血浆 MBG（0.5 ± 0.1 与 1.6 ± 0.5 nmol/L；<0.01）升高、红细胞 Na/K-ATPase 活性降低（2.7 ± 0.2 与 1.5 ± 0.2 µmol Pi/mL/hr；<0.01）、Fli-1 水平降低 9 倍和胎盘胶原-1 升高 2.5 倍有关（<0.01）与对照组相比。将 1 nmol/L MBG 孵育于对照组患者的脐动脉中，与用安慰剂孵育的脐动脉相比，Fli-1 水平降低了 4 倍，胶原-1 水平升高了 2 倍（<0.01），即生理浓度的 MBG 在体外模拟了 PE 的作用。PE 患者的脐动脉中胶原-1 的丰度比对照组高 4 倍，而这种与 PE 相关的纤维化可通过单克隆抗-MBG 抗体在体外逆转。
这些结果表明，升高的胎盘 MBG 水平与 PE 中胎盘和脐动脉纤维化的发展有关。
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