Sechenov Institute of Evolutionary Physiology and Biochemistry, 194223 St. Petersburg, Russia.
Department of Obstetrics and Gynecology, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia.
Int J Mol Sci. 2022 Mar 19;23(6):3336. doi: 10.3390/ijms23063336.
Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Recently, we demonstrated that (i) MBG induces fibrosis in rat tissues via a mechanism involving Fli1, a negative regulator of collagen-1 synthesis, and (ii) MBG sensitive Na/K-ATPase inhibition is reversed by mineralocorticoid antagonists. We hypothesized that in human PE elevated MBG level is associated with the development of fibrosis of the umbilical arteries and that this fibrosis can be attenuated by canrenone. Fifteen patients with PE (mean BP = 118 ± 4 mmHg; 34 ± 2 years; 38 ± 0.3 weeks gest. age) and twelve gestational age-matched normal pregnant subjects (mean BP = 92 ± 2 mmHg; 34 ± 1 years; 39 ± 0.2 weeks gest. age) were enrolled in the study. PE was associated with a higher plasma MBG level, with a four-fold decrease in Fli1 level and a three-fold increase in collagen-1 level in the PE umbilical arteries vs. those from the normal subjects (p < 0.01). Isolated rings of umbilical arteries from the subjects with PE exhibited impaired responses to the relaxant effect of sodium nitroprusside vs. control vessels (EC50 = 141 nmol/L vs. EC50 = 0.9 nmol/L; p < 0.001). The effects of PE on Fli1 and collagen-1 were blocked by the in vitro treatment of umbilical arteries by 10 μmol/L canrenone. Similar results were obtained for umbilical arteries pretreated with MBG. These data demonstrate that elevated MBG level is implicated in the development of the fibrosis of umbilical arteries in PE, and that this could be blocked by mineralocorticoid antagonists.
先前的研究表明，包括 Na/K-ATP 酶抑制剂 marinobufagenin（MBG）在内的强心甾类物质与子痫前期（PE）的发病机制有关。最近，我们证明了（i）MBG 通过涉及胶原-1 合成的负调节剂 Fli1 的机制在大鼠组织中诱导纤维化，以及（ii）MBG 敏感的 Na/K-ATP 酶抑制可被盐皮质激素拮抗剂逆转。我们假设，在人类 PE 中，升高的 MBG 水平与脐动脉纤维化的发展有关，并且这种纤维化可以被坎利酮减弱。本研究纳入了 15 例 PE 患者（平均血压 = 118 ± 4 mmHg；34 ± 2 岁；38 ± 0.3 孕周）和 12 例年龄匹配的正常妊娠孕妇（平均血压 = 92 ± 2 mmHg；34 ± 1 岁；39 ± 0.2 孕周）。PE 与血浆 MBG 水平升高有关，与正常孕妇相比，PE 脐动脉中的 Fli1 水平降低了四倍，胶原-1 水平升高了三倍（p < 0.01）。PE 患者的脐动脉环对硝普钠的舒张反应减弱，与对照血管相比，EC50 为 141 nmol/L 对 EC50 = 0.9 nmol/L（p < 0.001）。10 μmol/L 坎利酮体外处理脐动脉可阻断 PE 对 Fli1 和胶原-1 的作用。用 MBG 预处理的脐动脉也得到了类似的结果。这些数据表明，MBG 水平升高与 PE 脐动脉纤维化的发展有关，而这种作用可以被盐皮质激素拮抗剂阻断。
