Sechenov Institute of Evolutionary Physiology and Biochemistry, 44 Torez Prospect, 194223 St. Petersburg, Russia.
State Institute of Highly Pure Biopreparations and Sechenov Institute of Evolutionary Physiology and Biochemistry, 44 Torez Prospect, 194223 St. Petersburg, Russia.
Int J Mol Sci. 2021 Feb 16;22(4):1941. doi: 10.3390/ijms22041941.
Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia that is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by the deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with the restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer; as Fli1 is a proto-oncogene, a hypothesis on the suppression of Fli1 by cardiotonic steroids as a potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia that is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable of impairing marinobufagenin-Na/K-ATPase interactions.
尽管进行了预防和尝试选择治疗方法，但子痫前期的频率并没有降低，它仍然在全球孕产妇死亡率和发病率的结构中占据主导地位。在这篇综述中，我们提出了一个新的子痫前期病因和发病机制理论，该理论基于 Na/K-ATPase 与其内源性配体（包括海兔毒素）的相互作用。海兔毒素的信号通路涉及转录因子 Fli1 的抑制，Fli1 是胶原合成的负调节剂，随后胶原在血管组织中沉积，血管功能发生改变。此外，体外和体内中和海兔毒素与 Fli1 的恢复有关。海兔毒素和 Fli1 之间的反比关系为癌症治疗开辟了新的可能性；由于 Fli1 是原癌基因，因此讨论了作为潜在抗肿瘤治疗策略的强心甾类抑制 Fli1 的假说。我们提出了一种新的子痫前期治疗方法，即通过单克隆抗体对海兔毒素进行免疫中和，从而破坏海兔毒素-Na/K-ATPase 相互作用。
