Role of cinobufotalin in the pathogenesis of preeclampsia: in vivo and in vitro studies

Abstract

ObjectivePreeclampsia (preE) is a hypertensive disorder of pregnancy. Cardiotonic steroids (CS) are endogenous inhibitors of Na+/K+ ATPase. We have shown that one CS, marinobufagenin (MBG), is elevated in preE prior to the development of symptoms. We have also demonstrated that MBG impairs cytotrophoblast (CTB) function, which is critical for placental development. We evaluated the effect of cinobufotalin (CINO), another CS, on pregnant rats and CTB cells to assess its role in preE.MethodsFour groups of rats were studied: normal pregnant (NP, n=10) rats, NP injected with MBG (NPM, n=10) rats, NP injected with CINO (NPC, n=10) rats, and a rat model of preE (PDS, n=10). CTB cell function and signaling were assayed after CINO treatment.ResultsNPC rats showed hypertension and proteinuria similar to PDS and NPM rats. CINO at ≥ 1 nM inhibited CTB cell proliferation, migration, and invasion but had no effect on cell viability. A higher percentage of cells were in the G0/G1 phase in groups treated with ≥ 1 nM CINO. CINO caused an increase in stress signaling p38 MAPK and a positive annexin‐V stain in CTB cells, indicating the activation of apoptotic signaling. However the CINO induced apoptotic signaling was prevented by p38 inhibition.ConclusionsWe have demonstrated that: 1) CINO induces preE in NP rats and 2) CINO impairs CTB cell function. Therefore, CINO may play a role in the pathogenesis of preE.