Cornin, a compound from Verbena officinalis L, ameliorates preeclampsia progression through activating NO signaling and deactivating NFκB.

Abstract

BACKGROUND: Preeclampsia (PE) is a common gestational disorder with high morbidity and mortality. There is currently no effective treatment for PE in clinic. Therefore, it is necessary to find a more effective treatment scheme. METHODS: Extra-villous TEV-1 cells, EA. hy926 cells, and human induced pluripotent stem cells (hiPSC)-derived vascular organoids in vitro, different PE-like mouse models in vivo, a zebrafish model in vivo, and human placenta tissues as well as isolated primary cytotrophoblasts (CTBs) were used in this study. RESULTS: We show herein that Cornin exerts protective effects against PE by activating the nitric oxide synthase 2/nitric oxide (NOS2/NO) signaling and suppressing the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling in both cultured trophoblasts and mouse placentas. Mechanistically, Cornin increases the stability of NOS2 by directly binding to ARG-536 of NOS2, while simultaneously, the interaction between NOS2 and NFκB is promoted, followed by the phosphorylation and activation of NOS2 as well as the dephosphorylation at Ser-536 and inactivation of NFκB. Ultimately, NO production is increased and inflammation is suppressed, accompanied by the reduced reactive oxygen species (ROS) levels, enhanced angiogenesis, and decreased expression of NFκB-directed target genes. Consistently, Cornin administration alleviates pregnant outcomes in PE mouse models. CONCLUSIONS: Collectively, our results provide an innovative basis for Cornin to intervene in the development of PE and ameliorate PE outcomes.