Exogenous Hydrogen Sulfide Prevents Necroptosis by Inhibiting p38MAPK Pathway Activation in JEG-3 Trophoblast Cells: A Role in Preeclampsia

Abstract

<b><i>Objectives:</i></b> Necroptosis, a form of programmed cell death, can occur in the placenta of patients with preeclampsia (PE). Hydrogen sulfide (H₂S) can inhibit necroptosis of human umbilical vein endothelial cells under the high glucose-induced injury. Whether H₂S can protect trophoblasts against necroptosis underlying PE has not been elucidated. This study aimed to explore the protective role of H₂S in trophoblast cells against necroptosis underlying PE. <b><i>Design:</i></b> This is an in vitro experimental study. <b><i>Participants:</i></b> A total of 10 pregnant women with severe PE and 10 matched control normotensive pregnant women were included. The placenta tissues were extracted from participators. The human JEG-3 trophoblasts were commercially available. <b><i>Methods:</i></b> The expression and localization of necrotic proteins were assayed in human placenta samples, and the effect of necrotic cell death on the proliferation and apoptosis of human JEG-3 trophoblasts was evaluated. The component expressions of inflammatory cytokine and p38MAPK signaling pathway were measured in samples pretreated with or without NaHS (H₂S donor) and SB203580 (p38 inhibitor). <b><i>Results:</i></b> RIPA1, RIPA3, and p-p38 levels were significantly higher in PE placental tissue, whereas cystathionine β-synthase expression was decreased. In JEG-3 trophoblasts, necroptosis increased apoptotic cell numbers, suppressed cell proliferation, increased inflammatory cytokine expression, and increased p38MAPK activation, which can be prevented by NaHS. <b><i>Limitations:</i></b> In the present study, we did not provide sufficient evidence that necroptosis was a part of the pathogenesis of PE. <b><i>Conclusions:</i></b> We proposed the putative role of necroptosis in early-onset PE, reflected by the blockage of caspase-8/3 and increased expression of RIPA1 and RIPA3 in PE placenta tissues. Furthermore, we demonstrated that exogenous H₂S protected cytotrophoblasts against ceramide-induced necroptosis via the p38MAPK pathway.