Oleanolic acid derivative OA17 inhibits trophoblast apoptosis by suppressing HIF-1α nuclear translocation in SLE-associated adverse pregnancy outcomes.

BACKGROUND

Systemic lupus erythematosus (SLE) primarily affects women of reproductive age and is associated with a high incidence of adverse pregnancy outcomes (APOs). Recent studies reveal that elevated HIF-1α expression in the placenta is involved in SLE-associated APOs and multiple pregnancy complications, but no clinically approved HIF-1α inhibitors exist to mitigate APOs. OA17, a pentacyclic triterpenoid derived from structural modification of oleanolic acid (OA), exhibits potent anti-inflammatory and antioxidant properties. However, OA17 function and the underlying mechanisms in SLE pregnancy outcomes remain unclear.

PURPOSE: The aim of this study was to explore the role of HIF-1α in SLE-associated APOs and to assess the therapeutic potential of OA17 as a novel treatment.

METHODS

Human placental samples and relevant clinical data were collected from participants to explore the mechanisms SLE-associated APOs. Additionally, HTR-8/SVneocells, an Extravillous trophoblast (EVT)-immortalized cell line, were subjected to hypoxia (1 % O₂) and chemicals known to stabilize HIF-1α (CoCl2 and DMOG) to mimic the upregulation of HIF-1α observed in SLE pregnancies. The relationship between HIF-1α and oxidative stress/apoptosis in the HTR-8/SVneo cells was explored through H2O2 stimulation, sh-HIF-1α, and CUT-TAG assay. Additionally, HTR-8/SVneo was treated with OA17 and pregnant MRL-lpr mice received continuous OA17 over two weeks.

RESULTS

We demonstrated that significantly increased levels of HIF-1α and heightened apoptosis in EVT cells within the placental tissues of SLE pregnancies. Mechanistically, HIF-1α bound to the SOD2 promoter to repress SOD2 transcription and regulate ROS to promote apoptosis. OA17 treatment in lupus-prone MRL/lpr mice alleviated renal injury, reduced oxidative stress and hypoxia-induced apoptosis in EVT cells by inhibiting HIF-1α nuclear translocation, thus improving APOs. In addition, OA17 treatment attenuated the biological functions of hypoxia-impaired EVT cells, including cell proliferation, invasion, and migration.

CONCLUSION

Our data suggest that elevated HIF-1α during SLE pregnancies can be considered a contributing factor to APOs, OA17 inhibits trophoblast apoptosis by suppressing HIF-1α nuclear translocation in SLE-associated APOs. OA17 could be a potential new drug for other pregnancy complications in the clinic.