Life sciences · 2025
TIGAR deficiency exacerbated preeclampsia by impairing autophagy and accelerating trophoblasts apoptosis upon excessive oxidative stress via the NRF2-ARE pathway.
СтатьяНазвание и аннотация: Перевод в очереди
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Guo Junjun, Zhou Meijuan, Li Shuxian, Wang Chunying, Fang Zhenya, Shao Xiaoping, Li Anna, Zhao Man, Liu Yu, Wang Xietong, Zhang Meihua
Аннотация
AIMS: Preeclampsia (PE) is the main cause of maternal and perinatal mortality, however, its pathogenetic mechanism is still elusive. TIGAR, as a p53-inducible regulator of glycolysis and apoptosis, is reported to alleviate oxidative stress. The aim of this study was to clarify the role of TIGAR in the development of PE and its mechanism.
MATERIALS AND METHODS: PE patients, L-NAME treated mice and H2O2 exposed HTR8 were well established for TIGAR evaluation. Fluorescent probes and inhibitors were used to detect autophagic flux regulated by TIGAR. SiRNAs, dual-luciferase reporter system, EMSA and CUT & RUN assay were used to explore the underlying mechanism.
KEY FINDINGS: We identified an elevated expression of TIGAR in the placentae of PE patients and H2O2 administrated trophoblasts, also TIGAR defect substantially increased the susceptibility of trophoblasts to oxidative pathology. Moreover, upon TIGAR depletion, autophagic flux was inhibited by obstructing the initiation of isolation membrane formation and apoptosis was accelerated concomitantly. Furthermore, these destabilizations were magnified in a redox-dependent manner, which could be restored with administration of NAC. Mechanically, compelling evidence demonstrated that TIGAR provoked surplus accumulation and nucleus translocation of NRF2 to mediate ARE-driven activation of antioxidant and detoxifying genes, such as NQO1 and HO-1, additionally, we first reported the direct DNA-sequencing binding of NRF2 on Bcl-2 in trophoblasts, which could elucidate the apoptosis attributing to TIGAR loss.
SIGNIFICANCE: Collectively, we revealed that TIGAR served as an effective factor in mediating cytoprotective autophagy against apoptosis, which may provide new ideas for the treatment of PE.
MATERIALS AND METHODS: PE patients, L-NAME treated mice and H2O2 exposed HTR8 were well established for TIGAR evaluation. Fluorescent probes and inhibitors were used to detect autophagic flux regulated by TIGAR. SiRNAs, dual-luciferase reporter system, EMSA and CUT & RUN assay were used to explore the underlying mechanism.
KEY FINDINGS: We identified an elevated expression of TIGAR in the placentae of PE patients and H2O2 administrated trophoblasts, also TIGAR defect substantially increased the susceptibility of trophoblasts to oxidative pathology. Moreover, upon TIGAR depletion, autophagic flux was inhibited by obstructing the initiation of isolation membrane formation and apoptosis was accelerated concomitantly. Furthermore, these destabilizations were magnified in a redox-dependent manner, which could be restored with administration of NAC. Mechanically, compelling evidence demonstrated that TIGAR provoked surplus accumulation and nucleus translocation of NRF2 to mediate ARE-driven activation of antioxidant and detoxifying genes, such as NQO1 and HO-1, additionally, we first reported the direct DNA-sequencing binding of NRF2 on Bcl-2 in trophoblasts, which could elucidate the apoptosis attributing to TIGAR loss.
SIGNIFICANCE: Collectively, we revealed that TIGAR served as an effective factor in mediating cytoprotective autophagy against apoptosis, which may provide new ideas for the treatment of PE.