Sulforaphane Acts Through NFE2L2 to Prevent Hypoxia-Induced Apoptosis in Porcine Granulosa Cells via Activating Antioxidant Defenses and Mitophagy

Abstract

In mammals, a vast majority of ovarian follicles undergo atresia, which is caused by granulosa cell (GC) apoptosis. GCs in follicles are exposed to low oxygen. Hypoxia triggers reactive oxygen species (ROS) generation, which leads to cell oxidative stress and apoptosis. Sulforaphane (SFN), a phytochemical isothiocyanate enriched in cruciferous vegetables, has exhibited a crucial role in mitigating oxidative stress. To explore the effect of SFN on porcine GC apoptosis in a hypoxic environment, we handled the established hypoxia model (1% O2) of cultured porcine GCs with SFN. Results showed that SFN rescued hypoxia-induced apoptosis and viability of GCs. Meanwhile, SFN increased the expression of antioxidant enzymes and reduced the accumulation of ROS in GC cytoplasm and mitochondria under hypoxia. Mechanically, SFN activated the transcription factor of redox-sensitive nuclear factor-erythroid 2-related factor 2 (NFE2L2) entering the nucleus, further inducing mitophagy and increased antioxidant capacity, finally alleviating the adverse effect of hypoxia on porcine GCs. In conclusion, SFN inhibited hypoxia-evoked GC apoptosis by activating antioxidant defenses and mitophagy through NFE2L2. New targets may be provided for regulating follicular development and atresia by these findings.

IGF‐I protects porcine granulosa cells from hypoxia‐induced apoptosis by promoting homologous recombination repair through the PI3K/AKT/E2F8/RAD51 pathway

“…Apoptosis and shedding of GCs are important characteristics of ovarian follicular atresia. Our many previous research demonstrated hypoxia‐induced GC cycle arrest and apoptosis may also be a key trigger for the initiation of porcine antral follicular atresia 6–9,14,33 . Our own RNA‐seq data implied that DNA damage repair pathways were enriched in the downregulated biological process in porcine GCs with high levels of hypoxia 14 .…”

“…Our many previous research demonstrated hypoxia-induced GC cycle arrest and apoptosis may also be a key trigger for the initiation of porcine antral follicular atresia. [6][7][8][9]14,33 Our own RNA-seq data implied that DNA damage repair pathways were enriched in the downregulated biological process in porcine GCs with high levels of hypoxia. 14 Single-stranded and double-stranded DNA damage and oxidized base damage (such as 8-oxoguanine and thymine glycol) are greatly exacerbated in cells under hypoxic conditions, which may be attributed to multiple mechanisms of mitochondrial ROS production in cells.…”

“…Hypoxic cells are subjected to various stresses, including DNA damage, cell cycle arrest and genetic mutation leading to cell apoptosis 3–5 . Our previous published studies have shown hypoxia can initiate porcine ovarian GCs apoptosis and then proceed to follicular atresia 6–9 . Although we have done a lot of work on hypoxia‐induced GCs apoptosis, this complex mechanism still needs to be further elucidated.…”

“…[3][4][5] Our previous published studies have shown hypoxia can initiate porcine ovarian GCs apoptosis and then proceed to follicular atresia. [6][7][8][9] Although we have done a lot of work on hypoxiainduced GCs apoptosis, this complex mechanism still needs to be further elucidated.…”

Cyanidin Alleviated CCl4-Induced Acute Liver Injury by Regulating the Nrf2 and NF-κB Signaling Pathways

“…Under normal conditions, Nrf2 is ubiquitinated and degraded in the cytoplasm by binding to Keap1. However, under stress conditions, Nrf2 dissociates from Keap1 and translocates into the nucleus to bind to the antioxidant response element, which initiates transcription and expression of downstream genes, such as HO-1, NQO-1, SOD, and CAT, which contribute to resistance to oxidative stress [ 31 , 32 ]. In this experiment, we found that HO-1 and NQO-1, two critical antioxidant enzymes, were remarkably upregulated at the transcriptional level by supplementation with Cy, compared to those in the model group.…”