Activation of endoplasmic reticulum stress mediates oxidative stress–induced apoptosis of granulosa cells in ovaries affected by endometrioma

Abstract

Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress–induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.

The impact of phthalate on reproductive function in women with endometriosis

“…Moreover, the granulosa cells from women with endometriosis expressed several transcripts associated with UPR and increased the phosphorylation of ER stress sensor proteins, including inositol‐requiring enzyme 1 and double‐stranded RNA‐activated protein kinase‐like ER kinase (PERK). These results suggested that high oxidative stress in the granulosa cells in women with endometriosis provoked ER stress and apoptosis 78 . These studies illustrated that endometriosis is harmful to the granulosa cells and might lead to ovarian dysfunction (Figure 1).…”

“…ER stress is significantly associated with oxidative stress. Treating the oxidative stress inducer caused upregulation of the unfold protein response (UPR)‐associated genes and apoptosis in human granulosa cells 78 . Moreover, the granulosa cells from women with endometriosis expressed several transcripts associated with UPR and increased the phosphorylation of ER stress sensor proteins, including inositol‐requiring enzyme 1 and double‐stranded RNA‐activated protein kinase‐like ER kinase (PERK).…”

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“…Therefore, antioxidant properties of TCPs against H 2 O 2 -induced HUVEC injury resulted from the downregulation of mRNA levels of GRP78, CHOP, and ATF4 and significant decrease of apoptosis proportion. Previous work demonstrated that higher levels of oxidative stress contributed to the activation of endoplasmic reticulum stress, which mediated oxidative stress-induced apoptosis via an extrinsic pathway (40). Therefore, the TCP pretreatment might decrease the oxidative stress in HUVECs, which contributed to the deactivation of endoplasmic reticulum stress and further decreased oxidative stress-induced apoptosis.…”

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“…Therapy with H 2 O 2 enhanced apoptosis as well as action of pro-apoptotic factors caspase 8 as well as caspase 3 both of which got ameliorated by TUDCA. This pointed that stimulated ER Stress stimulated by oxidative stress in GCs in ovaries having Endometrioma modulates apoptosis of these cells causing ovarian dysfunction in Endometriosis patients [6].…”