miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.
miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.
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miR-181a 通过下调 SIRT1 增加 FoxO1 乙酰化并促进颗粒细胞凋亡
DOI：
10.1038/cddis.2017.467
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发表时间：
2017-10-05
影响因子：
9
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Zhang M;Zhang Q;Hu Y;Xu L;Jiang Y;Zhang C;Ding L;Jiang R;Sun J;Sun H;Yan G
氧化应激通过诱导颗粒细胞（GC）凋亡损害卵泡发育，这涉及促凋亡因子叉头框O1（FoxO1）转录活性的增强。然而，氧化应激促进FoxO1活性的机制仍不清楚。在此，我们发现miR - 181a在过氧化氢（H₂O₂）处理的颗粒细胞以及3 - 硝基丙酸（NP）诱导的卵巢氧化应激体内模型中表达上调。miR - 181a过表达促进颗粒细胞凋亡，而内源性miR - 181a的敲低则阻断H₂O₂诱导的细胞凋亡。此外，我们确定了沉默调节蛋白1（SIRT1），一种抑制颗粒细胞中FoxO1乙酰化的去乙酰化酶，被miR - 181a下调，并逆转了H₂O₂和miR - 181a对FoxO1乙酰化和颗粒细胞凋亡的促进作用。重要的是，体内卵巢氧化应激模型中miR - 181a表达的降低通过上调SIRT1表达和FoxO1去乙酰化抑制了凋亡。总之，我们的结果表明，miR - 181a在体外和体内均通过靶向SIRT1介导氧化应激诱导的FoxO1乙酰化和颗粒细胞凋亡。
Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H 2 O 2)-treated GCs and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. miR-181a overexpression promoted GC apoptosis, whereas knockdown of endogenous miR-181a blocked H 2 O 2-induced cell apoptosis. Moreover, we identified that Sirtuin 1 (SIRT1), a deacetylase that suppresses FoxO1 acetylation in GCs, was downregulated by miR-181a and reversed the promoting effects of H 2 O 2 and miR-181a on FoxO1 acetylation and GC apoptosis. Importantly, decreased miR-181a expression in the in vivo ovarian oxidative stress model inhibited apoptosis by upregulating SIRT1 expression and FoxO1 deacetylation. Together, our results suggest that miR-181a mediates oxidative stress-induced FoxO1 acetylation and GC apoptosis by targeting SIRT1 both in vitro and in vivo.
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