Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy
Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy
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FSH通过抑制自噬对抗小鼠卵巢颗粒细胞氧化损伤的保护机制
DOI：
10.1080/15548627.2017.1327941
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Sun, Shao-chen
中科院分区：
文献类型：
--
作者：
Shen, Ming;Jiang, Yi;Sun, Shao-chen
氧化应激诱导的颗粒细胞（GCs）死亡是卵泡闭锁的常见原因。卵泡刺激素（FSH）已被证明可以防止GCs氧化损伤，尽管其潜在机制仍有待阐明。在这里，我们首次报道了通过一些新的信号效应器抑制自噬细胞死亡，参与了fsh介导的GCs对氧化损伤的保护。在体内和体外氧化应激条件下，FSH处理显著降低氧化损伤引起的GCs活力下降，同时降低了巨噬/自噬通量。与FSH处理相比，阻断自噬对氧化诱导的细胞死亡的抑制水平相似，但FSH并没有进一步提高自噬抑制剂预处理的GCs的存活率。进一步的研究表明，激活磷酸肌肽3-激酶(PI3K)-AKT-MTOR（雷帕霉素[丝氨酸/苏氨酸激酶]的机制靶点）信号通路是fsh介导的GCs在氧化应激诱导的自噬中存活所必需的。此外，FSH- pi3k - akt轴也通过靶向FOXO1下调自噬反应，而在GCs中FOXO1的组成性激活不仅消除了FSH的保护作用，而且从MAP1LC3B-II蛋白水平到自噬基因表达，解放了自噬过程。此外，FSH抑制乙酰化FOXO1的产生及其与Atg蛋白的相互作用，随后降低氧化应激下自噬细胞死亡水平。综上所述，我们的发现提示了一种涉及FSH-FOXO1信号的新机制，通过抑制自噬来防御GCs的氧化损伤，这可能是临床治疗无排卵障碍的潜在途径。
ABSTRACT Oxidative stress-induced granulosa cell (GCs) death represents a common reason for follicular atresia. Follicle-stimulating hormone (FSH) has been shown to prevent GCs from oxidative injury, although the underlying mechanism remains to be elucidated. Here we first report that the suppression of autophagic cell death via some novel signaling effectors is engaged in FSH-mediated GCs protection against oxidative damage. The decline in GCs viability caused by oxidant injury was remarkably reduced following FSH treatment, along with impaired macroautophagic/autophagic flux under conditions of oxidative stress both in vivo and in vitro. Blocking of autophagy displayed similar levels of suppression in oxidant-induced cell death compared with FSH treatment, but FSH did not further improve survival of GCs pretreated with autophagy inhibitors. Further investigations revealed that activation of the phosphoinositide 3-kinase (PI3K)-AKT-MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling pathway was required for FSH-mediated GCs survival from oxidative stress-induced autophagy. Additionally, the FSH-PI3K-AKT axis also downregulated the autophagic response by targeting FOXO1, whereas constitutive activation of FOXO1 in GCs not only abolished the protection from FSH, but also emancipated the autophagic process, from the protein level of MAP1LC3B-II to autophagic gene expression. Furthermore, FSH inhibited the production of acetylated FOXO1 and its interaction with Atg proteins, followed by a decreased level of autophagic cell death upon oxidative stress. Taken together, our findings suggest a new mechanism involving FSH-FOXO1 signaling in defense against oxidative damage to GCs by restraining autophagy, which may be a potential avenue for the clinical treatment of anovulatory disorders.