Oxidative stress increases the 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism
Oxidative stress increases the 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism
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在高雄激素血症的发展过程中，氧化应激通过 p38 α 增加肾上腺 P450c17 的 17,20-裂解酶催化活性
DOI：
10.1016/j.mce.2019.01.020
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发表时间：
2019
影响因子：
4.1
通讯作者：
Jie Qiao
中科院分区：
文献类型：
--
作者：
Wenjiao Zhu;Bing Han;Mengxia Fan;Nan Wang;Hao Wang;Hui Zhu;Tong Cheng;Shuangxia Zhao;Huaidong Song;Jie Qiao
原因不明的高雄激素性寡排卵是多囊卵巢综合征（PCOS）的主要特征。P450c17磷酸化选择性地增加17，20-裂解酶活性和雄激素生物合成，但对17 α-羟化酶的影响最小。最近的研究发现丝裂原活化蛋白激酶14（MAPK 14，p38 α）是通过P450c17磷酸化增强17，20-裂解酶活性的激酶。我们研究了氧化剂诱导的氧化应激是否通过氧化剂敏感的p38 α信号通路增加17，20-裂解酶活性。用棕榈酸、过氧化氢和4-羟基-2-壬烯醛（HNE）3种氧化剂处理NCI-H295R肾上腺细胞，模拟PCOS的过度氧化应激。氧化剂暴露显著诱导脱氢表雄酮的产生，并增加p38 α的磷酸化和活化，但对17 α-羟孕酮的影响远不清楚。所有处理均未改变P450c17及其必需因子POR和b5的表达。LC-MS/MS显示NCI-H295R细胞中DHEA产量增加。p38 α抑制和siRNA介导的沉默均减弱了H2O2或0.45 - 0.75 mM PA介导的DHEA产生增加，17 OHP水平相对稳定，表明激活的p38 α介导氧化应激诱导的17，20-裂解酶激活和雄激素合成刺激，这可能是PCOS高雄激素血症的基础。
Unexplained hyperandrogenic oligoanovulation is a main feature of polycystic ovary syndrome (PCOS). P450c17 phosphorylation selectively increases 17,20-lyase activity and androgen biosynthesis but minimally affects 17α-hydroxylase. Studies have recently identified mitogen-activated protein kinase 14 (MAPK14, p38α) as the kinase responsible for enhancing 17,20-lyase activity through P450c17 phosphorylation. We investigated whether oxidant-induced oxidative stress increases 17,20-lyase activity through oxidant-sensitive p38α signaling pathways. NCI-H295R adrenal cells were treated with three oxidants, palmitate, H2O2and 4-hydroxy-2-nonenal (HNE), to simulate the excessive oxidative stress of PCOS. Oxidant exposure significantly induced dehydroepiandrosterone production and increased p38α phosphorylation and activation, but the effect on 17α-hydroxyprogesterone production was far less clear. None of the treatments altered the expression of P450c17 or its necessary factors POR and b5. LC-MS/MS revealed increased DHEA production in NCI-H295R cells. Both p38α inhibition and siRNA-mediated silencing attenuated H2O2- or 0.45–0.75 mM PA-mediated augmentation of DHEA production with relatively stable 17OHP levels, indicating that activated p38α mediates oxidative stress-induced 17,20-lyase activation and androgen synthesis stimulation, which may underlie hyperandrogenism in PCOS.