Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero.
Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero.
复制标题
作者：
Cheng X;Chapple SJ;Patel B;Puszyk W;Sugden D;Yin X;Mayr M;Siow RC;Mann GE
妊娠期糖尿病（GDM）的宫内暴露与日后患2型糖尿病和心血管疾病的风险增加有关，但其潜在机制仍有待阐明。我们研究了GDM对人胎儿内皮细胞蛋白质组、氧化还原状态和核因子红细胞2相关因子2（Nrf 2）介导的抗氧化基因表达的影响。蛋白质组学分析显示，参与氧化还原稳态的蛋白质在GDM中发生了显著改变，并与线粒体超氧化物生成增加、蛋白质氧化、DNA损伤和谷胱甘肽（GSH）合成减少相关。在GDM细胞中，脂质过氧化产物4-羟基壬烯醛（HNE）不能诱导核Nrf 2积累和Nrf 2及其靶基因NAD（P）H：醌氧化还原酶1（NQO 1）、Bach 1、胱氨酸/谷氨酸转运蛋白和谷氨酸半胱氨酸连接酶的mRNA和/或蛋白表达。尽管Nrf 2或NQO 1启动子中CpG岛的甲基化未被GDM改变，但DJ-1水平降低和磷酸化糖原合成酶激酶3β水平升高可能是Nrf 2信号转导受损的原因。HNE诱导的GSH和NQO 1水平的增加被正常细胞中的Nrf 2小干扰RNA废除，并且GDM细胞中Nrf 2的过表达部分恢复了NQO 1的诱导。胎儿内皮Nrf 2的失调可能导致后代患2型糖尿病和心血管疾病的风险增加。
In utero exposure to gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes and cardiovascular disease in later life, yet the underlying mechanisms remain to be elucidated. We examined the effects of GDM on the proteome, redox status, and nuclear factor erythroid 2–related factor 2 (Nrf2)-mediated antioxidant gene expression in human fetal endothelial cells. Proteomic analysis revealed that proteins involved in redox homeostasis were significantly altered in GDM and associated with increased mitochondrial superoxide generation, protein oxidation, DNA damage, and diminished glutathione (GSH) synthesis. In GDM cells, the lipid peroxidation product 4-hydroxynonenal (HNE) failed to induce nuclear Nrf2 accumulation and mRNA and/or protein expression of Nrf2 and its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1), Bach1, cystine/glutamate transporter, and glutamate cysteine ligase. Although methylation of CpG islands in Nrf2 or NQO1 promoters was unaltered by GDM, decreased DJ-1 and increased phosphorylated glycogen synthase kinase 3β levels may account for impaired Nrf2 signaling. HNE-induced increases in GSH and NQO1 levels were abrogated by Nrf2 small interfering RNA in normal cells, and overexpression of Nrf2 in GDM cells partially restored NQO1 induction. Dysregulation of Nrf2 in fetal endothelium may contribute to the increased risk of type 2 diabetes and cardiovascular disease in offspring.
登录
查看更多内容
DOI：
10.3945/ajcn.110.008326
发表时间：
2011-06
期刊：
The American journal of clinical nutrition
影响因子：
--
作者：
Fraser A;Tilling K;Macdonald-Wallis C;Hughes R;Sattar N;Nelson SM;Lawlor DA
通讯作者：
Lawlor DA
影响因子：
10.9
作者：
Pinney, Sara E.;Simmons, Rebecca A.
通讯作者：
Simmons, Rebecca A.
影响因子：
7.7
作者：
Ceriello, A;delloRusso, P;Cerutti, P
通讯作者：
Cerutti, P
妊娠糖尿病，现有糖尿病和糖尿的关联与后代肥胖和心脏代谢结果的关联。
影响因子：
16.2
作者：
Patel S;Fraser A;Davey Smith G;Lindsay RS;Sattar N;Nelson SM;Lawlor DA
通讯作者：
Lawlor DA
影响因子：
7.7
作者：
Nelson, Scott M.;Sattar, Naveed;Lindsay, Robert S.
通讯作者：
Lindsay, Robert S.