High-glucose-induced prostaglandin E2 and peroxisome proliferator-activated receptor δ promote mouse embryonic stem cell proliferation
High-glucose-induced prostaglandin E2 and peroxisome proliferator-activated receptor δ promote mouse embryonic stem cell proliferation
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DOI：
10.1634/stemcells.2007-0786
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Han, Ho Jae
中科院分区：
文献类型：
--
作者：
Kim, Yun Hee;Han, Ho Jae
过氧化物酶体增殖物激活受体是一种核受体，与胚泡着床、细胞周期和糖尿病的发病机制有关。然而，在胚胎干细胞中，这种效应背后的信号级联在很大程度上是未知的。本研究检测了小鼠胚胎干细胞中活性氧物种介导的前列腺素E-2(PGE(2))/过氧化物酶体增殖物激活受体(PPAR)增量与高糖水平下的生长反应之间是否存在关联。高浓度葡萄糖(25 MM)显著增加[H-3]胸腺嘧啶核苷掺入水平、5-溴-2‘-脱氧尿苷掺入水平和细胞数量。此外，25 mM葡萄糖可增加细胞内的氧自由基、胞浆磷脂酶A(2)的磷酸化(CPLA(2))和[H-3]花生四烯酸([H-3]AA)的释放。此外，25 mM葡萄糖还可促进环氧合酶-2(COX-2)蛋白表达，从而刺激PGE(2)的合成。随后，高糖诱导的PGE(2)通过E型前列腺素受体直接或通过Akt磷酸化间接刺激PPAR Delta的表达。PPAR Delta拮抗剂可抑制25 mM葡萄糖诱导的DNA合成。此外，转染PPAR Delta特异性小干扰核糖核酸抑制了25 mM葡萄糖诱导的DNA合成和G1/S期进展。25毫摩尔葡萄糖还可上调细胞周期调节蛋白(细胞周期蛋白E/细胞周期蛋白依赖性激酶[CDK]2和细胞周期蛋白D1/CDK4)的水平，降低p21(WAF1/Cip1)和p27(Kip1)的表达，这些蛋白的表达可被抑制CPLA(2)、COX-2或PPAR Delta信号通路所阻断。综上所述，高糖促进小鼠胚胎干细胞生长部分是通过CPLA(2)介导的PGE(2)合成，部分是通过PPAR增量通路。
Peroxisome proliferator-activated receptor is a nuclear receptor that has been implicated in blastocyst implantation, cell cycle, and pathogenesis of diabetes. However, the signal cascades underlying this effect are largely unknown in embryo stem cells. This study examined whether or not there is an association between the reactive oxygen species-mediated prostaglandin E-2 (PGE(2))/peroxisome proliferator-activated receptor (PPAR) delta and the growth response to high glucose levels in mouse ESCs. A high concentration of glucose (25 mM) significantly increased the level of [H-3] thymidine incorporation, the level of 5-bromo-2'-deoxyuridine incorporation, and the number of cells. Moreover, 25 mM glucose increased the intracellular reactive oxygen species, phosphorylation of the cytosolic phospholipase A(2) (cPLA(2)), and the release of [H-3] arachidonic acid ([H-3] AA). In addition, 25 mM glucose also increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of PGE(2). Subsequently, high glucose-induced PGE(2) stimulated PPAR delta expression directly or through Akt phosphorylation indirectly through the E type prostaglandin receptor receptors. The PPAR delta antagonist inhibited the 25 mM glucose-induced DNA synthesis. Moreover, transfection with a pool of PPAR delta-specific small interfering RNA inhibited the 25 mM glucose-induced DNA synthesis and G1/S phase progression. Twenty-five millimolar glucose also increased the level of the cell cycle regulatory proteins (cyclin E/cyclin-dependent kinase [CDK] 2 and cyclin D1/CDK 4) and decreased p21(WAF1/Cip1) and p27(Kip1), which were blocked by the inhibition of the cPLA(2), COX-2, or PPAR delta pathways. In conclusion, high glucose promotes mouse ESC growth in part through the cPLA(2)-mediated PGE(2) synthesis and in part through PPAR delta pathways.