Increased autophagy in placentas of intrauterine growth-restricted pregnancies.
Increased autophagy in placentas of intrauterine growth-restricted pregnancies.
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DOI：
10.1371/journal.pone.0040957
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hsieh TT
中科院分区：
文献类型：
--
作者：
Hung TH;Chen SF;Lo LM;Li MJ;Yeh YL;Hsieh TT
不明原因的宫内生长受限（IUGR）可能是胎盘功能不全的结果；然而，其病因尚不完全清楚。我们推测 IUGR 胎盘形成缺陷会导致细胞生物能稳态失调，导致绒毛滋养层自噬增加。这项工作的目的是（1）比较正常或IUGR妊娠妇女胎盘自噬、p53表达和细胞凋亡的差异； （2）研究缺氧的影响以及p53在调节滋养层自噬中的作用； (3)探讨缺氧滋养层细胞自噬与凋亡的关系。与正常孕妇相比，IUGR 女性胎盘中自噬相关蛋白 LC3B-II、beclin-1 和损伤调节自噬调节剂 (DRAM) 的水平较高，p53 和 caspase 裂解的细胞角蛋白 18 (M30) 也增加。此外，与标准条件下培养的对照相比，在存在或不存在 nutlin-3（一种 p53 活性刺激剂）的情况下，在缺氧（2% 氧气）下培养的细胞滋养层具有更高水平的 LC3B-II、DRAM 和 M30 蛋白，并且 Bax mRNA 表达增加。相比之下，缺氧期间给予pifithrin-α（一种p53活性抑制剂）导致蛋白质水平与对照组相似。此外，与缺氧条件下的对照相比，转染 LC3B、beclin-1 或 DRAM siRNA 的细胞滋养层具有更高水平的 M30。然而，用Bcl-2或Bax siRNA转染并没有引起缺氧细胞滋养层中LC3B-II水平的任何显着变化。总之，这些结果表明 IUGR 中的自噬和细胞凋亡之间存在串扰，并且 p53 在调节滋养层细胞响应缺氧应激的周转中发挥着关键而复杂的作用。
Unexplained intrauterine growth restriction (IUGR) may be a consequence of placental insufficiency; however, its etiology is not fully understood. We surmised that defective placentation in IUGR dysregulates cellular bioenergic homeostasis, leading to increased autophagy in the villous trophoblast. The aims of this work were (1) to compare the differences in autophagy, p53 expression, and apoptosis between placentas of women with normal or IUGR pregnancies; (2) to study the effects of hypoxia and the role of p53 in regulating trophoblast autophagy; and (3) to investigate the relationship between autophagy and apoptosis in hypoxic trophoblasts. Compared with normal pregnant women, women with IUGR had higher placental levels of autophagy-related proteins LC3B-II, beclin-1, and damage-regulated autophagy modulator (DRAM), with increased p53 and caspase-cleaved cytokeratin 18 (M30). Furthermore, cytotrophoblasts cultured under hypoxia (2% oxygen) in the presence or absence of nutlin-3 (a p53 activity stimulator) had higher levels of LC3B-II, DRAM, and M30 proteins and increased Bax mRNA expression compared with controls cultured under standard conditions. In contrast, administration of pifithrin-α (a p53 activity inhibitor) during hypoxia resulted in protein levels that were similar to those of the control groups. Moreover, cytotrophoblasts transfected with LC3B, beclin-1, or DRAM siRNA had higher levels of M30 compared with the controls under hypoxia. However, transfection with Bcl-2 or Bax siRNA did not cause any significant change in the levels of LC3B-II in hypoxic cytotrophoblasts. Together, these results suggest that there is a crosstalk between autophagy and apoptosis in IUGR and that p53 plays a pivotal and complex role in regulating trophoblast cell turnover in response to hypoxic stress.
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发表时间：
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影响因子：
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