title: Increased autophagy in placentas of intrauterine growth-restricted pregnancies.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei, Taipei, Taiwan. thh20@adm.cgmh.org.tw
authors: Tai-Ho
authors: TH
authors: Hung
authors: Szu-Fu
authors: SF
authors: Chen
authors: Liang-Ming
authors: LM
authors: Lo
authors: Meng-Jen
authors: MJ
authors: Li
authors: Yi-Lin
authors: YL
authors: Yeh
authors: T'sang-T'ang
authors: TT
authors: Hsieh
mesh_terms: D000328:Adult; D017209:Apoptosis; D001343:Autophagy; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53