Abstract
BackgroundUnexplained 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.Methodology/Principal FindingsCompared 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/SignificanceTogether, 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.
Highlights
Autophagy is a catabolic process that involves the invagination and degradation of cytoplasmic components through a lysosomal pathway [1]
The aims of this work were (1) to compare autophagy in the placentas from women with normal pregnancies to those with pregnancies complicated by intrauterine growth restriction (IUGR), preeclampsia (PE), or both (PE+IUGR); (2) to study the levels of p53 and trophoblast apoptosis in the placentas between women with normal and IUGR pregnancies; (3) to examine the effects of hypoxia and reagents that regulate the activity of p53 on trophoblast autophagy; and (4) to investigate the relationship between autophagy and apoptosis in trophoblasts exposed to hypoxia
Because there was no difference in the levels of placental LC3BII between women with normal or PE pregnancies and because accumulating evidence suggests that PE and PE+IUGR may have different pathophysiologies [8,26], we focused our subsequent investigations on the differences in autophagy between women with normal pregnancies and those with pregnancies complicated by IUGR only
Summary
Autophagy is a catabolic process that involves the invagination and degradation of cytoplasmic components through a lysosomal pathway [1]. Proteins and organelles are sequestered into double-membrane vesicles called autophagosomes. Autophagy is rapidly upregulated under conditions, such as starvation, growth factor deprivation, and hypoxia, when cells need to generate intracellular nutrients and energy [2]. Autophagy is involved in removing damaged mitochondria or other organelles and degrading intracellular pathogens and protein aggregates that are too large to be removed by the ubiquitin-proteasomal system [3]. These functions of autophagy favor the adaptation of cells and could promote cellular survival during aging, infectious diseases, and neurodegenerative processes. 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
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