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Cited by 48Pregnancy and preeclampsia studiesCancer, Hypoxia, and MetabolismReproductive System and Pregnancy

Proteasomal Activity in Placentas from Women with Preeclampsia and Intrauterine Growth Restriction: Implications for Expression of HIF-α Proteins

Rajakumar, A., Michael, H.M., Daftary, A., Jeyabalan, A., Gilmour, C., Conrad, K.P.·2008·Placenta
DOI 10.1016/j.placenta.2007.11.015
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Abstract

Hypoxia-inducible transcription factor-1alpha and -2alpha (HIF-alpha) proteins and regulated genes are increased in preeclamptic (PE) placentas. Although placental hypoxia likely stabilizes HIF-alpha proteins, we previously reported that there is also a defect in oxygen-dependent reduction of HIF-alpha proteins in PE relative to normal pregnant (NP) placentas that could contribute to their over-expression. After a 4-h exposure to 2% oxygen, placental villous explants were exposed to 21% oxygen over 90 min. As assessed by Western analysis, the defective oxygen-dependent reduction of HIF-1alpha protein in villous explants from PE placenta was unaffected by the protein synthesis inhibitor, cycloheximide. However, after incubation with the proteasomal inhibitor, clasto-lactacystin, oxygen-dependent reduction of HIF-1alpha protein was markedly and similarly impaired in the villous explants from both normal and PE placentas. Thus, impairment of protein degradation rather than increased synthesis causes inadequate oxygen-dependent reduction of HIF-1alpha protein in PE placentas. Immunoprecipitation studies revealed comparable association of HIF-1alpha with von Hippel Lindau (VHL) protein in placentas from NP and PE women. Furthermore, prolyl hydroxylase-3 protein was appropriately upregulated in the PE placentas as determined by Western analysis paralleling the increases of HIF-alpha proteins. These results suggest that molecular events leading to the formation of the HIF-1alpha:VHL:ubiquitin ligase complex are most likely not impaired in PE placentas. Finally, proteasomal trypsin, chymotrypsin, and peptidyl glutamyl-like activities were significantly reduced by approximately 1/3 in PE placentas by using specific peptide substrates coupled to a fluorescent tag. Unexpectedly, however, they were even further decreased in placentas from normotensive women delivering growth restricted babies >37 weeks gestation-placentas which do not have elevated HIF-alpha proteins. In conclusion, accumulation of HIF-alpha proteins in PE placentas may occur as a consequence of both increased formation secondary to relative ischemia/hypoxia and reduced degradation after reperfusion/oxygenation consequent to proteasomal dysfunction. In contrast, in placentas from normotensive women delivering growth restricted babies >37 weeks gestation, proteasomal activity, albeit markedly reduced, is adequate to cope with degradation of HIF-alpha proteins, which have not been increased by an hypoxic environment.

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  • Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular the early-onset form when the PHDs do not appear to sense oxygen, and may be responsible for abnormal placental secretion of angiogenic regulatory factors.

    “Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular of the early-onset form when the PHDs do not appear to sense oxygen (90, 448, 467), and may be responsible for the abnormal placental secretion of angiogenic regulatory factors that is thought to precipitate the clinical syndrome (413).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [448]

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Authors
Rajakumar, A., Michael, H. M., Daftary, A., Jeyabalan, A., Gilmour, C., & Conrad, K. P.
Affiliations
  • University of Pittsburgh (US)
  • Allegheny General Hospital (US)
Corresponding author
Conrad, K.P.
ORCID
Venue
Placenta
Publisher
Elsevier BV
Published
2008-03
Volume
29
Issue
3
Pages
290-299
ISSN
0143-4004 (ISSN-L)
DOI
10.1016/j.placenta.2007.11.015
OpenAlex
W2047868879
Cited by
48
References
32
Citations by year
2026: 1 · 2025: 4 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 2 · 2012: 5
FWCI
4.97
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Placenta (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01-HD30367, P01HD030367, K12 HD 43441, K12HD043441)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
Keywords
preeclampsia, fetal growth restriction, HIF-1α, HIF-2α, proteasome, placental hypoxia, oxygen-dependent degradation, von Hippel-Lindau protein, prolyl hydroxylase 3, ubiquitin ligase, proteasome activity, placental villi, protein degradation
MeSH terms
Adult, Birth Weight, Cells, Cultured, Chorionic Villi, Female, Fetal Growth Retardation, Gestational Age, Humans, Infant, Newborn, Organ Culture Techniques, Oxygen Consumption, Placenta, Pre-Eclampsia, Pregnancy, Procollagen-Proline Dioxygenase, Protein Processing, Post-Translational, Cell Hypoxia, Proteasome Endopeptidase Complex, Hypoxia-Inducible Factor 1, alpha Subunit

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