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Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude
Open accessAbstract
Pregnancy at high altitude is associated with a reduction in birth weight of ~100 g/1000 m of ascent. The underlying mechanisms are unclear but may involve alteration in energy‐demanding activities, such as protein synthesis. To test this hypothesis, both in vivo and in vitro approaches were used. Placental tissues from pregnant women residing at 3100 m were studied, and placental cells were incubated under hypoxia. In the 3100‐m placentas, we observed dilation of endoplasmic reticulum (ER) cisternae, increased phosphorylation of eukaryotic initiation factor 2 subunit α (P‐eIF2α), reduced AKT phosphorylation, and reduced P‐4E‐BP1 but increased 4E‐BP1 protein compared to sea level controls. These findings suggest the presence of ER stress and protein synthesis inhibition. Hypoxia (1% O 2 ) reduced proliferation of trophoblast‐like JEG‐3 cells, BeWo cells, and placental fibroblasts by ~40, ~60, and ~18%, respectively. Sublethal dosage of salubrinal, an eIF2α phosphatase inhibitor, increased P‐eIF2α and reduced BeWo cell and placental fibroblast proliferation by ~50%. Administration of the PI‐3K inhibitor LY294002 also reduced JEG‐3 proliferation. Our results demonstrate that exposure to chronic hypobaric hypoxia causes mild placental ER stress, which, in turn, modulates protein synthesis and slows proliferation. These effects may account for the reduced placental villous volume, and contribute to the low birth weight that typifies high‐altitude populations.—Yung, H. W., Cox, M., Tissot van Patot, M., Burton, G. J. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude. FASEB J. 26, 1970‐1981 (2012). www.fasebj.org
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“Mild activation of the UPR, with phosphorylation of eIF2α alone, has been reported in the high-altitude human placenta, where it may mediate homeostatic adaptations to the hypobaric hypoxia experienced (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“Equally, evidence of translational arrest has been reported in human placentas from normal healthy pregnancies at high altitude (3,100 m) where growth of the villus tree is impaired (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
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“These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
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“These placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“However, there is evidence for a decrease in protein synthesis in the placenta of non-native women at high altitude (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“Most of the data relating to regulation of protein synthesis in response to hypoxia come from the cancer field (542, 585, 586), but it appears that the same pathways are operative in the placenta under physiological and pathological conditions (596, 598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,014
eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation
Gingras, A., Raught, B., & Sonenberg, N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.913 · Cited by 2,103
Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword?
Malhotra, J. D., & Kaufman, R. J. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1782 · Cited by 1,588
Regulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., & Su, B. (2006) · Cell · doi:10.1016/j.cell.2006.08.033 · Cited by 1,407
A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress
Boyce, M., Bryant, K. F., Jousse, C., Long, K., Harding, H. P., Scheuner, D. L., Kaufman, R. J., Ma, D., Coen, D. M., Ron, D., et al. (2005) · Science · doi:10.1126/science.1101902 · Cited by 1,403
Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
Scheuner, D. L., Song, B., McEwen, E. L., Liu, C., Laybutt, D. R., Gillespie, P. J., Saunders, T. L., Bonner‐Weir, S., & Kaufman, R. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00265-9 · Cited by 1,355
Coping with stress: eIF2 kinases and translational control
Wek, R. C., Jiang, H.-Y., & Anthony, T. G. (2005) · Biochemical Society Transactions · doi:10.1042/bst0340007 · Cited by 1,353
Regulation of 4E-BP1 phosphorylation: a novel two-step mechanismPreprint
Gingras, A., Gygi, S. P., Raught, B., Polakiewicz, R. D., Abraham, R. T., Hoekstra, M. F., Aebersold, R. H., & Sonenberg, N. (1999) · Genes & Development · doi:10.1101/gad.13.11.1422 · Cited by 1,348
Lu, P. D., Harding, H. P., & Ron, D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408003 · Cited by 1,006
NAVÉ, B. T., Ouwens, D. M., Withers, D. J., Alessi, D. R., & Shepherd, P. R. (1999) · Biochemical Journal · doi:10.1042/bj3440427 · Cited by 926
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Wouters, B. G., & Koritzinsky, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2501 · Cited by 894
Hierarchical phosphorylation of the translation inhibitor 4E-BP1
Gingras, A.-C., Raught, B., Gygi, S. P., Niedzwiecka, A., Miron, M., Burley, S. K., Polakiewicz, R. D., Wyslouch-Cieszynska, A., Aebersold, R., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.912401 · Cited by 883
ER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Bi, M., Naczki, C., Koritzinsky, M., Fels, D. R., Blais, J. D., Hu, N., Harding, H. P., Novoa, I., Varia, M. A., Raleigh, J. A., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600777 · Cited by 756
Molecular mechanisms of translation initiation in eukaryotes
Pestova, T. V., KOLUPAEVA, V. G., Lomakin, I. B., Pilipenko, E. V., Shatsky, I. N., Agol, V. I., & Hellen, C. U. T. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111145798 · Cited by 742
Control of p70 S6 kinase by kinase activity of FRAP in vivo
Brown, E. J., Beal, P. A., Keith, C. T., Chen, J., Shin, T. B., & Schreiber, S. L. (1995) · Nature · doi:10.1038/377441a0 · Cited by 705
Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase
Koromilas, A. E., Roy, S., Barber, G. N., Katze, M. G., & Sonenberg, N. (1992) · Science · doi:10.1126/science.1382315 · Cited by 532
Coping with stress: eIF2 kinases and translational control
Jiang, H.-Y., Wek, R. C., & Anthony, T. G. (2005) · Biochemical Society Transactions · doi:10.1042/bst20060007 · Cited by 522
Yung, H.-W., Calabrese, S., Hynx, D., Hemmings, B. A., Cetin, I., Charnock-Jones, D. S., & Burton, G. J. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.071193 · Cited by 388
Self-citationProtein Kinase Bα/Akt1 Regulates Placental Development and Fetal Growth
Yang, Z.-Z., Tschopp, O., Hemmings-Mieszczak, M., Feng, J., Brodbeck, D., Perentes, E., & Hemmings, B. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302847200 · Cited by 384
Iwawaki, T., Akai, R., Yamanaka, S., & Kohno, K. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903775106 · Cited by 377
Koritzinsky, M., Magagnin, M. G., van den Beucken, T., Seigneuric, R., Savelkouls, K. G. M., Dostie, J., Pyronnet, S., Kaufman, R. J., Weppler, S. A., Voncken, J. W., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600998 · Cited by 369
What is the restriction point?
Zetterberg, A., Larsson, O., & Wiman, K. G. (1995) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(95)80067-0 · Cited by 351
Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during Labor
Cindrová‐Davies, T., Yung, H. W., Johns, J., Spasić-Bošković, O., Korolchuk, S., Jauniaux, E. R. M., Burton, G. J., & Jones, D. S. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070528 · Cited by 299
Self-citationKeyes, L. E., Armaza, F. J., Niermeyer, S., Vargas, E., Young, D. A., & Moore, L. G. (2003) · Pediatric Research · doi:10.1203/01.pdr.0000069846.64389.dc · Cited by 285
Drogat, B., Auguste, P., Nguyên, D. T., Bouchecareilh, M., Pineau, R., Nalbantoglu, J. N., Kaufman, R. J., Chevet, É., Bikfalvi, A., & Moenner, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3235 · Cited by 237
Effects of Altitude versus Economic Status on Birth Weight and Body Shape at Birth
Giussani, D. A., Phillips, P. S., Anstee, S., & Barker, D. J. P. (2001) · Pediatric Research · doi:10.1203/00006450-200104000-00009 · Cited by 230
Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival
Liu, L., Wise, D. R., Diehl, J. A., & Simon, M. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805056200 · Cited by 206
Placental Oxygen Consumption. Part I: In Vivo Studies—A Review
Carter, A. M. (2000) · Placenta · doi:10.1053/plac.1999.0513 · Cited by 196
Moore, L. G., Young, D., McCullough, R. E., Droma, T., & Zamudio, S. (2001) · American Journal of Human Biology · doi:10.1002/ajhb.1102 · Cited by 194
Cindrová‐Davies, T., Spasić-Bošković, O., Jauniaux, E. R. M., Jones, D. S., & Burton, G. J. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.061035 · Cited by 190
Self-citationYamaguchi, S., Ishihara, H., Yamada, T., Tamura, A., Usui, M., Tominaga, R., Munakata, Y., Satake, C., Katagiri, H., Tashiro, F., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.01.008 · Cited by 189
Walsh, B. J., Tonkonogi, M., Söderlund, K., Hultman, E., Saks, V. A., & Sahlin, K. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.00971.x · Cited by 172
Yung, H. W., Charnock-Jones, D. S., & Burton, G. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017894 · Cited by 158
Self-citationJulian, C. G., Wilson, M. J., Lopez, M., Yamashiro, H., Tellez, W., Rodriguez, A., Bigham, A. W., Shriver, M. D., Rodriguez, C., Vargas, E., et al. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90945.2008 · Cited by 141
Fetal biometry at 4300 m compared to sea level in Peru
Krampl, E., LEES, C. C., Bland, M., Dorado, J. E., Moscoso, G. J., & Campbell, S. C. (2000) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.2000.00156.x · Cited by 128
Colleoni, F., Padmanabhan, N., Yung, H.-W., Watson, E. D., Cetin, I., Tissot van Patot, M. C., Burton, G. J., & Murray, A. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055194 · Cited by 128
Self-citationReshetnikova, O. S., Burton, G. J., & Milovanov, A. P. (1994) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(94)90402-2 · Cited by 127
Self-citationYung, H. W., Korolchuk, S., Tolkovsky, A. M., Jones, D. S., & Burton, G. J. (2006) · The FASEB Journal · doi:10.1096/fj.06-6054com · Cited by 126
Self-citationHigh-altitude ancestry protects against hypoxia-associated reductions in fetal growth
Julian, C. G., Vargas, E., Armaza, J. F., Wilson, M. J., Niermeyer, S., & MOORE, L. G. (2007) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/adc.2006.109579 · Cited by 122
The role of oxygen in prenatal growth: studies in the chick embryo
Giussani, D. A., Salinas, C. E., Villena, M., & Blanco, C. E. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.141572 · Cited by 120
Where the O2goes to: preservation of human fetal oxygen delivery and consumption at high altitude
Postigo, L., Heredia, G., Illsley, N. P., Torricos, T., Dolan, C., Echalar, L., Tellez, W., Maldonado, I., Brimacombe, M., Balanza, E., et al. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.163634 · Cited by 115
Jackson, M. R., Mayhew, T. M., & Haas, J. D. (1987) · Placenta · doi:10.1016/0143-4004(87)90077-4 · Cited by 112
Illsley, N. P., Caniggia, I., & Zamudio, S. (2010) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082798ni · Cited by 107
Human placental metabolic adaptation to chronic hypoxia, high altitude: hypoxic preconditioning
Tissot van Patot, M. C., Murray, A. J., Beckey, V., Cindrova-Davies, T., Johns, J., Zwerdlinger, L., Jauniaux, E., Burton, G. J., & Serkova, N. J. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00383.2009 · Cited by 107
Self-citationAn upstream open reading frame within an IRES controls expression of a specific VEGF-A isoform
Bastide, A., Karaa, Z. S., Bornes, S., Hiéblot, C., Lacazette, É., Prats, H., & Touriol, C. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn093 · Cited by 85
Karim, M. M., Hughes, J. M. X., Warwicker, J., Scheper, G. C., Proud, C. G., & McCarthy, J. E. G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011068200 · Cited by 74
In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus
Raman, L., Tkáč, I., Ennis, K., Georgieff, M., Rolf Gruetter, A., & Rao, R. (2005) · Developmental Brain Research · doi:10.1016/j.devbrainres.2005.02.013 · Cited by 73
Jackson, M., Mayhew, T. M., & Haas, J. D. (1987) · PubMed · Cited by 72
Placental Villus Morphology in Relation to Maternal Hypoxia at High Altitude
Espinoza, J., Sebire, N. J., McAuliffe, F., Krampl, E., & Nicolaides, K. H. (2001) · Placenta · doi:10.1053/plac.2001.0696 · Cited by 67
Continuous heat shock enhances translational initiation directed by internal ribosomal entry site
Kim, Y. K., & Jang, S. K. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02154-x · Cited by 57
JAN, E., THOMPSON, S. R., WILSON, J. E., PESTOVA, T. V., HELLEN, C. U. T., & SARNOW, P. (2001) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2001.66.285 · Cited by 46
van Patot, M. C. T., Valdez, M., Becky, V., Cindrová‐Davies, T., Johns, J., Zwerdling, L., Jauniaux, E. R. M., & Burton, G. J. (2009) · Placenta · doi:10.1016/j.placenta.2009.04.002 · Cited by 42
Self-citationBalancing of energy‐consuming processes of K 562 cells
Siems, W. G., Schmidt, H., Gruner, S., & Jakstadt, M. (1992) · Cell Biochemistry and Function · doi:10.1002/cbf.290100110 · Cited by 37
Soma, H., Hata, T., Oguro, T., Fujita, K., Kudo, M., & Vaidya, U. (2005) · Medical Molecular Morphology · doi:10.1007/s00795-004-0259-y · Cited by 37
Choi, S., Oh, S., Kim, J., Sadovsky, Y., & Roh, C. (2007) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.08.029 · Cited by 33
Hypoxia induces electron transport chain dysfunction in human placental mitochondria
Colleoni, F., Yung, H. W., Padmanabhan, N., Cetin, I., van Patot, M., Burton, G. J., & Murray, A. J. (2011) · Placenta · Cited by 1
Self-citationKuzawa, C. W. (1998) · doi:10.1002/(sici)1096-8644(1998)107:27+
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Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717
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Lockhart, S. M., Saudek, V., & O’Rahilly, S. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa007 · Cited by 256
Gestational Hypoxia and Developmental Plasticity
Ducsay, C. A., Goyal, R., Pearce, W. J., Wilson, S. M., Hu, X., & Zhang, L. (2018) · Physiological Reviews · doi:10.1152/physrev.00043.2017 · Cited by 208
Measuring high-altitude adaptation
MOORE, L. G. (2017) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00321.2017 · Cited by 205
Metadata
- Authors
- Yung, H. W., Cox, M., van Patot, M. T., & Burton, G. J.
- Affiliations
- University of Cambridge (GB)
- Centre for Trophoblast Research University of Cambridge Cambridge UK
- Corresponding author
- Burton, Graham J.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2012-01-20
- Volume
- 26
- Issue
- 5
- Pages
- 1970-1981
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3336782
- OpenAlex
- W2115115666
- Cited by
- 112
- References
- 62
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 5 · 2013: 10 · 2012: 4
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The FASEB Journal (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (084804/2/08/Z)
- Topics
- Health Sciences › Medicine › Physiology (medical) › High Altitude and Hypoxia
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- endoplasmic reticulum stress, hypoxia, high altitude, placenta, protein synthesis inhibition, eIF2α phosphorylation, 4E-BP1, Akt phosphorylation, PI3K signaling, salubrinal, cell proliferation, low birth weight, trophoblast
- MeSH terms
- Altitude, Endoplasmic Reticulum, Female, Humans, Phosphoproteins, Phosphorylation, Placenta, Pregnancy, Protein Biosynthesis, Blotting, Western, Eukaryotic Initiation Factor-2, Oxidative Stress, Cell Cycle Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Real-Time Polymerase Chain Reaction
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