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Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation


Aboouf, Mostafa A; Thiel, Cora S; Borisov, Sergey M; Tauber, Svantje; Bönzli, Eva; Schetle, Nelli; Ullrich, Oliver; Gassmann, Max; Vogel, Johannes (2023). Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation. Scientific Reports, 13(1):14514.

Abstract

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells’ expression profile instantaneously by rapidly translocating—most likely cytoskeleton-dependently—into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g–1.8g–0g–1.8g–1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.

Abstract

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells’ expression profile instantaneously by rapidly translocating—most likely cytoskeleton-dependently—into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g–1.8g–0g–1.8g–1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Veterinary Physiology
05 Vetsuisse Faculty > Veterinary Clinic > Department of Clinical Diagnostics and Services
05 Vetsuisse Faculty > Center for Clinical Studies
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Multidisciplinary
Uncontrolled Keywords:Multidisciplinary
Language:English
Date:4 September 2023
Deposited On:10 Oct 2023 08:11
Last Modified:30 May 2024 01:46
Publisher:Nature Publishing Group
ISSN:2045-2322
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41598-023-41686-1
PubMed ID:37666879
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)