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Temporal Rac1 – HIF-1 crosstalk modulates hypoxic survival of aged neurons

Güntert, Tanja; Gassmann, Max; Ogunshola, Omolara O (2016). Temporal Rac1 – HIF-1 crosstalk modulates hypoxic survival of aged neurons. Brain Research, 1642:298-307.

Abstract

Neurodegenerative diseases are frequently associated with hypoxic conditions. During hypoxia the neuronal cytoskeleton is rapidly reorganized and such abnormalities are directly linked to adverse outcomes. Besides their roles as master regulators of the cytoskeleton, the Rho GTPases are also involved in cellular processes stimulated by hypoxic stress. We investigated the contribution of Rac1-mediated signaling to hypoxic responses of mature neurons using primary cortical cells cultured for 17 days in vitro. We show Rac1 is both upregulated and activated during hypoxia. Pharmacological inhibition of Rac1, but not RhoA, completely abrogated hypoxic HIF-1α stabilization and expression of the HIF-1 targets VEGF and GLUT1. Furthermore activity of JNK and GSK3β were also highly dependent on Rac1 activity and biphasic effects were observed after 6 and 24 h of exposure. Notably, inhibition of either pathway suppressed HIF-1α accumulation. Although inhibition of Rac1 did not affect neuronal viability during acute exposure cell death was strongly induced after 24 h revealing a time-dependent effect of Rac1 signaling on survival. Thus hypoxia-activated Rac1 is critical for neuronal HIF-1α stabilization and survival during oxygen deprivation via integration of complex signaling cascades.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > Molecular Biology
Health Sciences > Neurology (clinical)
Life Sciences > Developmental Biology
Uncontrolled Keywords:GSK3, HIF-1α, In vitro, JNK, Neuronal survival
Language:English
Date:2016
Deposited On:25 Apr 2016 16:02
Last Modified:15 Oct 2024 01:38
Publisher:Elsevier
ISSN:0006-8993
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.brainres.2016.03.025
PubMed ID:27018294

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