title: Temporal Rac1 - HIF-1 crosstalk modulates hypoxic survival of aged neurons.
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 24h 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 24h 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.
authors.affiliation: Institute of Veterinary Physiology Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260 & Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, University of Zurich, Zurich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Güntert
authors.affiliation: Institute of Veterinary Physiology Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260 & Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, University of Zurich, Zurich, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Institute of Veterinary Physiology Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260 & Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, University of Zurich, Zurich, Switzerland. Electronic address: larao@access.uzh.ch.
authors.forename: Omolara O
authors.initials: OO
authors.lastname: Ogunshola
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D002534:Hypoxia, Brain / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein
keywords: GSK3; HIF-1α; In vitro; JNK; Neuronal survival