Format

Send to

Choose Destination
Dev Neurosci. 2019 Mar 5:1-10. doi: 10.1159/000495879. [Epub ahead of print]

HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia.

Author information

1
Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
2
Central Laboratory, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
3
Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
4
Department of Pediatrics, University of California San Francisco, San Francisco, California, USA, Donna.Ferriero@ucsf.edu.
5
Department of Neurology, University of California San Francisco, San Francisco, California, USA, Donna.Ferriero@ucsf.edu.

Abstract

Hypoxia-inducible factor 1α (HIF1α) is a key regulator of oxygen homeostasis, and its target genes mediate adaptive, protective, and pathological processes. The role of HIF1α in neuronal survival is controversial and the brain maturation stage is important in determining its function in brain ischemia or hypoxia-ischemia (HI). In this study, we used neuron-specific HIF1α knockout mice at postnatal day 9 (P9), and immature cortical neurons (days 7-8 in vitro) treated with the HIF1α inhibitor 2-methoxyestradiol (2ME2) or stabilizer dimethyloxalylglycine (DMOG), to examine the function of neuronal HIF1α in neonatal HI in vivo (Vannucci model) and in vitro (oxygen glucose deprivation, OGD). Inhibition of HIF1α with 2ME2 in primary neurons or deletion of neuronal HIF1α in P9 mice increased both necrotic and apoptotic cell death following HI, as evaluated by the protein levels of 145/150-kDa and 120-kDa spectrin breakdown products 24 h after HI. DMOG attenuated neuronal death right after OGD. Acute pharmacological manipulation of HIF1α synchronously regulated the expression of its targets, vascular endothelial growth factor (VEGF) and erythropoietin (Epo), in the same manner. The in vivo findings agree with our previous data using the same HIF1α-deficient mice at an earlier age. This study confirms the role of neuronal HIF1α signaling in the endogenous protective responses following HI in the developing brain.

KEYWORDS:

Brain; Development; Hypoxia-inducible factor 1α; Hypoxia/ischemia

PMID:
30836371
PMCID:
PMC6728223
[Available on 2020-09-05]
DOI:
10.1159/000495879
Free full text

Supplemental Content

Full text links

Icon for S. Karger AG, Basel, Switzerland
Loading ...
Support Center