Hypoxia-Inducible Factor 1 Protects Hypoxic Astrocytes against Glutamate Toxicity

Abstract

Stroke is a major neurological disorder characterized by an increase in the Glu (glutamate) concentration resulting in excitotoxicity and eventually cellular damage and death in the brain. HIF-1 (hypoxia-inducible factor-1), a transcription factor, plays an important protective role in promoting cellular adaptation to hypoxic conditions. It is known that HIF-1α, the regulatable subunit of HIF-1, is expressed by astrocytes under severe ischaemia. However, the effect of HIF-1 on astrocytes following Glu toxicity during ischaemia has not been well studied. We investigated the role of HIF-1 in protecting ischaemic astrocytes against Glu toxicity. Immunostaining with GFAP (glial fibrillary acidic protein) confirmed the morphological modification of astrocytes in the presence of 1 mM Glu under normoxia. Interestingly, when the astrocytes were exposed to severe hypoxia (0.1% O2), the altered cell morphology was ameliorated with up-regulation of HIF-1α. To ascertain HIF-1's protective role, effects of two HIF-1α inhibitors, YC-1 [3-(50-hydroxymethyl-20-furyl)-1-benzylindazole] and 2Me2 (2-methoxyoestradiol), were tested. Both the inhibitors decreased the recovery in astrocyte morphology and increased cell death. Given that ischaemia increases ROS (reactive oxygen species), we examined the role of GSH (reduced glutathione) in the mechanism for this protection. GSH was increased under hypoxia, and this correlated with an increase in HIF-1α stabilization in the astrocytes. Furthermore, inhibition of GSH with BSO (l-butathione sulfoximine) decreased HIF-1α expression, suggesting its role in the stabilization of HIF-1α. Overall, our results indicate that the expression of HIF-1α under hypoxia has a protective effect on astrocytes in maintaining cell morphology and viability in response to Glu toxicity.

Interleukin‐1β protects astrocytes against oxidant‐induced injury via an NF‐κB‐Dependent upregulation of glutathione synthesis

“…GSH has been reported to protect astrocytes against various insults (Badawi et al 2012; Kim et al 2003; Scheiber and Dringen 2013). Herein, we demonstrate that IL-1β exposure renders mouse astrocytes more resistant to toxic insult mediated by the organic hydroperoxide, tBOOH, and by FeSO 4 (Figure 7), most likely by eliminating the enhanced ROS production that follows their exposure (shown directly for tBOOH in Figure 9).…”

Hypoxia-Induced Neuroinflammatory White-Matter Injury Reduced by Minocycline in SHR/SP

“…31 HIF-1α has been shown to have a key role in brain edema formation and BBB disruption via a molecular pathway involving MMP-9 in brain trauma, but this is the first report to link the two in chronic vascular disease. 16 Previous investigations have showed that hypoxia-induced MMP-9 expression leads to vascular leakage, which could be reduced by MMP inhibition; in mice exposed to hypoxia, the resulting edema formation was mediated by MMP-9-dependent tight junction rearrangement, which was blocked with an MMP-9 inhibitor.…”

Hypoxia‐inducible factor signalling mechanisms in the central nervous system

“…When HIF‐1α stabilization is inhibited before exposure to a hypoxic stress, astrocytes suffer increased cell death due to glutamate toxicity (Badawi et al . ). Conversely, upregulation of HIF‐1α is associated with protection from ischaemia–reperfusion injury in astrocytes (Du et al .…”