| First Author | Zera K | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 10 | Pages | e0186707 |
| PubMed ID | 29045486 | Mgi Jnum | J:246597 |
| Mgi Id | MGI:5920784 | Doi | 10.1371/journal.pone.0186707 |
| Citation | Zera K, et al. (2017) Thiamine deficiency activates hypoxia inducible factor-1alpha to facilitate pro-apoptotic responses in mouse primary astrocytes. PLoS One 12(10):e0186707 |
| abstractText | Thiamine is an essential enzyme cofactor required for proper metabolic function and maintenance of metabolism and energy production in the brain. In developed countries, thiamine deficiency (TD) is most often manifested following chronic alcohol consumption leading to impaired mitochondrial function, oxidative stress, inflammation and excitotoxicity. These biochemical lesions result in apoptotic cell death in both neurons and astrocytes. Comparable histological injuries in patients with hypoxia/ischemia and TD have been described in the thalamus and mammillary bodies, suggesting a congruency between the cellular responses to these stresses. Consistent with hypoxia/ischemia, TD stabilizes and activates Hypoxia Inducible Factor-1alpha (HIF-1alpha) under physiological oxygen levels. However, the role of TD-induced HIF-1alpha in neurological injury is currently unknown. Using Western blot analysis and RT-PCR, we have demonstrated that TD induces HIF-1alpha expression and activity in primary mouse astrocytes. We observed a time-dependent increase in mRNA and protein expression of the pro-apoptotic and pro-inflammatory HIF-1alpha target genes MCP1, BNIP3, Nix and Noxa during TD. We also observed apoptotic cell death in TD as demonstrated by PI/Annexin V staining, TUNEL assay, and Cell Death ELISA. Pharmacological inhibition of HIF-1alpha activity using YC1 and thiamine repletion both reduced expression of pro-apoptotic HIF-1alpha target genes and apoptotic cell death in TD. These results demonstrate that induction of HIF-1alpha mediated transcriptional up-regulation of pro-apoptotic/inflammatory signaling contributes to astrocyte cell death during thiamine deficiency. |
