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Hypoxia Inducible Factor (HIF)‐1α is a Transcriptional Mediator for Thiamine Insufficiency Induced Neurotoxicity
Author(s) -
Valle Maria Luisa,
Zastre Jason
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03943
Subject(s) - neurotoxicity , thiamine , oxidative stress , hypoxia (environmental) , programmed cell death , hyperphosphorylation , mediator , endocrinology , medicine , biology , microbiology and biotechnology , chemistry , apoptosis , biochemistry , phosphorylation , toxicity , organic chemistry , oxygen
Age‐dependent decline in vitamin B1 (thiamine) levels has a devastating impact on the brain parenchyma. The neurotoxicity promoted by chronic thiamine insufficiency (TI) is a well‐established comorbidity of Alzheimer's Disease (AD), the most prevalent age‐related metabolic neurodegenerative disease. Inadequate levels of blood thiamine and derivates highly correlate with senile dementia prognosis as predictive peripheral AD biomarker. Impaired activity of thiamine‐dependent enzymes due to TI, dramatically decreased cerebral oxidative metabolism promoting oxidative stress, mitochondrial damage, inflammation, and eventually neuronal loss. Furthermore, age‐related decline in TI potentiates the AD neuropathology triggering the amyloid plaque formation and hyperphosphorylation of tau. We previously showed that TI stabilizes Hypoxia Inducible Factor ‐1α (HIF‐1α), the main transcription factor involved in hypoxic stress, leading to HIF‐1α induced pro‐apoptotic and pro‐inflammatory response. Among the transcriptionally activated HIF‐1α target genes, TI triggered the expression of the pro‐apoptotic protein BCL2/adenovirus E1B 19 kDa protein‐interacting protein‐3 (BNIP‐3). Induction of BNIP‐3 leads to its mitochondria migration where eventually triggers cell death via loss of membrane potential and increase in reactive oxygen species. To date, despite the well‐established correlation between TI and neuropathogenesis, the molecular mechanism underlying the TI mediated neurotoxicity is still unknown. Therefore, we hypothesize that HIF‐1α may be a critical upstream mediator between thiamine insufficiency and neurotoxicity. In this study, hippocampal murine cells (HT22) treated in TI conditions exhibited a significant increase in protein and mRNA levels of HIF‐1α. Increase in BNIP‐3 and other HIF‐1α target genes (LDHA, VEGF, BACE‐1, MCP‐1) implicated in pro‐inflammatory and pro‐apoptotic response was also detected. Treatment with 50 μM and 100 μM of the thiamine antagonist Pyrithiamine (PT) up to 5 days significantly decrease HT22 viability to 30% and 20%, respectively. HIF‐1α silencing via shRNA attenuated the neurotoxic response improving viability up to 60% with the same PT doses. In order to better characterize the HIF‐1α response, BNIP‐3 was also silenced via shRNA. In congruency with HIF‐1α shRNA result, we found a 2‐fold decrease in PT‐induced toxicity in BNIP‐3 shRNA transduced cells. Localization of BNIP‐3 in mitochondria and loss of mitochondrial potential after PT treatment further highlighted the involvement of the HIF‐1α ‐ BNIP‐3 response in TI induced neuronal death. Overall, these findings suggest a central role for HIF‐1α as upstream regulator in TI mediated neurotoxicity.