Hypoxia-inducible factor prolyl 4-hydroxylase inhibition: A target for neuroprotection in the central nervous system

Ambreena Siddiq, Issam A. Ayoub, Juan C. Chavez, Leila Aminova, Sapan Shah, Joseph C. LaManna, Stephanie M. Patton, James R. Connor, Robert A. Cherny, Irene Volitakis, Ashley I. Bush, Ingrid Langsetmo, Todd Seeley, Volkmar Gunzler, Rajiv R. Ratan

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Abstract

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1α and HIF-2α. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1α and up-regulate HIF-dependent target genes (e.g. enolase, p21waf1/cip1, vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.

Original languageEnglish (US)
Pages (from-to)41732-41743
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number50
DOIs
StatePublished - Dec 16 2005

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Siddiq, A., Ayoub, I. A., Chavez, J. C., Aminova, L., Shah, S., LaManna, J. C., Patton, S. M., Connor, J. R., Cherny, R. A., Volitakis, I., Bush, A. I., Langsetmo, I., Seeley, T., Gunzler, V., & Ratan, R. R. (2005). Hypoxia-inducible factor prolyl 4-hydroxylase inhibition: A target for neuroprotection in the central nervous system. Journal of Biological Chemistry, 280(50), 41732-41743. https://doi.org/10.1074/jbc.M504963200