Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system.
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-1alpha and HIF-2alpha. 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-1alpha and up-regulate HIF-dependent target genes (e.g. enolase, p21(waf1/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.
Siddiq
Ambreena
A
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ayoub
Issam A
IA
Chavez
Juan C
JC
Aminova
Leila
L
Shah
Sapan
S
LaManna
Joseph C
JC
Patton
Stephanie M
SM
Connor
James R
JR
Cherny
Robert A
RA
Volitakis
Irene
I
Bush
Ashley I
AI
Langsetmo
Ingrid
I
Seeley
Todd
T
Gunzler
Volkmar
V
Ratan
Rajiv R
RR
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D005452:Fluoresceins / Q000737:chemistry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007501:Iron / Q000737:chemistry; D008156:Luciferases / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008970:Molecular Weight; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010455:Peptides / Q000737:chemistry; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015032:Zinc / Q000737:chemistry; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004921:Erythropoietin; D005452:Fluoresceins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D008156:Luciferases; D010455:Peptides; D010751:Phosphopyruvate Hydratase; D011393:Procollagen-Proline Dioxygenase; D042461:Vascular Endothelial Growth Factor A; D015032:Zinc; D000099162:Endothelial PAS Domain-Containing Protein 1; C493958:Cdkn1a protein, rat; C497444:Hif1a protein, rat; C007740:fluorexon