HIF prolyl hydroxylase inhibition increases cell viability and potentiates dopamine release in dopaminergic cells

• Published in: Journal of neurochemistry Vol. 115; no. 1; pp. 209 - 219
• Main Authors: Johansen, Jens Leander, Sager, Thomas Nikolaj, Lotharius, Julie, Witten, Louise, Mørk, Arne, Egebjerg, Jan, Thirstrup, Kenneth
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-10-2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Anemia; Anemias. Hemoglobinopathies; Animal models; Animals; Biological and medical sciences; Blotting, Western; Cell culture; Cell Line; Cell survival; Cell Survival - drug effects; Cellular biology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dioxygenases - antagonists & inhibitors; Diseases of red blood cells; Dopamine; Dopamine - biosynthesis; Dopamine - metabolism; Dopamine - physiology; Enzyme Inhibitors - pharmacology; Erythropoietin; Gene expression; Genes, Reporter; Hematologic and hematopoietic diseases; HIF prolyl hydroxylase; Homeostasis; Humans; Hypoxia; Hypoxia-inducible factors; Ischemia; Luciferases - genetics; Medical sciences; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - physiology; Movement disorders; Neurochemistry; Neurodegenerative diseases; Neurology; Neurons - drug effects; Neurons - metabolism; Oxidative stress; Parkinson disease; Parkinson's disease; PC12 Cells; Pheochromocytoma cells; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; prolyl hydroxylase; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Therapeutic applications; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism; tyrosine hydroxylase; Oxidative stress; Parkinson's disease; Rat; Homeostasis; Parkinson disease; Cardiovascular disease; Hemopathy; HIF prolyl hydroxylase; Gene; Ischemia; Degenerative disease; Release; Nervous system diseases; Oxygen; Dopamine; Anemia; Rodentia; Catecholamine; Gene expression; Survival; Protein; Cerebral disorder; tyrosine hydroxylase; Vertebrata; Mammalia; Central nervous system disease; Neurotransmitter; Hypoxia; Subtype; Viability; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06917.x

J. Neurochem. (2010) 115, 209-219. Hypoxia-inducible factor (HIF) controls the expression of genes that adapts the cellular condition to accommodate oxidative stress. The potential beneficial effect of HIF up-regulation in ischemia has recently gained interest substantiated by the known HIF-regulation of erythropoietin and other hypoxia accommodating genes. So far the perspectives for HIF up-regulation has been focused on anemia and ischemia related diseases but little information is available about the relevance of HIF biology for neurodegenerative disease like Parkinson's disease. We therefore sought out to characterize the effect of HIF-up-regulation on survival and dopamine homeostasis in dopaminergic cells. We used a low molecular weight HIF prolyl hydroxylase (HPH) inhibitor and lentiviral based shRNA knockdown of HPH subtypes as molecular tools to increase HIF protein level and downstream HIF-regulated genes. We show that HIF induction results in protection against oxidative stress in cellular models based on PC12 cells and LUHMES cells. In addition, HPH inhibition elevates tyrosine hydroxylase expression and activity, which causes increased dopamine synthesis and release in both PC12 cells and a primary rat ventral mesencephalic cell culture. All together these findings suggest that prolyl hydroxylases may represent novel targets for therapeutic intervention in disorders characterized by dopamine homeostasis dysregulation like Parkinson's disease.