Prolyl hydroxylase inhibitors delay neuronal cell death caused by trophic factor deprivation.
Nerve growth factor (NGF) serves a critical survival-promoting function for developing sympathetic neurons. Following removal of NGF, sympathetic neurons undergo apoptosis characterized by the activation of c-Jun N-terminal kinases (JNKs), up-regulation of BH3-only proteins including BcL-2-interacting mediator of cell death (BIM)(EL), release of cytochrome c from mitochondria, and activation of caspases. Here we show that two small-molecule prolyl hydroxylase inhibitors frequently used to activate hypoxia-inducible factor (HIF) - ethyl 3,4-dihydroxybenzoic acid (DHB) and dimethyloxalylglycine (DMOG) - can inhibit apoptosis caused by trophic factor deprivation. Both DHB and DMOG blocked the release of cytochrome c from mitochondria after NGF withdrawal, whereas only DHB blocked c-Jun up-regulation and phosphorylation. DHB, but not DMOG, also attenuated the induction of BIM(EL) in NGF-deprived neurons, suggesting a possible mechanism whereby DHB could inhibit cytochrome c release. DMOG, on the other hand, was substantially more effective at stabilizing HIF-2alpha and inducing expression of the HIF target gene hexokinase 2 than was DHB. Thus, while HIF prolyl hydroxylase inhibitors can delay cell death in NGF-deprived neurons, they do so through distinct mechanisms that, at least in the case of DHB, are partly independent of HIF stabilization.
Lomb
David J
DJ
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Straub
Jennifer A
JA
Freeman
Robert S
RS
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D062385:Hydroxybenzoates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D020932:Nerve Growth Factor / Q000172:deficiency*; D009474:Neurons / Q000187:drug effects*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology
D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; D016755:Proto-Oncogene Proteins c-jun; C018063:ethyl protocatechuate; D045304:Cytochromes c; D020932:Nerve Growth Factor; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine