title: Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by "antioxidant" metal chelators: From ferroptosis to stroke.
abstract: Neurologic conditions including stroke, Alzheimer disease, Parkinson disease, and Huntington disease are leading causes of death and long-term disability in the United States, and efforts to develop novel therapeutics for these conditions have historically had poor success in translating from bench to bedside. Hypoxia-inducible factor (HIF)-1α mediates a broad, evolutionarily conserved, endogenous adaptive program to hypoxia, and manipulation of components of the HIF pathway is neuroprotective in a number of human neurological diseases and experimental models. In this review, we discuss molecular components of one aspect of hypoxic adaptation in detail and provide perspective on which targets within this pathway seem to be ripest for preventing and repairing neurodegeneration. Further, we highlight the role of HIF prolyl hydroxylases as emerging targets for the salutary effects of metal chelators on ferroptosis in vitro as well in animal models of neurological diseases.
authors: Graduate Program in Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Rachel E
authors: RE
authors: Speer
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Saravanan S
authors: SS
authors: Karuppagounder
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Manuela
authors: M
authors: Basso
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Sama F
authors: SF
authors: Sleiman
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Amit
authors: A
authors: Kumar
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: David
authors: D
authors: Brand
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Natalya
authors: N
authors: Smirnova
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Irina
authors: I
authors: Gazaryan
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA.
authors: Soah J
authors: SJ
authors: Khim
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA; Burke Medical Research Institute, White Plains, NY 10605, USA. Electronic address: rrrr2001@med.cornell.edu.
authors: Rajiv R
authors: RR
authors: Ratan
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D002614:Chelating Agents / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008670:Metals / Q000378:metabolism; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D018384:Oxidative Stress; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D051793:Hypoxia-Inducible Factor 1; D008670:Metals; D018696:Neuroprotective Agents
keywords: Free radicals; Hypoxia-inducible factors; Metal chelators; Neurodegeneration; Prolyl hydroxylases; Transcription
references: Mol Cell Biol. 2000 Jan;20(1):402-15
references: 10594042
references: Mol Cell Biol. 2005 Jun;25(12):4853-62
references: 15923604
references: Eur J Pharmacol. 2010 May 10;633(1-3):24-32
references: 20153315
references: J Biol Chem. 1993 Oct 15;268(29):21513-8
references: 8408001
references: Nat Rev Cancer. 2003 Oct;3(10):721-32
references: 13130303
references: Neurochem Int. 2010 Oct;57(3):198-205
references: 20546814
references: J Pharmacol Exp Ther. 2009 Sep;330(3):679-86
references: 19509317
references: PLoS One. 2011 Mar 29;6(3):e18269
references: 21479246
references: Eur J Neurosci. 2006 Apr;23(7):1757-65
references: 16623832
references: Genes Dev. 2000 Jan 1;14(1):34-44
references: 10640274
references: Stroke. 2004 Nov;35(11 Suppl 1):2687-9
references: 15472113
references: Trends Biochem Sci. 2012 Sep;37(9):364-72
references: 22818162
references: Biochem J. 2004 Aug 1;381(Pt 3):761-7
references: 15104534
references: Nature. 1999 May 20;399(6733):271-5
references: 10353251
references: Cell. 1994 Oct 7;79(1):13-21
references: 7923371
references: Cancer Res. 2005 Apr 15;65(8):3299-306
references: 15833863
references: Biochem J. 2006 Jan 15;393(Pt 2):471-80
references: 16176182
references: Cell. 2002 Nov 27;111(5):709-20
references: 12464182
references: Hum Mol Genet. 1999 Mar;8(3):425-30
references: 9949201
references: Mol Cell. 2005 Dec 9;20(5):687-98
references: 16337593
references: Parkinsons Dis. 2012;2012:364684
references: 22666629
references: J Biol Chem. 2004 Jan 23;279(4):2550-8
references: 14600153
references: J Biol Chem. 2002 Oct 18;277(42):39887-98
references: 12169691
references: Biochem Biophys Res Commun. 2004 Nov 5;324(1):394-400
references: 15465032
references: Hum Mol Genet. 2008 Aug 1;17(15):2265-73
references: 18424449
references: Blood. 2012 Feb 2;119(5):1292-301
references: 22144179
references: Ann N Y Acad Sci. 2008 Dec;1147:383-94
references: 19076458
references: FEBS Lett. 1997 Sep 1;414(1):117-21
references: 9305743
references: J Neural Transm Suppl. 2006;(71):163-72
references: 17447427
references: Mol Cell Biol. 2007 May;27(9):3253-65
references: 17325032
references: J Neurosci. 2009 Jul 8;29(27):8828-38
references: 19587290
references: J Neurosci Res. 2013 Aug;91(8):1066-75
references: 23456821
references: Nat Rev Drug Discov. 2009 Feb;8(2):139-52
references: 19165233
references: Ann N Y Acad Sci. 2004 Mar;1012:306-25
references: 15105275
references: Nat Med. 2011 Jul 07;17(7):796-808
references: 21738161
references: J Neurochem. 2007 Dec;103(5):1897-906
references: 17760870
references: J Biol Chem. 2003 Aug 15;278(33):30772-80
references: 12788921
references: Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):105-10
references: 16373502
references: J Biol Chem. 2000 Feb 18;275(7):4618-27
references: 10671489
references: Biochem Biophys Res Commun. 2006 Dec 15;351(2):313-20
references: 17069766
references: Science. 1999 Jan 22;283(5401):496-7
references: 9988650
references: J Neurosci. 2002 Oct 15;22(20):8922-31
references: 12388599
references: EMBO Mol Med. 2010 Sep;2(9):349-70
references: 20665636
references: Neurosci Lett. 2005 May 6;379(2):96-100
references: 15823423
references: Brain Pathol. 2011 May;21(3):249-62
references: 21029239
references: J Neurosci. 2012 May 9;32(19):6561-9
references: 22573678
references: J Biol Chem. 2011 Mar 4;286(9):6963-70
references: 21193393
references: J Biol Chem. 2004 Sep 10;279(37):38458-65
references: 15247232
references: Ageing Res Rev. 2004 Jul;3(3):327-43
references: 15231240
references: Am J Pathol. 2011 Jan;178(1):4-11
references: 21224036
references: Biochem Soc Trans. 2009 Feb;37(Pt 1):291-4
references: 19143649
references: J Exp Med. 2008 May 12;205(5):1227-42
references: 18458112
references: J Cereb Blood Flow Metab. 2011 Jan;31(1):132-43
references: 20407463
references: J Biol Chem. 2000 Apr 21;275(16):12200-6
references: 10766856
references: Cell Metab. 2009 Jan 7;9(1):11-22
references: 19117543
references: Neurobiol Dis. 2013 Jan;49:13-21
references: 22944173
references: Nat Neurosci. 2011 Oct 26;14(11):1369-73
references: 22030547
references: Arch Neurol. 2003 Dec;60(12):1685-91
references: 14676042
references: Trends Pharmacol Sci. 2008 May;29(5):268-75
references: 18384889
references: Science. 1999 Apr 23;284(5414):657-61
references: 10213691
references: Science. 2001 Apr 20;292(5516):464-8
references: 11292862
references: NeuroRx. 2004 Jan;1(1):26-35
references: 15717005
references: Curr Neurovasc Res. 2011 Feb;8(1):44-51
references: 21208160
references: Genes Dev. 1999 Jan 1;13(1):64-75
references: 9887100
references: J Neurosci. 1996 Feb 1;16(3):1150-62
references: 8558244
references: Mol Cell. 2007 Jan 26;25(2):207-17
references: 17244529
references: J Neurosurg Anesthesiol. 2009 Jan;21(1):31-9
references: 19098621
references: J Biol Chem. 2005 Dec 16;280(50):41732-43
references: 16227210
references: FEBS Lett. 2010 Jul 16;584(14):3073-9
references: 20621833
references: J Biol Chem. 2009 Oct 16;284(42):29065-76
references: 19679656
references: Neuroscientist. 2009 Jun;15(3):243-60
references: 19181875
references: Neurobiol Dis. 2008 Sep;31(3):433-41
references: 18602008
references: Essays Biochem. 2005;41:1-14
references: 16250894
references: Exp Neurol. 2005 Oct;195(2):407-15
references: 16023639
references: J Biol Chem. 2002 Jan 4;277(1):9-12
references: 11707426
references: J Biol Chem. 2007 Dec 21;282(51):37064-73
references: 17965024
references: Mol Cell. 2006 Oct 6;24(1):39-50
references: 17018291
references: PLoS One. 2009;4(4):e5077
references: 19347037
references: Science. 2003 Dec 12;302(5652):1975-8
references: 14671307
references: Mol Cell Biol. 2005 Aug;25(15):6415-26
references: 16024780
references: J Neurosci. 2008 Feb 20;28(8):1988-93
references: 18287515
references: J Neurosci. 2003 May 1;23(9):3597-606
references: 12736330
references: J Cereb Blood Flow Metab. 2008 Mar;28(3):612-20
references: 17895908
references: Science. 2001 Nov 9;294(5545):1337-40
references: 11598268
references: Mol Cell Biol. 2009 Aug;29(15):4080-90
references: 19470762
references: J Neurosci. 1994 Jul;14(7):4385-92
references: 8027786
references: FEBS Lett. 2003 Aug 14;549(1-3):105-9
references: 12914934
references: Mol Cell Biol. 2008 Apr;28(8):2701-17
references: 18285459
references: J Cereb Blood Flow Metab. 2011 Jun;31(6):1412-23
references: 21245873
references: J Cereb Blood Flow Metab. 2012 Jul;32(7):1347-61
references: 22415525
references: Brain Res Dev Brain Res. 2001 Dec 31;132(2):121-9
references: 11744116
references: J Biol Chem. 1996 Jul 26;271(30):17771-8
references: 8663540
references: J Neurosci. 2011 May 4;31(18):6858-70
references: 21543616
references: J Biol Chem. 2001 Oct 26;276(43):39805-11
references: 11514583
references: Exp Physiol. 2006 Sep;91(5):807-19
references: 16857720
references: J Cereb Blood Flow Metab. 2008 Jan;28(1):1-16
references: 17684514
references: Biochem Soc Trans. 2008 Jun;36(Pt 3):472-8
references: 18481984
references: J Exp Med. 1984 Nov 1;160(5):1532-43
references: 6333485
references: Crit Rev Biochem Mol Biol. 2010 Apr;45(2):106-24
references: 20199358
references: Cancer Res. 1994 Mar 15;54(6):1425-30
references: 8137243
references: Lancet. 1991 Jun 1;337(8753):1304-8
references: 1674295
references: J Biol Chem. 2002 Jul 19;277(29):26351-5
references: 12042299
references: J Neurochem. 2005 May;93(3):513-25
references: 15836611
references: J Biol Chem. 2007 Jul 13;282(28):20534-43
references: 17502379
references: Acta Cir Bras. 2007 Mar-Apr;22(2):125-9
references: 17375219
references: Science. 2001 Apr 20;292(5516):468-72
references: 11292861
references: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18154-9
references: 17114296
references: J Cereb Blood Flow Metab. 2002 May;22(5):520-5
references: 11973424
references: Nat Rev Cancer. 2008 Nov;8(11):851-64
references: 18846101
references: Chem Biol. 2010 Apr 23;17(4):380-91
references: 20416509
references: J Cell Sci. 2010 Sep 1;123(Pt 17):2976-86
references: 20699359
references: Exp Brain Res. 2012 Jun;219(3):381-90
references: 22547371
references: Cancer Cell. 2009 Nov 6;16(5):413-24
references: 19878873
references: Nature. 2012 May 06;486(7401):126-9
references: 22678294
references: J Neurosci. 1999 Nov 15;19(22):9821-30
references: 10559391
references: EMBO J. 2000 Jan 4;19(1):94-102
references: 10619848
references: J Biol Chem. 2010 Oct 8;285(41):31277-84
references: 20675386
references: J Neurochem. 2009 Mar;108(5):1309-21
references: 19183269
references: J Biol Chem. 1982 Mar 10;257(5):2543-8
references: 6277905
references: Proc Natl Acad Sci U S A. 1977 Jan;74(1):54-8
references: 264694
references: J Neurotrauma. 1996 Apr;13(4):223-31
references: 8860203
references: Antioxid Redox Signal. 2010 Apr;12(4):435-43
references: 19659431
references: Exp Neurol. 2011 Aug;230(2):302-10
references: 21619879
references: J Neurosci. 2007 Jun 6;27(23):6320-32
references: 17554006
references: EMBO Rep. 2011 Jan;12(1):63-70
references: 21109780
references: Neurobiol Aging. 2013 Feb;34(2):562-75
references: 22717236
references: Mol Biol Cell. 2007 Dec;18(12):4691-7
references: 17898080
references: Circulation. 2011 Feb 1;123(4):e18-e209
references: 21160056
references: Biochemistry (Mosc). 2012 Oct;77(10):1108-19
references: 23157291
references: J Biol Chem. 2005 Feb 4;280(5):3996-4003
references: 15557337
references: Neurosci Bull. 2008 Apr;24(2):89-95
references: 18369388
references: Ann Neurol. 2000 Sep;48(3):285-96
references: 10976634
references: J Biol Chem. 1999 Nov 12;274(46):32631-7
references: 10551817
references: Cell. 2012 May 25;149(5):1060-72
references: 22632970
references: J Biol Chem. 2011 Apr 15;286(15):13041-51
references: 21335549
references: Neurobiol Dis. 2012 Feb;45(2):733-42
references: 22061780
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4281-6
references: 12640146
references: J Biol Chem. 2006 Nov 3;281(44):33095-106
references: 16954218
references: Sci Signal. 2009 Jul 07;2(78):ra33
references: 19584355