Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

Saravanan S. Karuppagounder, Ishraq Alim, Soah J. Khim, Megan W. Bourassa, Sama F. Sleiman, Roseleen John, Cyrille C. Thinnes, Tzu Lan Yeh, Marina Demetriades, Sandra Neitemeier, Dana Cruz, Irina Gazaryan, David W. Killilea, Lewis Morgenstern, Guohua Xi, Richard F. Keep, Timothy Schallert, Ryan V. Tappero, Jian Zhong, Sunghee Cho & 12 others Frederick R. Maxfield, Theodore R. Holman, Carsten Culmsee, Guo Hua Fong, Yijing Su, Guo Li Ming, Hongjun Song, John W. Cave, Christopher J. Schofield, Frederick Colbourne, Giovanni Coppola, Rajiv R. Ratan

Research output: Contribution to journalArticle

Abstract

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection fromoxidativedeath invitroor fromICHinvivobyadaptaquinwasassociatedwithsuppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

Original languageEnglish (US)
Article number328ra29
JournalScience Translational Medicine
Volume8
Issue number328
DOIs
StatePublished - Mar 2 2016

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Prolyl Hydroxylases
Intracranial Hemorrhages
Cerebral Hemorrhage
Rodentia
Iron
Oxygen
Oxidative Stress
Enzymes
Therapeutics
Hydroxyquinolines
Brain
Chelating Agents
Blood-Brain Barrier
Zinc
Protein Isoforms
Molecular Weight
Hypoxia

ASJC Scopus subject areas

  • Medicine(all)

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Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. / Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.; Bourassa, Megan W.; Sleiman, Sama F.; John, Roseleen; Thinnes, Cyrille C.; Yeh, Tzu Lan; Demetriades, Marina; Neitemeier, Sandra; Cruz, Dana; Gazaryan, Irina; Killilea, David W.; Morgenstern, Lewis; Xi, Guohua; Keep, Richard F.; Schallert, Timothy; Tappero, Ryan V.; Zhong, Jian; Cho, Sunghee; Maxfield, Frederick R.; Holman, Theodore R.; Culmsee, Carsten; Fong, Guo Hua; Su, Yijing; Ming, Guo Li; Song, Hongjun; Cave, John W.; Schofield, Christopher J.; Colbourne, Frederick; Coppola, Giovanni; Ratan, Rajiv R.

In: Science Translational Medicine, Vol. 8, No. 328, 328ra29, 02.03.2016.

Research output: Contribution to journalArticle

Karuppagounder, SS, Alim, I, Khim, SJ, Bourassa, MW, Sleiman, SF, John, R, Thinnes, CC, Yeh, TL, Demetriades, M, Neitemeier, S, Cruz, D, Gazaryan, I, Killilea, DW, Morgenstern, L, Xi, G, Keep, RF, Schallert, T, Tappero, RV, Zhong, J, Cho, S, Maxfield, FR, Holman, TR, Culmsee, C, Fong, GH, Su, Y, Ming, GL, Song, H, Cave, JW, Schofield, CJ, Colbourne, F, Coppola, G & Ratan, RR 2016, 'Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models', Science Translational Medicine, vol. 8, no. 328, 328ra29. https://doi.org/10.1126/scitranslmed.aac6008
Karuppagounder, Saravanan S. ; Alim, Ishraq ; Khim, Soah J. ; Bourassa, Megan W. ; Sleiman, Sama F. ; John, Roseleen ; Thinnes, Cyrille C. ; Yeh, Tzu Lan ; Demetriades, Marina ; Neitemeier, Sandra ; Cruz, Dana ; Gazaryan, Irina ; Killilea, David W. ; Morgenstern, Lewis ; Xi, Guohua ; Keep, Richard F. ; Schallert, Timothy ; Tappero, Ryan V. ; Zhong, Jian ; Cho, Sunghee ; Maxfield, Frederick R. ; Holman, Theodore R. ; Culmsee, Carsten ; Fong, Guo Hua ; Su, Yijing ; Ming, Guo Li ; Song, Hongjun ; Cave, John W. ; Schofield, Christopher J. ; Colbourne, Frederick ; Coppola, Giovanni ; Ratan, Rajiv R. / Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. In: Science Translational Medicine. 2016 ; Vol. 8, No. 328.
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abstract = "Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection fromoxidativedeath invitroor fromICHinvivobyadaptaquinwasassociatedwithsuppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.",
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T1 - Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

AU - Karuppagounder, Saravanan S.

AU - Alim, Ishraq

AU - Khim, Soah J.

AU - Bourassa, Megan W.

AU - Sleiman, Sama F.

AU - John, Roseleen

AU - Thinnes, Cyrille C.

AU - Yeh, Tzu Lan

AU - Demetriades, Marina

AU - Neitemeier, Sandra

AU - Cruz, Dana

AU - Gazaryan, Irina

AU - Killilea, David W.

AU - Morgenstern, Lewis

AU - Xi, Guohua

AU - Keep, Richard F.

AU - Schallert, Timothy

AU - Tappero, Ryan V.

AU - Zhong, Jian

AU - Cho, Sunghee

AU - Maxfield, Frederick R.

AU - Holman, Theodore R.

AU - Culmsee, Carsten

AU - Fong, Guo Hua

AU - Su, Yijing

AU - Ming, Guo Li

AU - Song, Hongjun

AU - Cave, John W.

AU - Schofield, Christopher J.

AU - Colbourne, Frederick

AU - Coppola, Giovanni

AU - Ratan, Rajiv R.

PY - 2016/3/2

Y1 - 2016/3/2

N2 - Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection fromoxidativedeath invitroor fromICHinvivobyadaptaquinwasassociatedwithsuppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

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