Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models
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. Here we show that the hypoxia-inducible factor prolyl-hydroxylase (HIF- PHD) family of iron-dependent oxygen sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in mouse striatum improved functional recovery following ICH. A low molecular weight hydroxyquinoline inhibitor of the HIF-PHDs, adaptaquin, reduced neuronal death and behavioral deficits following ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of expression of the prodeath factor ATF4 rather than activation of a HIF-dependent prosurvival pathway. In conclusion, 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 following ICH in multiple rodent species.
- Authors:
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- Burke Medical Research Inst., White Plains, NY (United States). Sperling Center for Hemorrhagic Stroke Recovery; Weill Medical Collage of Cornell Univ., New York, NY (United States). Feil Family Brain and Mind Research Inst.
- Univ. of Alberta, Edmonton, AB (Canada)
- Univ. of Oxford (United Kingdom)
- Phillips-Univ. Marburg, Marburg (Germany). Inst. fuer Pharmakologie and Klinische Pharmazie
- Weill Medical Collage of Cornell Univ., New York, NY (United States). Dept. of Biochemistry
- Childrenâs Hospital of Oakland, Oakland, CA (United States)
- Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurology
- Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
- Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
- Univ. of Texas, Austin, TX (United States). Dept. of Psychology
- Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
- Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry
- Univ. of Connecticut Health Center, Farmington, CT (United States). Center for Vascular Biology
- Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States). Inst.for Cell Engineering
- Univ. of California, Los Angeles, CA (United States). Dept. of Psychiatry
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1340386
- Report Number(s):
- BNL-112574-2016-JA
Journal ID: ISSN 1946-6234
- Grant/Contract Number:
- SC0012704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Translational Medicine
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 328; Journal ID: ISSN 1946-6234
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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, Guohu, Keep, Richard F., Schallert, Timothy, Tappero, Ryan V., Zhong, Jian, Cho, Sunghee, Maxfield, Frederick R., Holman, T. R., Culmsee, Carsten, Fong, Guo-Hua -H., Su, Yijing, Ming, Guo-li, Song, Hongjun, Cave, John W., Schofield, Christopher J., Colbourne, Frederick, Coppola, Giovanni, and 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. United States: N. p., 2016.
Web. doi: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, Guohu, Keep, Richard F., Schallert, Timothy, Tappero, Ryan V., Zhong, Jian, Cho, Sunghee, Maxfield, Frederick R., Holman, T. R., Culmsee, Carsten, Fong, Guo-Hua -H., 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. United States. 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, Guohu, Keep, Richard F., Schallert, Timothy, Tappero, Ryan V., Zhong, Jian, Cho, Sunghee, Maxfield, Frederick R., Holman, T. R., Culmsee, Carsten, Fong, Guo-Hua -H., Su, Yijing, Ming, Guo-li, Song, Hongjun, Cave, John W., Schofield, Christopher J., Colbourne, Frederick, Coppola, Giovanni, and Ratan, Rajiv R. Wed .
"Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models". United States. https://doi.org/10.1126/scitranslmed.aac6008. https://www.osti.gov/servlets/purl/1340386.
@article{osti_1340386,
title = {Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models},
author = {Karuppagounder, Saravanan S. and Alim, Ishraq and Khim, Soah J. and Bourassa, Megan W. and Sleiman, Sama F. and John, Roseleen and Thinnes, Cyrille C. and Yeh, Tzu-Lan and Demetriades, Marina and Neitemeier, Sandra and Cruz, Dana and Gazaryan, Irina and Killilea, David W. and Morgenstern, Lewis and Xi, Guohu and Keep, Richard F. and Schallert, Timothy and Tappero, Ryan V. and Zhong, Jian and Cho, Sunghee and Maxfield, Frederick R. and Holman, T. R. and Culmsee, Carsten and Fong, Guo-Hua -H. and Su, Yijing and Ming, Guo-li and Song, Hongjun and Cave, John W. and Schofield, Christopher J. and Colbourne, Frederick and Coppola, Giovanni and Ratan, Rajiv R.},
abstractNote = {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. Here we show that the hypoxia-inducible factor prolyl-hydroxylase (HIF- PHD) family of iron-dependent oxygen sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in mouse striatum improved functional recovery following ICH. A low molecular weight hydroxyquinoline inhibitor of the HIF-PHDs, adaptaquin, reduced neuronal death and behavioral deficits following ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of expression of the prodeath factor ATF4 rather than activation of a HIF-dependent prosurvival pathway. In conclusion, 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 following ICH in multiple rodent species.},
doi = {10.1126/scitranslmed.aac6008},
journal = {Science Translational Medicine},
number = 328,
volume = 8,
place = {United States},
year = {Wed Mar 02 00:00:00 EST 2016},
month = {Wed Mar 02 00:00:00 EST 2016}
}
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