Reference : Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent ...
Scientific journals : Article
Human health sciences : Multidisciplinary, general & others
http://hdl.handle.net/10993/26335
Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
English
Karuppagounder, Saravanan S. [> >]
Alim, Ishraq [> >]
Khim, Soah J. [> >]
Bourassa, Megan W. [> >]
Sleiman, Sama F. [> >]
John, Roseleen [> >]
Thinnes, Cyrille [University of Oxford > Department of Chemistry]
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. [> >]
2016
Science translational medicine
8
328
328ra29
Yes (verified by ORBilu)
International
1946-6234
1946-6242
United States
[en] 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 from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression 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.
http://hdl.handle.net/10993/26335
Copyright (c) 2016, American Association for the Advancement of Science.

There is no file associated with this reference.

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.