Document Detail


Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states.
MedLine Citation:
PMID:  23350672     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase-1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme-hemopexin complexes, and physiologically relevant ROS, for example, H(2)O(2) and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~twofold after heme-hemopexin endocytosis by iron from heme catabolism via the iron-regulatory element of hAPP mRNA. Heme-hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert-butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H(2)O(2) in vitro. Apo-hemopexin, which predominates in non-hemolytic states, resists damage by H(2)O(2) and HOCl, except for the highest concentrations likely in vivo. Heme-albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme, thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons.
Authors:
Peter Hahl; Taron Davis; Cecilia Washburn; Jack T Rogers; Ann Smith
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-25
Journal Detail:
Title:  Journal of neurochemistry     Volume:  125     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-22     Completed Date:  2013-05-13     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  89-101     Citation Subset:  IM    
Copyright Information:
© 2013 International Society for Neurochemistry.
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MeSH Terms
Descriptor/Qualifier:
Amyloid beta-Protein Precursor / metabolism
Apoproteins / metabolism
Brain / metabolism*,  pathology
Brain Injuries / metabolism,  pathology
Cell Line, Tumor
Cerebral Hemorrhage / metabolism,  pathology
Endocytosis
Enzyme Induction
Heme / metabolism
Heme Oxygenase-1 / metabolism
Hemopexin / metabolism*
Humans
Inflammation / metabolism,  pathology
Neurons / metabolism*
Peroxides / pharmacology
Reactive Oxygen Species / metabolism
Grant Support
ID/Acronym/Agency:
R21 NS077079/NS/NINDS NIH HHS; R21DK64363/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Protein Precursor; 0/Apoproteins; 0/Peroxides; 0/Reactive Oxygen Species; 42VZT0U6YR/Heme; 9013-71-2/Hemopexin; EC 1.14.99.3/Heme Oxygenase-1
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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