Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states.
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.
School of Biological Sciences, University of Missouri - Kansas City, Kansas City, MO, USA.
Peter
P
Hahl
Taron
T
Davis
Cecilia
C
Washburn
Jack T
JT
Rogers
Ann
A
Smith
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001059:Apoproteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis; D004790:Enzyme Induction; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D010545:Peroxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D001059:Apoproteins; D010545:Peroxides; D017382:Reactive Oxygen Species; D006418:Heme; D006466:Hemopexin; D051547:Heme Oxygenase-1