Heme-hemopexin complex attenuates neuronal cell death and stroke damage.
Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the pro-oxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum. Using the transient ischemia model (90-min middle cerebral artery occlusion followed by 96-h survival), we provide evidence that HPX is protective in the brain, as neurologic deficits and infarct volumes were significantly greater in HPX(-/-) than in wild-type mice. Addressing the potential protective HPX cellular pathway, we observed that exogenous free heme decreased cell survival in primary mouse cortical neuron cultures, whereas the heme bound to HPX was not toxic. Heme-HPX complexes induce HO1 and, consequently, protect primary neurons against the toxicity of both heme and pro-oxidant tert-butyl hydroperoxide; such protection was decreased in HO1(-/-) neuronal cultures. Taken together, these data show that HPX protects against heme-induced toxicity and oxidative stress and that HO1 is required. We propose that the heme-HPX system protects against stroke-related damage by maintaining a tight balance between free and bound heme. Thus, regulating extracellular free heme levels, such as with HPX, could be neuroprotective.
Li
Rung-chi
RC
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Saleem
Sofiyan
S
Zhen
Gehua
G
Cao
Wangsen
W
Zhuang
Hean
H
Lee
Jongseok
J
Smith
Ann
A
Altruda
Fiorella
F
Tolosano
Emanuela
E
Doré
Sylvain
S
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D006418:Heme / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006466:Hemopexin / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006418:Heme; D006466:Hemopexin; D051547:Heme Oxygenase-1