Heme–Hemopexin Complex Attenuates Neuronal Cell Death and Stroke Damage

Journal of Cerebral Blood Flow and Metabolism - Tập 29 Số 5 - Trang 953-964 - 2009
Rung-chi Li1, Sofiyan Saleem2, Gehua Zhen2, Wangsen Cao2, Hean Zhuang2, Jong-Suk Lee2, Ann Smith3, Fiorella Altruda4, Emanuela Tolosano4, Sylvain Doré2
1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
21Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
32School of Biological Science, Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri, USA
43Department of Genetics, Biology, and Biochemistry, and the Molecular Biotechnology Center, University of Torino, Torino, Italy

Tóm tắt

Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the prooxidant 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 prooxidant 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.

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Journal of Cerebral Blood Flow and Metabolism

Tập 29 Số 5

953-964

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