Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia

S. Doré, S. Goto, K. Sampei, S. Blackshaw, L. D. Hester, T. Ingi, A. Sawa, R. J. Traystman, R. C. Koehler, S. H. Snyder

Research output: Contribution to journalArticle

Abstract

Heme oxygenase (HO) cleaves the heme ring to form biliverdin, which is rapidly reduced to bilirubin, carbon monoxide, and iron. HO1, the first form of the enzyme discovered, is an inducible protein, concentrated in tissues that are exposed to degrading red blood cells and stimulated by hemolysis and numerous other toxic perturbations to eliminate potentially toxic heme. By contrast, HO2 is constitutive and most highly concentrated in neural tissues. Carbon monoxide, formed from HO2, is a putative neurotransmitter in the brain and peripheral autonomic nervous system. HO1 regulates the efflux of potentially toxic iron from cells, as iron efflux is deficient in mice with targeted deletion of HO1 (HO1(-/-)), and transfection of HO1 facilitates iron efflux. Bilirubin appears to be a physiologic neuroprotectant. Activation of HO2 by phorbol esters, that stimulate protein kinase C to phosphorylate HO2, augments production of bilirubin which protects brain cultures from oxidative stress. Bilirubin itself in nanomolar concentrations is neuroprotective, while HO2 deletion (HO2(-/-)) leads to increased neurotoxicity in brain cultures and increased neural damage following transient cerebral ischemia in intact mice. Mechanisms whereby HO2 provides neuroprotection have not been clarified including whether protection is primarily associated with apoptotic or necrotic cell death. Moreover, the generality of neurotoxic stimuli influenced by HO2 has been unclear. We now demonstrate increased neuronal death in cerebellar granule cultures of HO2(-/-) mice with a selective augmentation of apoptotic death. We also demonstrate that HO2 transfection rescues apoptotic death. In intact mice, we show an increased incidence of apoptotic morphology in the penumbra area surrounding the infarct core in HO2(-/-) mice undergoing transient focal ischemia. (C) 2000 IBRO.

Original languageEnglish (US)
Pages (from-to)587-592
Number of pages6
JournalNeuroscience
Volume99
Issue number4
DOIs
StatePublished - Aug 23 2000

Keywords

  • Bilirubin
  • Cell death
  • Heme
  • Occlusion
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia'. Together they form a unique fingerprint.

  • Cite this