Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury

Sylvain Doré, Masaaki Takahashi, Christopher D. Ferris, Lynda D Hester, Daniel Guastella, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR). Two HO active isozymes exist: HO1, an inducible heat shock protein, and HO2, which is constitutive and highly concentrated in neurons. We demonstrate a neuroprotective role for BR formed from HO2. Neurotoxicity elicited by hydrogen peroxide in hippocampal and cortical neuronal cultures is prevented by the phorbol ester, phorbol 12-myristate 13-acetate (PMA) via stimulation of protein kinase C. We observe phosphorylation of HO2 through the protein kinase C pathway with enhancement of HO2 catalytic activity and accumulation of BR in neuronal cultures. The neuroprotective effects of PMA are prevented by the HO inhibitor tin protoporphyrin IX and in cultures from mice with deletion of HO2 gene. Moreover, BR, an antioxidant, is neuroprotective at nanomolar concentrations.

Original languageEnglish (US)
Pages (from-to)2445-2450
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number5
DOIs
StatePublished - Mar 2 1999

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Bilirubin
Heme Oxygenase (Decyclizing)
Oxidative Stress
Neurons
Wounds and Injuries
Protein Kinase C
Acetates
Biliverdine
Gene Deletion
Neuroprotective Agents
Phorbol Esters
Carbon Monoxide
Heat-Shock Proteins
Heme
Hydrogen Peroxide
Isoenzymes
Iron
Antioxidants
Phosphorylation
heme oxygenase-2

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. / Doré, Sylvain; Takahashi, Masaaki; Ferris, Christopher D.; Hester, Lynda D; Guastella, Daniel; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 5, 02.03.1999, p. 2445-2450.

Research output: Contribution to journalArticle

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AB - Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR). Two HO active isozymes exist: HO1, an inducible heat shock protein, and HO2, which is constitutive and highly concentrated in neurons. We demonstrate a neuroprotective role for BR formed from HO2. Neurotoxicity elicited by hydrogen peroxide in hippocampal and cortical neuronal cultures is prevented by the phorbol ester, phorbol 12-myristate 13-acetate (PMA) via stimulation of protein kinase C. We observe phosphorylation of HO2 through the protein kinase C pathway with enhancement of HO2 catalytic activity and accumulation of BR in neuronal cultures. The neuroprotective effects of PMA are prevented by the HO inhibitor tin protoporphyrin IX and in cultures from mice with deletion of HO2 gene. Moreover, BR, an antioxidant, is neuroprotective at nanomolar concentrations.

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