Cerebroprotective functions of HO-2

Research output: Contribution to journalReview article

54 Citations (Scopus)

Abstract

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, die end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BKca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of Mr, channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilimbin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an cifective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.

Original languageEnglish (US)
Pages (from-to)443-453
Number of pages11
JournalCurrent Pharmaceutical Design
Volume14
Issue number5
DOIs
StatePublished - Feb 1 2008

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Carbon Monoxide
Oxidants
Cerebrovascular Circulation
NADPH Oxidase
Guanylate Cyclase
Gene Deletion
Brain
Electron Transport
Heme
Seizures
Oxidative Stress
Homeostasis
Pharmacology
Biliverdine
Housekeeping
Vascular System Injuries
Enzyme Inhibitors
Electron Transport Complex IV
Cellular Structures
Post Translational Protein Processing

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

Cerebroprotective functions of HO-2. / Parfenova, Elena; Leffler, Charles.

In: Current Pharmaceutical Design, Vol. 14, No. 5, 01.02.2008, p. 443-453.

Research output: Contribution to journalReview article

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