Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP

Jijun Chen, Yajun Tu, Erin C. Connolly, Gabriele V. Ronnett

Research output: Contribution to journalArticle

Abstract

Heme oxygenase (HO) enzymes catalyze the breakdown of heme to iron, carbon monoxide (CO), and biliverdin, which is rapidly converted to bilirubin. HO-2 has been implicated in protection against oxidative stress, ischemia, and traumatic brain injury. The neuroprotective effects of HO-2 have been attributed to the generation of bilirubin, which is an important radical scavenger. However, the mechanism by which HO-2 provides protection is unclear. We utilized the olfactory system as a model to define the roles of HO-2 in glutathione depletion-induced oxidative injury, since olfactory receptor neurons (ORNs) express high levels of HO isoforms. We demonstrated that L-buthionine-[S, R]-sulfoximine (BSO), an inhibitor of glutathione biosynthesis, lowered glutathione levels and induced apoptosis of ORNs. Despite the presence of HO-1 in ORNs, HO-2 null animals displayed increased levels of neuronal death after BSO treatment compared to wild type mice. Levels of bilirubin and cGMP were also reduced in HO-2 null mice. Primary cultures of ORNs confirmed that the neuroprotective role of HO-2 was mediated by bilirubin and cGMP. Taken together, these results suggest that HO-2 plays a major role in neuroprotection from oxidative stress, an effect that is mediated by cGMP and bilirubin.

Original languageEnglish (US)
Pages (from-to)121-131
Number of pages11
JournalCurrent Neurovascular Research
Volume2
Issue number2
DOIs
StatePublished - Apr 2005

Fingerprint

Cyclic GMP
Bilirubin
Glutathione
Olfactory Receptor Neurons
Apoptosis
Heme Oxygenase (Decyclizing)
Oxidative Stress
Biliverdine
Heme Oxygenase-1
heme oxygenase-2
Neuroprotective Agents
Carbon Monoxide
Heme
Protein Isoforms
Ischemia
Iron
Wounds and Injuries
Enzymes

Keywords

  • Bilirubin
  • Cyclic GMP
  • Heme oxygenase-2
  • Olfaction
  • Oxidative stress

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP. / Chen, Jijun; Tu, Yajun; Connolly, Erin C.; Ronnett, Gabriele V.

In: Current Neurovascular Research, Vol. 2, No. 2, 04.2005, p. 121-131.

Research output: Contribution to journalArticle

Chen, Jijun ; Tu, Yajun ; Connolly, Erin C. ; Ronnett, Gabriele V. / Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP. In: Current Neurovascular Research. 2005 ; Vol. 2, No. 2. pp. 121-131.
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