Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP.
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.
Chen
Jijun
J
Department of Neuroscience, 1006B Preclinical Teaching Building, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Tu
Yajun
Y
Connolly
Erin C
EC
Ronnett
Gabriele V
GV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001663:Bilirubin / Q000037:antagonists & inhibitors / Q000502:physiology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency*; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism*; D018034:Olfactory Receptor Neurons / Q000201:enzymology / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D019328:Buthionine Sulfoximine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2; D005978:Glutathione; D006152:Cyclic GMP; D001663:Bilirubin