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Mol Med. 1999 October; 5(10): 656–663.
PMCID: PMC2230472

Heme oxygenase-2 is neuroprotective in cerebral ischemia.


Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is not significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.

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Selected References

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  • Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517–554. [PubMed]
  • Ewing JF, Maines MD. Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. Brain Res Brain Res Protoc. 1997 May;1(2):165–174. [PubMed]
  • Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH. Carbon monoxide: a putative neural messenger. Science. 1993 Jan 15;259(5093):381–384. [PubMed]
  • Zakhary R, Poss KD, Jaffrey SR, Ferris CD, Tonegawa S, Snyder SH. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14848–14853. [PubMed]
  • Doré S, Takahashi M, Ferris CD, Zakhary R, Hester LD, Guastella D, Snyder SH. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2445–2450. [PubMed]
  • Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987 Feb 27;235(4792):1043–1046. [PubMed]
  • Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1996 Feb;16(2):250–255. [PubMed]
  • Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919–10924. [PubMed]
  • Poss KD, Thomas MJ, Ebralidze AK, O'Dell TJ, Tonegawa S. Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice. Neuron. 1995 Oct;15(4):867–873. [PubMed]
  • Burnett AL, Johns DG, Kriegsfeld LJ, Klein SL, Calvin DC, Demas GE, Schramm LP, Tonegawa S, Nelson RJ, Snyder SH, et al. Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med. 1998 Jan;4(1):84–87. [PubMed]
  • Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997 Oct;3(10):1089–1095. [PubMed]
  • Jay TM, Lucignani G, Crane AM, Jehle J, Sokoloff L. Measurement of local cerebral blood flow with [14C]iodoantipyrine in the mouse. J Cereb Blood Flow Metab. 1988 Feb;8(1):121–129. [PubMed]
  • Ayata C, Ayata G, Hara H, Matthews RT, Beal MF, Ferrante RJ, Endres M, Kim A, Christie RH, Waeber C, et al. Mechanisms of reduced striatal NMDA excitotoxicity in type I nitric oxide synthase knock-out mice. J Neurosci. 1997 Sep 15;17(18):6908–6917. [PubMed]
  • Schaeren-Wiemers N, Gerfin-Moser A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry. 1993 Dec;100(6):431–440. [PubMed]
  • Nimura T, Weinstein PR, Massa SM, Panter S, Sharp FR. Heme oxygenase-1 (HO-1) protein induction in rat brain following focal ischemia. Brain Res Mol Brain Res. 1996 Apr;37(1-2):201–208. [PubMed]
  • Takeda A, Onodera H, Sugimoto A, Itoyama Y, Kogure K, Shibahara S. Increased expression of heme oxygenase mRNA in rat brain following transient forebrain ischemia. Brain Res. 1994 Dec 12;666(1):120–124. [PubMed]
  • Koistinaho J, Miettinen S, Keinänen R, Vartiainen N, Roivainen R, Laitinen JT. Long-term induction of haem oxygenase-1 (HSP-32) in astrocytes and microglia following transient focal brain ischaemia in the rat. Eur J Neurosci. 1996 Nov;8(11):2265–2272. [PubMed]
  • Geddes JW, Pettigrew LC, Holtz ML, Craddock SD, Maines MD. Permanent focal and transient global cerebral ischemia increase glial and neuronal expression of heme oxygenase-1, but not heme oxygenase-2, protein in rat brain. Neurosci Lett. 1996 Jun 7;210(3):205–208. [PubMed]
  • Yamaguchi T, Terakado M, Horio F, Aoki K, Tanaka M, Nakajima H. Role of bilirubin as an antioxidant in an ischemia-reperfusion of rat liver and induction of heme oxygenase. Biochem Biophys Res Commun. 1996 Jun 5;223(1):129–135. [PubMed]
  • Smith DR, Striplin CD, Geller AM, Mailman RB, Drago J, Lawler CP, Gallagher M. Behavioural assessment of mice lacking D1A dopamine receptors. Neuroscience. 1998 Sep;86(1):135–146. [PubMed]
  • Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Barañano DE, Doré S, et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999 Jul;1(3):152–157. [PubMed]
  • Smith A, Alam J, Escriba PV, Morgan WT. Regulation of heme oxygenase and metallothionein gene expression by the heme analogs, cobalt-, and tin-protoporphyrin. J Biol Chem. 1993 Apr 5;268(10):7365–7371. [PubMed]
  • Huang KP, Huang FL, Mahoney CW, Chen KH. Protein kinase C subtypes and their respective roles. Prog Brain Res. 1991;89:143–155. [PubMed]
  • Minetti M, Mallozzi C, Di Stasi AM, Pietraforte D. Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma. Arch Biochem Biophys. 1998 Apr 15;352(2):165–174. [PubMed]
  • Wu TW, Wu J, Li RK, Mickle D, Carey D. Albumin-bound bilirubins protect human ventricular myocytes against oxyradical damage. Biochem Cell Biol. 1991 Oct-Nov;69(10-11):683–688. [PubMed]
  • Ewing JF, Haber SN, Maines MD. Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperthermia causes rapid induction of mRNA and protein. J Neurochem. 1992 Mar;58(3):1140–1149. [PubMed]
  • Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem. 1994 Jan;40(1):18–23. [PubMed]
  • Gopinathan V, Miller NJ, Milner AD, Rice-Evans CA. Bilirubin and ascorbate antioxidant activity in neonatal plasma. FEBS Lett. 1994 Aug 1;349(2):197–200. [PubMed]
  • Hegyi T, Goldie E, Hiatt M. The protective role of bilirubin in oxygen-radical diseases of the preterm infant. J Perinatol. 1994 Jul-Aug;14(4):296–300. [PubMed]
  • Heyman E, Ohlsson A, Girschek P. Retinopathy of prematurity and bilirubin. N Engl J Med. 1989 Jan 26;320(4):256–256. [PubMed]

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