This study was supported by NIEHS grant ES04391. We are grateful to Dr. Michael Fowler for assistance in providing transgenic newborn mice, Xiaojun Wang for assistance with northern blot analysis, and Suzanne Bono for manuscript preparation. We thank Drs. Robert S. Freeman and Nariman Panahian for helpful discussion and comments and Sangstat Medical Corporation for the generous gift of peptides.

  • 1
    Abraham N.G., Lavrovsky Y., Schwartzman M.L., Stoltz R.A., Levere R.D., Gerritsen M.E., Shibahara S., Kappas A. (1995) Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells : protective effect against heme and hemoglobin toxicity.Proc. Natl. Acad. Sci. USA 92,67986802.
  • 2
    Ankarcrona M., Dypbukt J.M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S.A., Nicotera P. (1995) Glutamate-induced neuronal death : a succession of necrosis or apoptosis depending on mitochondrial function.Neuron 15,961973.
    Balla J., Jacob H.S., Balla G., Nath K., and Vercellotti G.M. (1992) Endothelial cell heme oxygenase and ferritin induction by heme proteins : a possible mechanism limiting shock damage.Trans Assoc. Am. Phys. 105,16.
  • 4
    Cruse I. & Maines M.D. (1988) Evidence suggesting that the two forms of heme oxygenase are products of different genes.J. Biol. Chem. 263,33483353.
  • 5
    Da Silva J.L., Morishita T., Escalante B., Staudinger R., Drummond G., Goligarsky M.S., Lutton J.D., Abraham N.G. (1996) Dual role of heme oxygenase in epithelial cell injury : contrasting effects of short-term and long-term exposure to oxidant stress.J. Lab. Clin. Med. 128,290296.
  • 6
    Dennery P.A., McDonagh A.F., Spitz D.R., Rodgers P.A., Stevenson D.K. (1995) Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia.Free Rad. Biol. Med. 19,395404.
  • 7
    Denninger J.W. & Marletta M.A. (1999) Guanylate cyclase and the NO/cGMP signaling pathway.Biochim. Biophys. Acta 1411,334350.
  • 8
    Du Y., Bales K.R., Dodel R.C., Hamilton-Byrd E., Horn J.W., Czilli D.L., Simmons L.K., Ni B., Paul S.M. (1997) Activation of a caspase 3-related cysteine protease is required for glutamatemediated apoptosis of cultured cerebellar granule neurons.Proc. Natl. Acad. Sci. USA 94,1165711662.
  • 9
    Dwyer B.E., Lu S., Laitinen J.T., Nishimura R.N. (1998) Protective properties of tin- and manganese-centered porphyrins against hydrogen peroxide-mediated injury in rat astroglial cells.J. Neurochem. 71,24972504.
  • 10
    Ewing J.F. & Maines M.D. (1991) Rapid induction of heme oxygenase-1 mRNA and protein by hyperthermia in rat brain : heme oxygenase-2 is not a heat shock protein.Proc. Natl. Acad. Sci. USA 88,53645368.
  • 11
    Favaron M., Manev H., Alho H., Bertolino M., Ferret B., Guidotti A., Costa E. (1988) Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex.Proc. Natl. Acad. Sci. USA 85,73517355.
  • 12
    Gunter T.E., Zuscik M.J., Puzas J.E., Gunter K.K., Rosier R.N. (1990) Cytosolic free calcium concentration in avian growth plate chondrocytes.Cell Calcium 11,445457.
  • 13
    Hansen T.W., Mathiesen S.B., Walaas S.I. (1996) Bilirubin has widespread inhibitory effects on protein phosphorylation.Pediatr. Res. 39,10721077.
  • 14
    Herdegen T., Claret F.X., Kallunki T., Martin-Villalba A., Winter C., Hunter T., Karin M. (1998) Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury.J. Neurosci. 18,51245135.
  • 15
    Iyer S., Woo J., Cornejo M.C., Gao L., McCoubrey W., Maines M., Buelow R. (1997) Characterization and biological significance of immunosuppressive peptide D2702.75-84(E [RIGHTWARDS ARROW] V) binding protein. Isolation of heme oxygenase-1.J. Biol. Chem. 273,26922697.
  • 16
    Juin P., Pelletier M., Oliver L., Tremblais K., Gregoire M., Meflah K., Vallette F.M. (1998) Induction of a caspase-3-like activity by calcium in normal cytosolic extracts triggers nuclear apoptosis in a cell-free system.J. Biol. Chem. 273,1755917564.
  • 17
    Kane D.J., Sarafian T.A., Anton R., Hahn H., Gralla E.B., Valentine J.S., Ord T., Bredesen D.E. (1993) Bcl-2 inhibition of neural death : decreased generation of reactive oxygen species.Science 262,12741277.
  • 18
    Keller J.N. & Mattson M.P. (1998) Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system.Rev. Neurosci. 9,105116.
  • 19
    Keyse S.M. & Tyrell R.M. (1989) Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide and sodium arsenite.Proc. Natl. Acad. Sci. USA 86,99103.
  • 20
    Kutty R.K. & Maines M.D. (1982) Oxidation of heme c derivatives by purified heme oxygenase : evidence for the presence of one molecular species of heme oxygenase in rat liver.J. Biol. Chem. 257,99449952.
  • 21
    Kwak J.Y., Takeshiege K., Cheung B.S., Minakami S. (1991) Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system.Biochim. Biophys. Acta 1076,369373.
  • 22
    Lafon-Cazal M., Pietri S., Culcasi M., Bockaert J. (1993) NMDA-dependent superoxide production and neurotoxicity.Nature 364,535537.
  • 23
    Maines M.D. (1992) Heme Oxygenase : Clinical Applications and Functions. CRC Press, Boca Raton, Florida.
  • 24
    Maines M.D. (1997) The heme oxygenase system : a regulator of second messenger gases.Annu. Rev. Pharmacol. Toxicol. 37,517554.
  • 25
    Maines M.D. & Trakshel G.M. (1992) Differential regulation of heme oxygenase isozymes by Sn- and Zn-protoporphyrins : possible relevance to suppression of hyperbilirubinemia.Biochim. Biophys. Acta 1131,166174.
  • 26
    Maines M.D., Trakshel G.M., Kutty R.K. (1986) Characterization of two constitutive forms of rat liver microsomal heme oxygenase ; only one molecular form is inducible.J. Biol. Chem. 261,411419.
  • 27
    Maines M.D., Polevoda B., Coban T., Johnson K., Stoliar S., Huang T.J., Panahian N., Cory-Slechta D.A., McCoubrey W.K.J r. (1998) Neuronal overexpression of heme oxygenase-1 correlates with an attenuated exploratory behavior and causes an increase in neuronal NADPH diaphorase staining.J. Neurochem. 70,20572069.
  • 28
    Maines M.D., Raju V.S., Panahian M. (1999) Spin trap (N-t-butyl-α-phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model : the role of the oxygenase in protection against oxidative injury. J. Pharmacol. Exp. Ther. 291,911919.
  • 29
    Mark J.A. & Maines M.D. (1992) Tin-protoporphyrin-mediated disruption in vivo of heme oxygenase-2 protein integrity and activity in rat brain.Pediatr. Res. 32,324329.
  • 30
    Marks G.S., Brien J.F., Nakatsu K., McLaughlin B.E. (1991) Does carbon monoxide have a physiological function ?Trends Pharmacol. Sci. 12,185188.
  • 31
    Matsuoka Y., Kitamura Y., Okazaki M., Kakimura J., Tooyama I., Kimura H., Taniguchi T. (1998) Kainic acid induction of heme oxygenase in vivo and in vitro.Neuroscience 85,12231233.
  • 32
    Matsuoka Y., Kitamura Y., Kakimura J., Taniguchi T. (1999) Expression of heme oxygenase-1 mediated by non-NMDA and metabotropic receptors in glial cells : possible involvement of reactive oxygen species production and protein kinase C activation.Neuropharmacology 38,825834.
  • 33
    Mattson M.P. (1996) Calcium and free radicals : mediators of neurotrophic factor and excitatory transmitter-regulated developmental plasticity and cell death.Perspect. Dev. Neurobiol. 3,7991.
  • 34
    McCoubrey W.J., Huang T.J., Maines M.D. (1997) Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3.Eur. J. Biochem. 247,725732.
  • 35
    McDonagh A.F. (1990) Is bilirubin good for you ?Clin. Perinatol. 17,359369.
  • 36
    Meldrum B. & Garthwaite J. (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease.Trends Pharmacol. Sci. 11,379387.
  • 37
    Miller T.M., Moulder K.I., Knudson C.M., Creedon D.J., Deshmukh M., Korsmeyer S.J., Johnson E.M.J r. (1997) Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death.J. Cell Biol. 139,205217.
  • 38
    Mosmann T. (1983) Rapid colorimetric assay for cellular growth and survival : application to proliferation and cytotoxicity assays.J. Immunol. Methods 65,5563.
  • 39
    Musser D.A. & Oseroff A.R. (1994) The use of tetrazolium salts to determine sites of damage to the mitochondrial electron transport chain in intact cells following in vitro photodynamic therapy with Photofrin II.Photochem. Photobiol. 59,621626.
  • 40
    Nicotera P., Ankarcrona M., Bonfoco E., Orrenius S., Lipton S.A. (1997) Neuronal necrosis and apoptosis : two distinct events induced by exposure to glutamate or oxidative stress.Adv. Neurol. 72,95101.
  • 41
    Otterbein L.E., Kolls J.K., Mantell L.L., Cook J.L., Alam J., Choi A.M. (1999) Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxiainduced lung injury.J. Clin. Invest. 103,10471054.
  • 42
    Panahian N., Yoshiura M., Maines M.D. (1999) Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice.J. Neurochem. 72,11871203.
  • 43
    Platt J.L. & Nath K.A. (1998) Heme oxygenase : protective gene or Trojan horse.Nat. Med. 4,13641366.
  • 44
    Raps S.P., Lai J.C., Hertz L., Cooper A.J. (1989) Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons.Brain Res. 493,398401.
  • 45
    Rosenkranz A.R., Schmaldienst S., Stuhlmeier K.M., Chen W., Knapp W., Zlabinger G.J. (1992) A microplate assay for the detection of oxidative products using 2′,7′-dichlorofluorescin-diacetate. J. Immunol. Methods 156,3945.
  • 46
    Rotenberg M.O. & Maines M.D. (1991) Characterization of a cDNA encoding rabbit brain heme oxygenase-2 and identification of a conserved domain among mammalian heme oxygenase isozymes : possible heme-binding site ?Arch. Biochem. Biophys. 290,336344.
  • 47
    Sano K., Nakamura H., Matsuo T. (1985) Mode of inhibitory action of bilirubin on protein kinase C.Pediatr. Res. 19,587590.
  • 48
    Schramm M., Eimerl S., Costa E. (1990) Serum and depolarizing agents cause acute neurotoxicity in cultured cerebellar granule cells : role of the glutamate receptor responsive to N-methyl-D-aspartate. Proc. Natl. Acad. Sci. USA 87,11931197.
  • 49
    Shibahara S., Muller R., Taguchi H., Yoshida T. (1985) Cloning and expression of cDNA for rat heme oxygenase.Proc. Natl. Acad. Sci. USA 82,78657869.
  • 50
    Simonian N.A. & Coyle J.T. (1996) Oxidative stress in neurodegenerative diseases.Annu. Rev. Pharmacol. Toxicol. 36,83106.
  • 51
    Smith M.A., Wehr K., Harris P.L.R., Siedlak S.L., Connor J.R., Perry G. (1998) Abnormal localization of iron regulatory protein in Alzheimer's disease.Brain Res. 788,232236.
  • 52
    Snyder S.H., Jaffrey S.R., Zakhary R. (1998) Nitric oxide and carbon monoxide : parallel roles as neural messengers.Brain Res. Brain Res. Rev. 26,167175.
  • 53
    Stout A.K., Raphael H.M., Kanterewicz B.I., Klann E., and Reynolds I.J. (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake.Nat. Neurosci. 1,366373.
  • 54
    Tan S., Wood M., Maher P. (1998) Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells.J. Neurochem. 71,95105.
  • 55
    Vile G.F. & Tyrrell R.M. (1993) Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin.J. Chem. Biol. 268,1467814681.
  • 56
    Vreman H.J., Ekstrand B.C., Stevenson D.K. (1993) Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity.Pediatr. Res. 33,195200.
  • 57
    Wolin M.S., Davidson C.A., Kaminski P.M., Fayngersh R.P., Mohazzab-H K.M. (1998) Oxidant—nitric oxide signalling mechanisms in vascular tissue. Biochemistry 63,810816.
  • 58
    Wu H. & Momand J. (1998) Pyrrolidine dithiocarbamate prevents P53 activation and promotes P53 cysteine residue oxidation.J. Biol. Chem. 273,1889818905.
  • 59
    Ye J. & Laychock S.G. (1998) A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-1beta.Endocrinology 139,41554163.