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Hemoglobin-derived Peptides as Novel Type of Bioactive Signaling Molecules

  • Review Article
  • Theme: Fishing for the Hidden Proteome in Health and Disease: Focus on Drug Abuse
  • Published:
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Abstract

Most bioactive peptides are generated by proteolytic cleavage of large precursor proteins followed by storage in secretory vesicles from where they are released upon cell stimulation. Examples of such bioactive peptides include peptide neurotransmitters, classical neuropeptides, and peptide hormones. In the last decade, it has become apparent that the breakdown of cytosolic proteins can generate peptides that have biological activity. A case in point and the focus of this review are hemoglobin-derived peptides. In vertebrates, hemoglobin (Hb) consists of a tetramer of two α- and two β-globin chains each containing a prosthetic heme group, and is primarily involved in oxygen delivery to tissues and in redox reactions (Schechter Blood 112:3927–3938, 2008). The presence of α- and/or β-globin chain in tissues besides red blood cells including rodent and human brain and peripheral tissues (Liu et al. Proc Natl Acad Sci USA 96:6643–6647, 1999; Newton et al. J Biol Chem 281:5668–5676, 2006; Wride et al. Mol Vis 9:360–396, 2003; Setton-Avruj Exp Neurol 203:568–578, 2007; Ohyagi et al. Brain Res 635:323–327, 1994; Schelshorn et al. J Cereb Blood Flow Metab 29:585–595, 2009; Richter et al. J Comp Neurol 515:538–547, 2009) suggests that globins and/or derived peptidic fragments might play additional physiological functions in different tissues. In support of this hypothesis, a number of Hb-derived peptides have been identified and shown to have diverse functions (Ivanov et al. Biopoly 43:171–188, 1997; Karelin et al. Neurochem Res 24:1117–1124, 1999). Modern mass spectrometric analyses have helped in the identification of additional Hb peptides (Newton et al. J Biol Chem 281:5668–5676, 2006; Setton-Avruj Exp Neurol 203:568–578, 2007; Gomes et al. FASEB J 23:3020–3029, 2009); the molecular targets for these are only recently beginning to be revealed. Here, we review the status of the Hb peptide field and highlight recent reports on the identification of a molecular target for a novel set of Hb peptides, hemopressins, and the implication of these peptides to normal cell function and disease. The potential therapeutic applications for these Hb-derived hemopressin peptides will also be discussed.

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References

  1. Fukui K, Shiomi H, Takagi H, Hayashi K, Kiso Y, Kitagawa K. Isolation from bovine brain of a novel analgesic peptapeptide, neo-kyotorphin, containing the Tyr-Arg (kyotorphin) unit. Neuropharmacology. 1983;22:191–6.

    Article  PubMed  CAS  Google Scholar 

  2. Brantl V, Gramsch C, Lottspeich F, Mertz R, Jaeger KH, Herz A. Novel opioid peptides derived from hemoglobin: hemorphins. Eur J Pharmacol. 1986;125:309–10.

    Article  PubMed  CAS  Google Scholar 

  3. Rioli V, Gozzo FC, Heimann AS, Linardi A, Krieger JE, Shida CS, et al. Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. J Biol Chem. 2003;278:8547–55.

    Article  PubMed  CAS  Google Scholar 

  4. Dale CS, Pagano Rde L, Rioli V. Hemopressin: a novel bioactive peptide derived from the alpha1-chain of hemoglobin. Mem Inst Oswaldo Cruz. 2005;100:105–6.

    Article  PubMed  CAS  Google Scholar 

  5. Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, et al. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci USA. 2007;104:20588–93.

    Article  PubMed  Google Scholar 

  6. Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, et al. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J. 2009;23(9):3020–9.

    Article  PubMed  CAS  Google Scholar 

  7. Nyberg F, Sanderson K, Glämsta EL. The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers. 1997;43:147–56.

    Article  PubMed  CAS  Google Scholar 

  8. Davis TP, Gillespie TJ, Porreca F. Peptide fragments derived from the beta-chain of hemoglobin (hemorphins) are centrally active in vivo. Peptides. 1989;10:747–51.

    Article  PubMed  CAS  Google Scholar 

  9. Zadina JE, Kastin AJ, Kersh D, Wyatt A. Tyr-MIF-1 and hemorphin can act as opiate agonists as well as antagonists in the guinea pig ileum. Life Sci. 1992;51:869–85.

    Article  PubMed  CAS  Google Scholar 

  10. Moeller I, Lew RA, Mendelsohn FA, Smith AI, Brennan ME, Tetaz TJ, et al. The globin fragment LVV-hemorphin-7 is an endogenous ligand for the AT4 receptor in the brain. J Neurochem. 1997;68:2530–7.

    Article  PubMed  CAS  Google Scholar 

  11. Moeller I, Albiston AL, Lew RA, Mendelsohn FA, Chai SY. A globin fragment, LVV-hemorphin-7, induces [3H]thymidine incorporation in a neuronal cell line via the AT4 receptor. J Neurochem. 1999;73:301–8.

    Article  PubMed  CAS  Google Scholar 

  12. Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001;276:48623–6.

    Article  PubMed  CAS  Google Scholar 

  13. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, et al. The angiotensin IV/AT4 receptor. Cell Mol Life Sci. 2004;61:2728–37.

    Article  PubMed  CAS  Google Scholar 

  14. Lew RA, Mustafa T, Ye S, McDowall SG, Chai SY, Albiston AL. Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP). J Neurochem. 2003;86:344–50.

    Article  PubMed  CAS  Google Scholar 

  15. Cejka J, Zelezná B, Velek J, Zicha J, Kunes J. LVV-hemorphin-7 lowers blood pressure in spontaneously hypertensive rats: radiotelemetry study. Physiol Res. 2004;53:603–7.

    PubMed  CAS  Google Scholar 

  16. Ianzer D, Konno K, Xavier CH, Stöcklin R, Santos RA, de Camargo AC, et al. Hemorphin and hemorphin-like peptides isolated from dog pancreas and sheep brain are able to potentiate bradykinin activity in vivo. Peptides. 2006;27:2957–66.

    Article  PubMed  CAS  Google Scholar 

  17. Fruitier-Arnaudin I, Cohen M, Bordenave S, Sannier F, Piot JM. Comparative effects of angiotensin IV and two hemorphins on angiotensin-converting enzyme activity. Peptides. 2002;23:1465–70.

    Article  PubMed  CAS  Google Scholar 

  18. Lee J, Albiston AL, Allen AM, Mendelsohn FA, Ping SE, Barrett GL, et al. Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats. Neuroscience. 2004;124:341–9.

    Article  PubMed  CAS  Google Scholar 

  19. Albiston AL, Pederson ES, Burns P, Purcell B, Wright JW, Harding JW, et al. Attenuation of scopolamine-induced learning deficits by LVV-hemorphin-7 in rats in the passive avoidance and water maze paradigms. Behav Brain Res. 2004;154:239–43.

    Article  PubMed  CAS  Google Scholar 

  20. Herbst JJ, Ross SA, Scott HM, Bobin SA, Morris NJ, Lienhard GE, et al. Insulin stimulates cell surface aminopeptidase activity toward vasopressin in adipocytes. Am J Physiol. 1997;272:E600–6.

    PubMed  CAS  Google Scholar 

  21. Matsumoto H, Nagasaka T, Hattori A, Rogi T, Tsuruoka N, Mizutani S, et al. Expression of placental leucine aminopeptidase/oxytocinase in neuronal cells and its action on neuronal peptides. Eur J Biochem. 2001;268:3259–66.

    Article  PubMed  CAS  Google Scholar 

  22. Kovacs GL, De Wied D. Peptidergic modulation of learning and memory processes. Pharmacol Rev. 1994;46:269–91.

    PubMed  CAS  Google Scholar 

  23. Engelmann M, Wotjak CT, Neumann I, Ludwig M, Landgraf R. (1996) Behavioural consequences of intracerebral vasopressin and oxytocin: focus on learning and memory. Neurosci Biobehav Rev. 1996;20:341–58.

    Article  PubMed  CAS  Google Scholar 

  24. Lee J, Chai SY, Mendelsohn FA, Morris MJ, Allen AM. Potentiation of cholinergic transmission in the rat hippocampus by angiotensin IV and LVV-hemorphin-7. Neuropharmacology. 2001;40:618–23.

    Article  PubMed  CAS  Google Scholar 

  25. Fernando RN, Albiston AL, Chai SY. The insulin-regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus-potential role in modulation of glucose uptake in neurones? Eur J Neurosci. 2008;28:588–98.

    Article  PubMed  Google Scholar 

  26. De Bundel D, Smolders I, Yang R, Albiston AL, Michotte Y, Chai SY. Angiotensin IV and LVV-haemorphin 7 enhance spatial working memory in rats: effects on hippocampal glucose levels and blood flow. Neurobiol Learn Mem. 2009;92:19–26.

    Article  PubMed  CAS  Google Scholar 

  27. Lammerich HP, Busmann A, Kutzleb C, Wendland M, Seiler P, Berger C, et al. Identification and functional characterization of hemorphins VV-H-7 and LVV-H-7 as low-affinity agonists for the orphan bombesin receptor subtype 3. Br J Pharmacol. 2003;138:1431–40.

    Article  PubMed  CAS  Google Scholar 

  28. Collinder E, Nyberg F, Sanderson-Nydahl K, Gottlieb-Vedi M, Lindholm A. The opioid haemorphin-7 in horses during low-speed and high-speed treadmill exercise to fatigue. J Vet Med A Physiol Pathol Clin Med. 2005;52:162–5.

    PubMed  CAS  Google Scholar 

  29. Feron D, Begu-Le Corroller A, Piot JM, Frelicot C, Vialettes B, Fruitier-Arnaudin I. Significant lower VVH7-like immunoreactivity serum level in diabetic patients: evidence for independence from metabolic control and three key enzymes in hemorphin metabolism, cathepsin D, ACE and DPP-IV. Peptides. 2009;30:256–61.

    Article  PubMed  CAS  Google Scholar 

  30. Poljak A, McLean CA, Sachdev P, Brodaty H, Smythe GA. Quantification of hemorphins in Alzheimer's disease brains. J Neurosci Res. 2004;75:704–14.

    Article  PubMed  CAS  Google Scholar 

  31. Fruitier I, Garreau I, Lacroix A, Cupo A, Piot JM. Proteolytic degradation of hemoglobin by endogenous lysosomal proteases gives rise to bioactive peptides: hemorphins. FEBS Lett. 1999;447:81–6.

    Article  PubMed  CAS  Google Scholar 

  32. Choisnard L, Durand D, Vercaigne-Marko D, Nedjar-Arroume N, Dhulster P, Guillochon D. A simple method for the two-step preparation of two pure haemorphins from a total haemoglobin peptic hydrolysate by conventional low-pressure chromatographies. Biotechnol Appl Biochem. 2001;34:173–81.

    Article  PubMed  CAS  Google Scholar 

  33. Piot JM, Zhao Q, Guillochon D, Ricart G, Thomas D. Isolation and characterization of two opioid peptides from a bovine hemoglobin peptic hydrolysate. Biochem Biophys Res Commun. 1992;89:101–10.

    Article  Google Scholar 

  34. Jinsmaa Y, Yoshikawa M. Release of hemorphin-5 from human hemoglobin by pancreatic elastase. Biosci Biotechnol Biochem. 2002;66:1130–2.

    Article  PubMed  CAS  Google Scholar 

  35. Garreau I, Cucumel K, Dagouassat N, Zhao Q, Cupo A, Piot JM. Hemorphin peptides are released from hemoglobin by cathepsin D. radioimmunoassay against the C-part of V-V-hemorphin-7: an alternative assay for the cathepsin D activity. Peptides. 1997;18:293–300.

    Article  PubMed  CAS  Google Scholar 

  36. Fruitier I, Garreau I, Piot JM. Cathepsin D is a good candidate for the specific release of a stable hemorphin from hemoglobin in vivo: VV-hemorphin-7. Biochem Biophys Res Commun. 1998;246:719–24.

    Article  PubMed  CAS  Google Scholar 

  37. Fruitier-Arnaudin I, Cohen M, Coitoux C, Piot JM. In vitro metabolism of LVV-hemorphin-7 by renal cytosol and purified prolyl endopeptidase. Peptides. 2003;24:1201–6.

    Article  PubMed  CAS  Google Scholar 

  38. Murillo L, Piot JM, Coitoux C, Fruitier-Arnaudin I. Brain processing of hemorphin-7 peptides in various subcellular fractions from rats. Peptides. 2006;27:3331–40.

    Article  PubMed  CAS  Google Scholar 

  39. John H, Schulz S, Forssmann WG. Comparative in vitro degradation of the human hemorphin LVV-H7 in mammalian plasma analysed by capillary zone electrophoresis and mass spectrometry. Biopharm Drug Dispos. 2007;28:73–85.

    Article  PubMed  CAS  Google Scholar 

  40. Cohen M, Fruitier-Arnaudin I, Piot JM. Hemorphins: substrates and/or inhibitors of dipeptidyl peptidase IV. Hemorphins N-terminus sequence influence on the interaction between hemorphins and DPPIV. Biochimie. 2004;86:31–7.

    Article  PubMed  CAS  Google Scholar 

  41. Fernando RN, Luff SE, Albiston AL, Chai SY. Sub-cellular localization of insulin-regulated membrane aminopeptidase, IRAP to vesicles in neurons. J Neurochem. 2007;102:967–76.

    Article  PubMed  CAS  Google Scholar 

  42. Kiso Y, Kitagawa K, Kawai N, Akita T, Takagi H, Amano H, et al. Neo-kyotorphin (Thr-Ser-Lys-Tyr-Arg), a new analgesic peptide. FEBS Lett. 1983;155:281–4.

    Article  PubMed  CAS  Google Scholar 

  43. Ueda H, Ge M, Satoh M, Takagi H. Non-opioid analgesia of the neuropeptide, neo-kyotorphin and possible mediation by inhibition of GABA release in the mouse brain. Peptides. 1987;8:905–9.

    Article  PubMed  CAS  Google Scholar 

  44. Kolaeva SH, Lee TF, Wang LC, Paproski SM. Effect of intracerebroventricular injection of neokyotorphin on the thermoregulatory responses in rats. Brain Res Bull. 1990;25:407–10.

    Article  PubMed  CAS  Google Scholar 

  45. Godlevsky LS, Shandra AA, Mikhaleva II, Vastyanov RS, Mazarati AM. Seizure-protecting effects of kyotorphin and related peptides in an animal model of epilepsy. Brain Res Bull. 1995;37:223–6.

    Article  PubMed  CAS  Google Scholar 

  46. Pokrovsky VM, Osadchiy OE. Regulatory peptides as modulators of vagal influence on cardiac rhythm. Can J Physiol Pharmacol. 1995;73:1235–45.

    PubMed  CAS  Google Scholar 

  47. Nedjar-Arroume N, Dubois-Delval V, Miloudi K, Daoud R, Krier F, Kouach M, et al. Isolation and characterization of four antibacterial peptides from bovine hemoglobin. Peptides. 2006;27:2082–9.

    Article  PubMed  CAS  Google Scholar 

  48. Popova IY, Vinogradova OS, Kokoz YM, Ziganshin RKh, Ivanov VT. Neuropeptide modulation of evoked responses of neurons in the medial septal region of hibernating ground squirrels in conditions of chronic isolation of the medial septal region from preoptic-hypothalamic structures. Neurosci Behav Physiol. 2003;33:521–8.

    Article  PubMed  Google Scholar 

  49. Bronnikov GE, Kolaeva SG, Dolgacheva LP, Kramarova LI. Kyotorphin suppresses proliferation and Ca2 + signaling in brown preadipocytes. Bull Exp Biol Med. 2006;141:223–5.

    Article  PubMed  CAS  Google Scholar 

  50. Blishchenko EY, Kalinina OA, Sazonova OV, Khaidukov SV, Egorova NS, Surovoy AY, et al. Endogenous fragment of hemoglobin, neokyotorphin, as cell growth factor. Peptides. 2001;22:1999–2008.

    Article  PubMed  CAS  Google Scholar 

  51. Sazonova OV, Blishchenko EY, Kalinina OA, Egorova NS, Surovoy AY, Philippova MM, et al. Proliferative activity of neokyotorphin-related hemoglobin fragments in cell cultures. Protein Pept Lett. 2003;10:386–95.

    Article  PubMed  CAS  Google Scholar 

  52. Sazonova OV, Blishchenko EY, Tolmazova AG, Khachin DP, Leontiev KV, Karelin AA, et al. Stimulation of fibroblast proliferation by neokyotorphin requires Ca influx and activation of PKA, CaMK II and MAPK/ERK. FEBS J. 2007;274:474–84.

    Article  PubMed  CAS  Google Scholar 

  53. Hazato T, Kase R, Ueda H, Takagi H, Katayama T. Inhibitory effects of the analgesic neuropeptides kyotorphin and neo-kyotorphin on enkephalin-degrading enzymes from monkey brain. Biochem Int. 1986;12:379–83.

    PubMed  CAS  Google Scholar 

  54. Ticu EL, Vercaigne-Marko D, Huma A, Artenie V, Toma O, Guillochon D. A kinetic study of bovine haemoglobin hydrolysis by pepsin immobilized on a functionalized alumina to prepare hydrolysates containing bioactive peptides. Biotechnol Appl Biochem. 2004;39:199–208.

    Article  PubMed  CAS  Google Scholar 

  55. Lignot B, Froidevaux R, Nedjar-Arroume N, Guillochon D. Solvent effect on kinetics of appearance of neokyotorphin, VV-haemorphin-4 and a bradykinin-potentiating peptide in the course of peptic hydrolysis of bovine haemoglobin. Biotechnol Appl Biochem. 1999;30:201–7.

    PubMed  CAS  Google Scholar 

  56. Zhao Q, Piot JM. Neokyotorphin formation and quantitative evolution following human hemoglobin hydrolysis with cathepsin D. Peptides. 1998;19:759–66.

    Article  PubMed  CAS  Google Scholar 

  57. Kase R, Sekine R, Katayama T, Takagi H, Hazato T. Hydrolysis of neo-kyotorphin (Thr-Ser-Lys-Tyr-Arg) and [Met]enkephalin-Arg6-Phe7 by angiotensin-converting enzyme from monkey brain. Biochem Pharmacol. 1986;35:4499–503.

    Article  PubMed  CAS  Google Scholar 

  58. Shiomi H, Kuraishi Y, Ueda H, Harada Y, Amano H, Takagi H. Mechanism of kyotorphin-induced release of Met-enkephalin from guinea pig striatum and spinal cord. Brain Res. 1981;221:161–9.

    Article  PubMed  CAS  Google Scholar 

  59. Moisan S, Harvey N, Beaudry G, Forzani P, Burhop KE, Drapeau G, et al. Structural requirements and mechanism of the pressor activity of Leu-Vall_Val-hemorphin-7, a fragment of hemoglobin beta-chain in rats. Peptides. 1998;19:119–31.

    Article  PubMed  CAS  Google Scholar 

  60. Dagouassat N, Garreau I, Zhao Q, Sannier F, Piot JM. Kinetic of in vitro generation of some hemorphins: early release of LVV-hemorphin-7, precursor of VV-hemorphin-7. Neuropeptides. 1996;30:1–5.

    Article  PubMed  CAS  Google Scholar 

  61. Blais PA, Cote J, Morin J, Larouche A, Gendron G, Fortier A, et al. Hypotensive effects of hemopressin and bradykinin in rabbits, rats and mice. A comparative study. Peptides. 2005;26:1317–22.

    Article  PubMed  CAS  Google Scholar 

  62. Lippton H, Lin B, Gumusel B, Witriol N, Wasserman A, Knight M. Hemopressin, a hemoglobin fragment, dilates the rat systemic vascular bed through the release of nitric oxide. Peptides. 2006;27:2284–8.

    Article  PubMed  CAS  Google Scholar 

  63. Dale CS, de Lima Pagano R, Rioli V, Hyslop S, Giorgi R, Ferro ES. Antinociceptive action of hemopressin in experimental hyperalgesia. Peptides. 2005;26:431–6.

    Article  PubMed  CAS  Google Scholar 

  64. Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Thér. 1957;111:409–19.

    PubMed  CAS  Google Scholar 

  65. Gupta A, Décaillot FM, Gomes I, Tkalych O, Heimann AS, Ferro ES, et al. Conformation state-sensitive antibodies to G-protein-coupled receptors. J Biol Chem. 2007;282:5116–24.

    Article  PubMed  CAS  Google Scholar 

  66. Dodd GT, Mancini G, Lutz B, Luckman SM. The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J Neurosci. 2010;30:7369–76.

    Article  PubMed  CAS  Google Scholar 

  67. Shoji M. Cerebrospinal fluid Abeta40 and Abeta42: natural course and clinical usefulness. Front Biosci. 2002;7:d997–1006.

    Article  PubMed  CAS  Google Scholar 

  68. Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, et al. Beta-amyloid monomers are neuroprotective. J Neurosci. 2009;29:10582–7.

    Article  PubMed  CAS  Google Scholar 

  69. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9.

    Article  PubMed  CAS  Google Scholar 

  70. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–42.

    Article  PubMed  CAS  Google Scholar 

  71. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998;95:6448–53.

    Article  PubMed  CAS  Google Scholar 

  72. Arevalo MA, Roldan PM, Chacón PJ, Rodríguez-Tebar A. Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration. J Neurochem. 2009;111:1425–33.

    Article  PubMed  CAS  Google Scholar 

  73. Watson D, Castaño E, Kokjohn TA, Kuo YM, Lyubchenko Y, Pinsky D, et al. Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease. Neurol Res. 2005;27:869–81.

    Article  PubMed  CAS  Google Scholar 

  74. Bhaskaran M, Chen H, Chen Z, Liu L. Hemoglobin is expressed in alveolar epithelial type II cells. Biochem Biophys Res Commun. 2005;333:1348–52.

    Article  PubMed  CAS  Google Scholar 

  75. Newton DA, Rao KM, Dluhy RA, Baatz JE. Hemoglobin is expressed by alveolar epithelial cells. J Biol Chem. 2006;281:5668–76.

    Article  PubMed  CAS  Google Scholar 

  76. Wride MA, Mansergh FC, Adams S, Everitt R, Minnema SE, Rancourt DE, et al. Expression profiling and gene discovery in the mouse lens. Mol Vis. 2003;9:360–96.

    PubMed  CAS  Google Scholar 

  77. Liu L, Zeng M, Stamler JS. Hemoglobin induction in mouse macrophages. Proc Natl Acad Sci USA. 1999;96:6643–7.

    Article  PubMed  CAS  Google Scholar 

  78. Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I, Son D, et al. Hemoglobin is expressed by mesangial cells and reduces oxidant stress. J Am Soc Nephrol. 2008;19:1500–8.

    Article  PubMed  CAS  Google Scholar 

  79. Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P, et al. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci USA. 2009;106:15454–9.

    Article  PubMed  Google Scholar 

  80. Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF. Neurons express hemoglobin alpha- and beta chains in rat and human brains. J Comp Neurol. 2009;515:538–47.

    Article  PubMed  CAS  Google Scholar 

  81. Schelshorn DW, Schneider A, Kuschinsky W, Weber D, Krüger C, Dittgen T, et al. Expression of hemoglobin in rodent neurons. J Cereb Blood Flow Metab. 2009;29:585–95.

    Article  PubMed  CAS  Google Scholar 

  82. Dugas JC, Tai YC, Speed TP, Ngai J. Barres BA Functional genomic analysis of oligodendrocyte differentiation. J Neurosci. 2006;26:10967–83.

    Article  PubMed  CAS  Google Scholar 

  83. Setton-Avruj CP, Musolino PL, Salis C, Allo M, Bizzozero O, Villar MJ, et al. Presence of alpha-globin mRNA and migration of bone marrow cells after sciatic nerve injury suggests their participation in the degeneration/regeneration process. Exp Neurol. 2007;203:568–78.

    Article  PubMed  CAS  Google Scholar 

  84. Hook V, Funkelstein L, Lu D, Bark S, Wegrzyn J, Hwang SR. Proteases for processing proneuropeptides into peptide neurotransmitters and hormones. Annu Rev Pharmacol Toxicol. 2008;48:393–423.

    Article  PubMed  CAS  Google Scholar 

  85. Wenzel T, Baumeister W. Thermoplasma acidophilum proteasomes degrade partially unfolded and ubiquitin-associated proteins. FEBS Lett. 1993;326:215–8.

    Article  PubMed  CAS  Google Scholar 

  86. Pacifici RE, Kono Y, Davies KJ. Hydrophobicity as the signal for selective degradation of hydroxyl radical-modified hemoglobin by the multicatalytic proteinase complex, proteasome. J Biol Chem. 1993;268:15405–11.

    PubMed  CAS  Google Scholar 

  87. Tai HC, Schuman EM. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci. 2008;9:826–38.

    Article  PubMed  CAS  Google Scholar 

  88. Kisselev AF, Akopian TN, Woo KM, Goldberg AL. The sizes of peptides generated from protein by mammalian 26 and 20S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. J Biol Chem. 1999;274:3363–71.

    Article  PubMed  CAS  Google Scholar 

  89. Nickel W, Rabouille C. Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol. 2009;10:148–55. Erratum in: Nat. Rev. Mo.l Cell Biol. 2009.

    Article  PubMed  CAS  Google Scholar 

  90. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–92.

    Article  PubMed  CAS  Google Scholar 

  91. Procko E, Gaudet R. Antigen processing and presentation: TAPping into ABC transporters. Curr Opin Immunol. 2009;21:84–91.

    Article  PubMed  CAS  Google Scholar 

  92. Procko E, O'Mara ML, Bennett WF, Tieleman DP, Gaudet R. The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter. FASEB J. 2009;23:1287–302.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by NIH grants DA019521 and GM071558 to LAD; FAPESP grants 04/04933-2 to ESF and 04/14258-0 to ASH and CNPq (to ESF).

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Correspondence to Andrea S. Heimann or Lakshmi A. Devi.

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Guest Editors: Rao S. Rapaka, Lloyd D. Fricker, and Jonathan V. Sweedler

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Gomes, I., Dale, C.S., Casten, K. et al. Hemoglobin-derived Peptides as Novel Type of Bioactive Signaling Molecules. AAPS J 12, 658–669 (2010). https://doi.org/10.1208/s12248-010-9217-x

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