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Brain Alpha- and Beta-Globin Expression after Intracerebral Hemorrhage

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Abstract

Our recent study has demonstrated that hemoglobin (Hb) is present in cerebral neurons, and neuronal Hb is inducible after cerebral ischemia. In the present study, we examined the effects of intracerebral hemorrhage (ICH) on the messenger RNA (mRNA) levels of the α-globin (HbA) and the β-globin (HbB) components of Hb and Hb protein in the brain in vivo and in vitro. In vivo, male Sprague–Dawley rats received either a needle insertion (sham) or an infusion of autologous whole blood into the basal ganglia and were killed at different time points. In vitro, cultured rat brain cells were used for HbA, HbB, and Hb determination. Cultured neurons were exposed to 50 or 100 µM hemin for 24 h. Some neurons also were treated with deferoxamine, an iron chelator, or vehicle. Levels of HbA and HbB, Hb, and hemopexin, a transporter of heme, were measured. We found that HbA, HbB, and Hb are primarily expressed in neurons, with much lower expression in astrocytes and microglia. HbA, HbB, and Hb expression in the perihematomal zone was increased after ICH and Hb was localized in neurons and glia. Hemin increased HbA, HbB, and hemopexin mRNA levels in cultured neurons. Deferoxamine reduced hemin-induced neuronal Hb expression. ICH increased HbA and HbB expression in the brain, which may potentially serve to buffer the heme released during clot resolution.

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References

  1. Hardison R (1998) Hemoglobins from bacteria to man: evolution of different patterns of gene expression. J Exp Biol 201(Pt 8):1099–1117

    CAS  PubMed  Google Scholar 

  2. Poyart C, Wajcman H, Kister J (1992) Molecular adaptation of hemoglobin function in mammals. Respir Physiol 90(1):3–17

    Article  CAS  PubMed  Google Scholar 

  3. Schelshorn DW, Schneider A, Kuschinsky W, Weber D, Kruger C, Dittgen T et al (2009) Expression of hemoglobin in rodent neurons. JCereb Blood Flow Metab 29(3):585–595

    Article  CAS  Google Scholar 

  4. Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF (2009) Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol 515(5):538–547

    Article  CAS  PubMed  Google Scholar 

  5. He Y, Hua Y, Liu W, Hu H, Keep RF, Xi G (2009) Effects of cerebral ischemia on neuronal hemoglobin. J Cereb Blood Flow Metab 29(3):596–605

    Article  CAS  PubMed  Google Scholar 

  6. Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89(6):991–996

    Article  CAS  PubMed  Google Scholar 

  7. Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5(1):53–63

    Article  PubMed  Google Scholar 

  8. Sadrzadeh SM, Anderson DK, Panter SS, Hallaway PE, Eaton JW (1987) Hemoglobin potentiates central nervous system damage. J Clin Invest 79(2):662–664

    Article  CAS  PubMed  Google Scholar 

  9. Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT (2002) Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg 96(2):287–293

    Article  PubMed  Google Scholar 

  10. Regan RF, Panter SS (1993) Neurotoxicity of hemoglobin in cortical cell culture. Neurosci Lett 153(2):219–222

    Article  CAS  PubMed  Google Scholar 

  11. Wang X, Mori T, Sumii T, Lo EH (2002) Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33(7):1882–1888

    Article  CAS  PubMed  Google Scholar 

  12. Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23(6):629–652

    Article  CAS  PubMed  Google Scholar 

  13. Rutherford TR, Clegg JB, Weatherall DJ (1979) K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin. Nature 280(5718):164–165

    Article  CAS  PubMed  Google Scholar 

  14. Fibach E, Kollia P, Schechter AN, Noguchi CT, Rodgers GP (1995) Hemin-induced acceleration of hemoglobin production in immature cultured erythroid cells: preferential enhancement of fetal hemoglobin. Blood 85(10):2967–2974

    CAS  PubMed  Google Scholar 

  15. Jiang Y, Wu J, Hua Y, Keep RF, Xiang J, Hoff JT et al (2002) Thrombin-receptor activation and thrombin-induced brain tolerance. J Cereb Blood Flow Metab 22(4):404–410

    Article  CAS  PubMed  Google Scholar 

  16. McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85(3):890–902

    Article  CAS  PubMed  Google Scholar 

  17. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  18. Xi G, Keep RF, Hua Y, Xiang J, Hoff JT (1999) Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 30(6):1247–1255

    CAS  PubMed  Google Scholar 

  19. Liu L, Zeng M, Stamler JS (1999) Hemoglobin induction in mouse macrophages. Proc Natl Acad Sci USA 96(12):6643–6647

    Article  CAS  PubMed  Google Scholar 

  20. Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I, Son D et al (2008) Hemoglobin is expressed by mesangial cells and reduces oxidant stress. J Am Soc Nephrol 19(8):1500–1508

    Article  CAS  PubMed  Google Scholar 

  21. Newton DA, Rao KM, Dluhy RA, Baatz JE (2006) Hemoglobin is expressed by alveolar epithelial cells. J Biol Chem 281(9):5668–5676

    Article  CAS  PubMed  Google Scholar 

  22. Ohyagi Y, Yamada T, Goto I (1994) Hemoglobin as a novel protein developmentally regulated in neurons. Brain Res 635(1–2):323–327

    Article  CAS  PubMed  Google Scholar 

  23. Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC et al (2003) Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 23(9):3807–3819

    CAS  PubMed  Google Scholar 

  24. Slemmon JR, Hughes CM, Campbell GA, Flood DG (1994) Increased levels of hemoglobin-derived and other peptides in Alzheimer's disease cerebellum. J Neurosci 14(4):2225–2235

    CAS  PubMed  Google Scholar 

  25. Wu CW, Liao PC, Yu L, Wang ST, Chen ST, Wu CM et al (2004) Hemoglobin promotes Abeta oligomer formation and localizes in neurons and amyloid deposits. Neurobiol Dis 17(3):367–377

    Article  CAS  PubMed  Google Scholar 

  26. Leffers H, Navarro VM, Nielsen JE, Mayen A, Pinilla L, Dalgaard M et al (2006) Increased expression of alpha- and beta-globin mRNAs at the pituitary following exposure to estrogen during the critical period of neonatal sex differentiation in the rat. J Steroid Biochem Mol Biol 99(1):33–43

    Article  CAS  PubMed  Google Scholar 

  27. Tahara T, Sun J, Igarashi K, Taketani S (2004) Heme-dependent up-regulation of the alpha-globin gene expression by transcriptional repressor Bach1 in erythroid cells. Biochem Biophys Res Commun 324(1):77–85

    Article  CAS  PubMed  Google Scholar 

  28. Tahara T, Sun J, Nakanishi K, Yamamoto M, Mori H, Saito T et al (2004) Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells. J Biol Chem 279(7):5480–5487

    Article  CAS  PubMed  Google Scholar 

  29. Zhu Y, Sun Y, Jin K, Greenberg DA (2002) Hemin induces neuroglobin expression in neural cells. Blood 100(7):2494–2498

    Article  CAS  PubMed  Google Scholar 

  30. Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G (2003) Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 34(12):2964–2969

    Article  CAS  PubMed  Google Scholar 

  31. Vincent SR, Das S, Maines MD (1994) Brain heme oxygenase isoenzymes and nitric oxide synthase are co-localized in select neurons. Neuroscience 63(1):223–231

    Article  CAS  PubMed  Google Scholar 

  32. Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P et al (2009) Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci USA 106(36):15454–15459

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants NS-017760, NS-039866, NS-047245 NS-052510, and NS-057539 from the National Institutes of Health (NIH) and 0755717Z and 0840016N from American Heart Association (AHA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and AHA. MMW is supported by NS-062816 and NS-054724.

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Correspondence to Guohua Xi.

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He, Y., Hua, Y., Lee, JY. et al. Brain Alpha- and Beta-Globin Expression after Intracerebral Hemorrhage. Transl. Stroke Res. 1, 48–56 (2010). https://doi.org/10.1007/s12975-009-0004-x

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  • DOI: https://doi.org/10.1007/s12975-009-0004-x

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