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Immenschuh S, Vijayan V, Janciauskiene S, et al. Heme as a Target for Therapeutic Interventions. Front Pharmacol. 2017;8:146doi: 10.3389/fphar.2017.00146.
Immenschuh, S., Vijayan, V., Janciauskiene, S., & Gueler, F. (2017). Heme as a Target for Therapeutic Interventions. Frontiers in pharmacology, 8146. https://doi.org/10.3389/fphar.2017.00146
Immenschuh, Stephan, et al. "Heme as a Target for Therapeutic Interventions." Frontiers in pharmacology vol. 8 (2017): 146. doi: https://doi.org/10.3389/fphar.2017.00146
Immenschuh S, Vijayan V, Janciauskiene S, Gueler F. Heme as a Target for Therapeutic Interventions. Front Pharmacol. 2017 Apr 04;8:146. doi: 10.3389/fphar.2017.00146. eCollection 2017. PMID: 28420988; PMCID: PMC5378770.
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Front Pharmacol. 2017 Apr 04;8:146. doi: 10.3389/fphar.2017.00146. eCollection 2017.

Heme as a Target for Therapeutic Interventions.

Frontiers in pharmacology

Stephan Immenschuh, Vijith Vijayan, Sabina Janciauskiene, Faikah Gueler

Affiliations

  1. Institute for Transfusion Medicine, Hannover Medical SchoolHannover, Germany.
  2. Department of Pulmonology, Hannover Medical SchoolHannover, Germany.
  3. Department of Nephrology, Hannover Medical SchoolHannover, Germany.

PMID: 28420988 PMCID: PMC5378770 DOI: 10.3389/fphar.2017.00146

Abstract

Heme is a complex of iron and the tetrapyrrole protoporphyrin IX with essential functions in aerobic organisms. Heme is the prosthetic group of hemoproteins such as hemoglobin and myoglobin, which are crucial for reversible oxygen binding and transport. By contrast, high levels of free heme, which may occur in various pathophysiological conditions, are toxic via pro-oxidant, pro-inflammatory and cytotoxic effects. The toxicity of heme plays a major role for the pathogenesis of prototypical hemolytic disorders including sickle cell disease and malaria. Moreover, there is increasing appreciation that detrimental effects of heme may also be critically involved in diseases, which usually are not associated with hemolysis such as severe sepsis and atherosclerosis. In mammalians homeostasis of heme and its potential toxicity are primarily controlled by two physiological systems. First, the scavenger protein hemopexin (Hx) non-covalently binds extracellular free heme with high affinity and attenuates toxicity of heme in plasma. Second, heme oxygenases (HOs), in particular the inducible HO isozyme, HO-1, can provide antioxidant cytoprotection via enzymatic degradation of intracellular heme. This review summarizes current knowledge on the pathophysiological role of heme for various diseases as demonstrated in experimental animal models and in humans. The functional significance of Hx and HOs for the regulation of heme homeostasis is highlighted. Finally, the therapeutic potential of pharmacological strategies that apply Hx and HO-1 in various clinical settings is discussed.

Keywords: heme; heme oxygenases; heme toxicity; hemolysis; hemopexin; inflammation; inflammatory diseases

References

  1. Kidney Int. 1995 Feb;47(2):592-602 - PubMed
  2. Semin Hematol. 1989 Apr;26(2):105-13 - PubMed
  3. Blood. 2013 Feb 21;121(8):1276-84 - PubMed
  4. Blood. 2013 Jul 11;122(2):282-92 - PubMed
  5. Nat Struct Biol. 1999 Oct;6(10):926-31 - PubMed
  6. Nat Med. 2007 Jun;13(6):703-10 - PubMed
  7. Proc Natl Acad Sci U S A. 1988 Jan;85(1):237-41 - PubMed
  8. J Biol Chem. 1975 Dec 25;250(24):9215-25 - PubMed
  9. Cell. 2014 Mar 13;156(6):1223-34 - PubMed
  10. Arch Biochem Biophys. 1988 Sep;265(2):539-50 - PubMed
  11. Arch Biochem Biophys. 1993 Jan;300(1):98-104 - PubMed
  12. Blood. 2014 Jun 12;123(24):3818-27 - PubMed
  13. Mol Med. 2016 Jul 19;22:null - PubMed
  14. J Am Coll Cardiol. 2013 May 7;61(18):1884-93 - PubMed
  15. Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):229-36 - PubMed
  16. Biochem Pharmacol. 2010 Dec 15;80(12 ):1895-903 - PubMed
  17. Blood. 1972 Dec;40(6):812-22 - PubMed
  18. Crit Care Med. 1991 Jul;19(7):973-6 - PubMed
  19. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1347-53 - PubMed
  20. Blood. 2012 Nov 1;120(18):3822-8 - PubMed
  21. Biochem J. 1967 Apr;103(1):1-18 - PubMed
  22. J Infect Dis. 2010 Aug 15;202(4):624-32 - PubMed
  23. Neuron. 1995 Oct;15(4):867-73 - PubMed
  24. J Immunol. 2006 Apr 1;176(7):4252-7 - PubMed
  25. Blood. 1982 Nov;60(5):1227-30 - PubMed
  26. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12 - PubMed
  27. Am J Respir Cell Mol Biol. 1995 Nov;13(5):595-601 - PubMed
  28. J Hepatol. 1999 Jan;30(1):61-9 - PubMed
  29. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8423-7 - PubMed
  30. J Biol Chem. 1994 Apr 29;269(17):12654-61 - PubMed
  31. BMJ. 2016 May 23;353:i1585 - PubMed
  32. Blood. 1968 Nov;32(5):811-5 - PubMed
  33. Cell. 1990 Nov 2;63(3):643-53 - PubMed
  34. Blood. 1999 Dec 1;94(11):3906-14 - PubMed
  35. Antioxid Redox Signal. 2010 Feb;12(2):305-20 - PubMed
  36. J Exp Med. 2009 May 11;206(5):1167-79 - PubMed
  37. Circulation. 2004 Sep 7;110(10 ):1296-302 - PubMed
  38. Trends Mol Med. 2016 Mar;22(3):200-13 - PubMed
  39. Cancer Sci. 2010 Jun;101(6):1409-16 - PubMed
  40. J Neuroinflammation. 2016 Feb 01;13:26 - PubMed
  41. Front Physiol. 2015 Jun 30;6:187 - PubMed
  42. Circulation. 2013 Mar 26;127(12):1317-29 - PubMed
  43. Free Radic Biol Med. 2005 Jul 1;39(1):1-25 - PubMed
  44. Crit Care. 2015 Apr 15;19:166 - PubMed
  45. Blood. 2001 Sep 15;98 (6):1802-11 - PubMed
  46. Am J Physiol Renal Physiol. 2004 Mar;286(3):F425-41 - PubMed
  47. Proc Natl Acad Sci U S A. 2016 Aug 30;113(35):E5144-52 - PubMed
  48. Front Pharmacol. 2012 May 04;3:77 - PubMed
  49. Blood. 2016 Jan 28;127(4):473-86 - PubMed
  50. Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55 - PubMed
  51. Semin Hematol. 1989 Apr;26(2):86-104 - PubMed
  52. J Am Heart Assoc. 2015 Jul 31;4(8):e002272 - PubMed
  53. J Infect Dis. 2016 Oct 15;214(8):1268-75 - PubMed
  54. J Biol Chem. 1986 Aug 25;261(24):11131-7 - PubMed
  55. Blood. 2014 Jan 16;123(3):377-90 - PubMed
  56. J Clin Invest. 2012 Apr;122(4):1444-58 - PubMed
  57. Endocrinology. 2009 May;150(5):2098-108 - PubMed
  58. J Clin Invest. 2005 Nov;115(11):3007-14 - PubMed
  59. J Immunol. 2010 Jul 15;185(2):1196-204 - PubMed
  60. Free Radic Biol Med. 2004 Oct 15;37(8):1097-104 - PubMed
  61. Antioxid Redox Signal. 2014 Apr 10;20(11):1810-26 - PubMed
  62. Nature. 1960 Dec 10;188:913-5 - PubMed
  63. Annu Rev Pharmacol Toxicol. 2010;50:323-54 - PubMed
  64. Nature. 2002 Feb 7;415(6872):673-9 - PubMed
  65. Clin Exp Immunol. 2005 Jun;140(3):547-55 - PubMed
  66. Am J Hum Genet. 2000 Jan;66(1):187-95 - PubMed
  67. Hum Gene Ther. 2011 Mar;22(3):271-82 - PubMed
  68. Free Radic Biol Med. 2013 Dec;65:908-15 - PubMed
  69. Proc Natl Acad Sci U S A. 1971 Nov;68(11):2725-9 - PubMed
  70. Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18004-9 - PubMed
  71. J Clin Invest. 2013 Nov;123(11):4809-20 - PubMed
  72. Transfusion. 2014 Jul;54(7):1712-24 - PubMed
  73. Biochemistry. 1995 Oct 17;34(41):13398-406 - PubMed
  74. Free Radic Biol Med. 2015 Jan;78:224-32 - PubMed
  75. Am J Med. 1988 Oct;85(4):538-40 - PubMed
  76. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15837-42 - PubMed
  77. Biochem J. 1998 Aug 15;334 ( Pt 1):141-6 - PubMed
  78. Proc Soc Exp Biol Med. 1997 Dec;216(3):456-63 - PubMed
  79. N Engl J Med. 1970 Nov 12;283(20):1090-4 - PubMed
  80. J Neuroinflammation. 2014 Dec 02;11:200 - PubMed
  81. J Clin Invest. 1992 Jul;90(1):267-70 - PubMed
  82. Am J Transplant. 2002 Aug;2(7):581-92 - PubMed
  83. Free Radic Biol Med. 2015 Dec;89:248-62 - PubMed
  84. J Clin Invest. 2006 Mar;116(3):808-16 - PubMed
  85. Blood. 2010 Dec 23;116(26):6054-62 - PubMed
  86. Cell Res. 2006 Aug;16(8):681-92 - PubMed
  87. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):E345 - PubMed
  88. Am J Pathol. 2004 Sep;165(3):1045-53 - PubMed
  89. Biochem J. 2003 May 1;371(Pt 3):887-95 - PubMed
  90. Annu Rev Pharmacol Toxicol. 1997;37:517-54 - PubMed
  91. Blood. 2002 Dec 1;100(12):4201-8 - PubMed
  92. Mol Endocrinol. 2008 Jul;22(7):1509-20 - PubMed
  93. Blood. 2005 Oct 1;106(7):2572-9 - PubMed
  94. Mol Med. 2016 Jan 08;:null - PubMed
  95. Front Pharmacol. 2014 Apr 08;5:61 - PubMed
  96. Blood. 2002 Mar 15;99(6):1894-901 - PubMed
  97. Am J Respir Crit Care Med. 2011 Apr 1;183(7):922-31 - PubMed
  98. Blood. 2002 Aug 1;100(3):879-87 - PubMed
  99. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1756-9 - PubMed
  100. Eur J Pharmacol. 2008 Mar 10;581(3):315-23 - PubMed
  101. J Biol Chem. 1968 Feb 10;243(3):465-75 - PubMed
  102. J Clin Invest. 1987 Feb;79(2):662-4 - PubMed
  103. Antioxid Redox Signal. 2016 Mar 30;:null - PubMed
  104. Transfusion. 2012 Jun;52(6):1184-95 - PubMed
  105. J Biol Chem. 2013 May 10;288(19):13194-203 - PubMed
  106. Front Physiol. 2014 Oct 28;5:415 - PubMed
  107. Crit Care. 2013 Nov 14;17(6):R272 - PubMed
  108. Front Pharmacol. 2012 May 07;3:81 - PubMed
  109. Transfusion. 2009 Jul;49(7):1384-94 - PubMed
  110. Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):12169-74 - PubMed
  111. Thromb Haemost. 2014 Jun;111(6):1077-88 - PubMed
  112. J Biol Chem. 1984 Jan 10;259(1):301-5 - PubMed
  113. Antioxid Redox Signal. 2007 Dec;9(12 ):2227-39 - PubMed
  114. Curr Opin Immunol. 2016 Feb;38:94-100 - PubMed
  115. Am J Pathol. 2008 Jul;173(1):289-99 - PubMed
  116. J Clin Invest. 1999 Jan;103(1):129-35 - PubMed
  117. Am J Physiol Renal Physiol. 2011 Jul;301(1):F162-70 - PubMed
  118. Free Radic Biol Med. 2000 Jan 15;28(2):289-309 - PubMed
  119. J Am Soc Nephrol. 2007 Feb;18(2):414-20 - PubMed
  120. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30 - PubMed
  121. Annu Rev Pathol. 2009;4:71-95 - PubMed
  122. Xenotransplantation. 2011 Nov-Dec;18(6):355-68 - PubMed
  123. Circulation. 2016 Sep 27;134(13):945-60 - PubMed
  124. Nature. 1963 Feb 9;197:602-3 - PubMed
  125. Ann Med. 1989 Aug;21(4):273-6 - PubMed
  126. J Exp Med. 1961 Mar 1;113:559-70 - PubMed
  127. J Biol Chem. 2007 Jul 13;282(28):20221-9 - PubMed
  128. Pharmacol Rev. 2008 Mar;60(1):79-127 - PubMed
  129. N Engl J Med. 1986 Jul 24;315(4):235-8 - PubMed
  130. Br Med J (Clin Res Ed). 1986 Aug 30;293(6546):538-9 - PubMed
  131. J Immunol. 2014 Jul 1;193(1):102-10 - PubMed
  132. J Clin Invest. 2013 Oct;123(10):4423-34 - PubMed
  133. Oxid Med Cell Longev. 2013;2013:639541 - PubMed
  134. Biochim Biophys Acta. 2012 Dec;1820(12 ):2020-9 - PubMed
  135. Biochem Pharmacol. 2000 Oct 15;60(8):1121-8 - PubMed
  136. J Biol Chem. 2005 Jun 10;280(23 ):21820-9 - PubMed
  137. Sci Transl Med. 2010 Sep 29;2(51):51ra71 - PubMed
  138. Kidney Int. 2005 Aug;68(2):603-10 - PubMed
  139. Antioxid Redox Signal. 2010 Oct 1;13(7):1087-123 - PubMed
  140. Br J Pharmacol. 2010 Dec;161(8):1751-62 - PubMed
  141. Blood. 2015 Jun 11;125(24):3805-14 - PubMed
  142. J Am Soc Nephrol. 2012 May;23 (5):781-4 - PubMed
  143. Toxicol Lett. 2005 Jul 4;157(3):175-88 - PubMed
  144. Blood. 1983 Feb;61(2):243-9 - PubMed
  145. J Biol Chem. 1985 Nov 25;260(27):14521-8 - PubMed
  146. Infect Immun. 2012 Apr;80(4):1445-54 - PubMed
  147. Lancet. 1995 Jan 21;345(8943):158-60 - PubMed
  148. J Immunol. 2004 Mar 1;172(5):2731-8 - PubMed
  149. Haematologica. 2016 Nov;101(11):e436-e439 - PubMed
  150. Free Radic Biol Med. 2015 Aug;85:207-18 - PubMed
  151. Antioxid Redox Signal. 2014 Apr 10;20(11):1789-809 - PubMed
  152. Free Radic Biol Med. 2015 Dec;89:931-43 - PubMed
  153. J Biol Chem. 1992 Sep 5;267(25):18148-53 - PubMed
  154. Antioxid Redox Signal. 2016 Jan 10;24(2):99-112 - PubMed
  155. Biochem J. 1980 Oct 1;191(1):95-102 - PubMed
  156. Biochim Biophys Acta. 1991 Feb 11;1062(1):51-8 - PubMed
  157. Proc Natl Acad Sci U S A. 1974 Nov;71(11):4293-7 - PubMed
  158. Biochim Biophys Acta. 1994 Sep 14;1194(2):264-70 - PubMed
  159. J Mol Med (Berl). 2010 Jul;88(7):665-75 - PubMed
  160. Circ Res. 2007 Oct 26;101(9):893-901 - PubMed
  161. Am J Med Sci. 1999 Oct;318(4):241-56 - PubMed
  162. Biochem J. 1990 Feb 1;265(3):621-36 - PubMed
  163. Pharmacol Rev. 2003 Sep;55(3):551-71 - PubMed
  164. Transplantation. 2016 Jan;100(1):176-83 - PubMed
  165. Kidney Int. 2015 Jul;88(1):95-108 - PubMed
  166. Blood. 2003 May 15;101(10):3953-9 - PubMed
  167. J Biol Chem. 2004 Mar 5;279(10 ):8919-29 - PubMed
  168. Lab Invest. 1991 May;64(5):648-55 - PubMed
  169. Nat Rev Immunol. 2008 Dec;8(12):958-69 - PubMed
  170. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24 - PubMed
  171. Hypertension. 2012 Aug;60(2):467-75 - PubMed
  172. J Biol Chem. 1983 Oct 10;258(19):12069-72 - PubMed
  173. Front Physiol. 2014 Oct 02;5:379 - PubMed
  174. Curr Med Chem. 2004 Apr;11(8):981-6 - PubMed
  175. Antioxid Redox Signal. 2013 Jun 10;18(17):2274-83 - PubMed
  176. Physiol Rev. 2006 Apr;86(2):583-650 - PubMed
  177. J Biol Chem. 1998 Nov 20;273(47):31388-94 - PubMed
  178. J Am Soc Nephrol. 1999 Aug;10(8):1700-8 - PubMed
  179. DNA Cell Biol. 2002 Apr;21(4):297-306 - PubMed
  180. Antioxid Redox Signal. 2016 Jul 20;25(3):165-83 - PubMed
  181. Biochim Biophys Acta. 2012 Sep;1823(9):1617-32 - PubMed
  182. Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):E4110-8 - PubMed
  183. Am J Physiol Renal Physiol. 2009 Nov;297(5):F1137-52 - PubMed
  184. J Histochem Cytochem. 2003 Dec;51(12 ):1621-31 - PubMed
  185. Nature. 1957 Aug 17;180(4581):326-8 - PubMed
  186. N Engl J Med. 2013 Aug 29;369(9):840-51 - PubMed
  187. J Lipid Res. 2009 Jul;50(7):1293-304 - PubMed
  188. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9285-9 - PubMed
  189. Free Radic Biol Med. 2004 Dec 15;37(12 ):2064-71 - PubMed
  190. Blood. 1997 Jan 1;89(1):1-25 - PubMed
  191. Int J Biochem. 1988;20(6):543-58 - PubMed
  192. J Biol Chem. 1981 Apr 25;256(8):3956-62 - PubMed
  193. Front Pharmacol. 2014 May 27;5:115 - PubMed
  194. Immunol Today. 1994 Feb;15(2):74-80 - PubMed
  195. Biochim Biophys Acta. 2014 Jul;1840(7):2351-60 - PubMed
  196. Mol Pharmacol. 1998 Mar;53(3):483-91 - PubMed

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