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Nrf2 Transcription Factor and Heme Oxygenase-1 as Modulators of Vascular Injury and Angiogenesis

  • Urszula Florczyk
  • Alicja Józkowicz
  • Józef DulakEmail author
Chapter

Abstract

The cytoprotective actions of Nrf2 transcription factor against vascular injuries associated with oxidative stress and tissue ischemia are widely reported. Amongst Nrf2 target genes, heme oxygenase-1 (HO-1) is responsible for at least a part of such protective effects by playing strong antioxidant and anti-inflammatory roles in the vascular system. Nonetheless, the area of Nrf2/HO-1 functioning could be extended to the control of vessel growth. Although the angiogenic involvement of HO-1 in physiological states and under conditions of tissue damage is well demonstrated, a direct role of Nrf2 in the process of blood vessel formation is just coming to light. Nrf2 has been linked to known angiogenic signaling pathways, comprising not only HO-1, but also vascular endothelial growth factor and hypoxia-inducible factor-1, and suggested to act in normal vascular development as well as in the formation of blood vessels nourishing tumor. Strikingly, Nrf2 deficiency may promote oxidative stress-related inflammatory neovascularization accompanying damaged/ischemic tissue regeneration. Thus, further studies are definitely required for a thorough assessment of Nrf2 place in the processes of blood vessel formation.

Keywords

Heme oxygenase-1 NF-E2-related factor 2 Angiogenesis Neovascularization Ischemia Proangiogenic cells Endothelial progenitor cells 

Notes

Acknowledgments

The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of the structural funds from the European Union and the Polish Ministry of Science and Higher Education (grants No: POIG.02.01.00-12 064/08, POIG 01.01.02-00-109/09, POIG.02.02.00-014/08, and 01.01.02-00-069/09).

References

  1. 1.
    Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85(4):241–272PubMedGoogle Scholar
  2. 2.
    Zhang X, Chen X, Song H, Chen HZ, Rovin BH (2005) Activation of the Nrf2/antioxidant response pathway increases IL-8 expression. Eur J Immunol 35(11):3258–3267PubMedGoogle Scholar
  3. 3.
    Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL (1999) Nrf2, a Cap‘n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274(37):26071–26078PubMedGoogle Scholar
  4. 4.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedGoogle Scholar
  5. 5.
    Misra MK, Sarwat M, Bhakuni P, Tuteja R, Tuteja N (2009) Oxidative stress and ischemic myocardial syndromes. Med Sci Monit 15(10):RA209–RA219PubMedGoogle Scholar
  6. 6.
    Bemeur C, Ste-Marie L, Montgomery J (2007) Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem Int 50(7–8):890–904PubMedGoogle Scholar
  7. 7.
    Mitra S, Deshmukh A, Sachdeva R, Lu J, Mehta JL (2011) Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy. Am J Med Sci 342(2):135–142PubMedGoogle Scholar
  8. 8.
    Donovan EL, McCord JM, Reuland DJ, Miller BF, Hamilton KL (2012) Phytochemical activation of Nrf2 protects human coronary artery endothelial cells against an oxidative challenge. Oxid Med Cell Longev 2012:132931PubMedCentralPubMedGoogle Scholar
  9. 9.
    Kim M, Kim S, Lim JH, Lee C, Choi HC, Woo CH (2012) Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. J Biol Chem 287(48):40722–40731PubMedGoogle Scholar
  10. 10.
    Ashino T, Yamamoto M, Yoshida T, Numazawa S (2013) Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia. Arterioscler Thromb Vasc Biol 33(4):760–768PubMedGoogle Scholar
  11. 11.
    Bitar MS, Al-Mulla F (2011) A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes. Am J Physiol Endocrinol Metab 301(6):E1119–E1129PubMedGoogle Scholar
  12. 12.
    Loboda A, Jazwa A, Grochot-Przeczek A, Rutkowski AJ, Cisowski J, Agarwal A, Jozkowicz A, Dulak J (2008) Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 10(10):1767–1812PubMedGoogle Scholar
  13. 13.
    Castilho A, Aveleira CA, Leal EC, Simoes NF, Fernandes CR, Meirinhos RI, Baptista FI, Ambrosio AF (2012) Heme oxygenase-1 protects retinal endothelial cells against high glucose- and oxidative/nitrosative stress-induced toxicity. PLoS One 7(8):e42428PubMedCentralPubMedGoogle Scholar
  14. 14.
    Ishikawa K, Sugawara D, Wang X, Suzuki K, Itabe H, Maruyama Y, Lusis AJ (2001) Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res 88(5):506–512PubMedGoogle Scholar
  15. 15.
    Yet SF, Layne MD, Liu X, Chen YH, Ith B, Sibinga NE, Perrella MA (2003) Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. FASEB J 17(12):1759–1761PubMedGoogle Scholar
  16. 16.
    Kim JY, Cho HJ, Sir JJ, Kim BK, Hur J, Youn SW, Yang HM, Jun SI, Park KW, Hwang SJ, Kwon YW, Lee HY, Kang HJ, Oh BH, Park YB, Kim HS (2009) Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia. Cardiovasc Res 82(3):550–560PubMedGoogle Scholar
  17. 17.
    Sambuceti G, Morbelli S, Vanella L, Kusmic C, Marini C, Massollo M, Augeri C, Corselli M, Ghersi C, Chiavarina B, Rodella LF, L'Abbate A, Drummond G, Abraham NG, Frassoni F (2009) Diabetes impairs the vascular recruitment of normal stem cells by oxidant damage, reversed by increases in pAMPK, heme oxygenase-1, and adiponectin. Stem Cells 27(2):399–407PubMedCentralPubMedGoogle Scholar
  18. 18.
    Fan J, Xu G, Jiang T, Qin Y (2012) Pharmacologic induction of heme oxygenase-1 plays a protective role in diabetic retinopathy in rats. Invest Ophthalmol Vis Sci 53(10):6541–6556PubMedGoogle Scholar
  19. 19.
    Liu X, Wei J, Peng DH, Layne MD, Yet SF (2005) Absence of heme oxygenase-1 exacerbates myocardial ischemia/reperfusion injury in diabetic mice. Diabetes 54(3):778–784PubMedGoogle Scholar
  20. 20.
    Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A 94(20):10919–10924PubMedCentralPubMedGoogle Scholar
  21. 21.
    Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A 94(20):10925–10930PubMedCentralPubMedGoogle Scholar
  22. 22.
    True AL, Olive M, Boehm M, San H, Westrick RJ, Raghavachari N, Xu X, Lynn EG, Sack MN, Munson PJ, Gladwin MT, Nabel EG (2007) Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circ Res 101(9):893–901PubMedGoogle Scholar
  23. 23.
    Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103(1):129–135PubMedCentralPubMedGoogle Scholar
  24. 24.
    Radhakrishnan N, Yadav SP, Sachdeva A, Pruthi PK, Sawhney S, Piplani T, Wada T, Yachie A (2011) Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J Pediatr Hematol Oncol 33(1):74–78PubMedGoogle Scholar
  25. 25.
    Taha H, Skrzypek K, Guevara I, Nigisch A, Mustafa S, Grochot-Przeczek A, Ferdek P, Was H, Kotlinowski J, Kozakowska M, Balcerczyk A, Muchova L, Vitek L, Weigel G, Dulak J, Jozkowicz A (2010) Role of heme oxygenase-1 in human endothelial cells: lesson from the promoter allelic variants. Arterioscler Thromb Vasc Biol 30(8):1634–1641PubMedCentralPubMedGoogle Scholar
  26. 26.
    Koizumi S (2007) Human heme oxygenase-1 deficiency: a lesson on serendipity in the discovery of the novel disease. Pediatr Int 49(2):125–132PubMedGoogle Scholar
  27. 27.
    Kim YM, Pae HO, Park JE, Lee YC, Woo JM, Kim NH, Choi YK, Lee BS, Kim SR, Chung HT (2011) Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 14(1):137–167PubMedGoogle Scholar
  28. 28.
    Deramaudt BM, Braunstein S, Remy P, Abraham NG (1998) Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem 68(1):121–127PubMedGoogle Scholar
  29. 29.
    Malaguarnera L, Pilastro MR, Quan S, Ghattas MH, Yang L, Mezentsev AV, Kushida T, Abraham NG, Kappas A (2002) Significance of heme oxygenase in prolactin-mediated cell proliferation and angiogenesis in human endothelial cells. Int J Mol Med 10(4):433–440PubMedGoogle Scholar
  30. 30.
    Jazwa A, Stepniewski J, Zamykal M, Jagodzinska J, Meloni M, Emanueli C, Jozkowicz A, Dulak J (2013) Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice. Cardiovasc Res 97(1):115–124PubMedGoogle Scholar
  31. 31.
    Suzuki M, Iso-o N, Takeshita S, Tsukamoto K, Mori I, Sato T, Ohno M, Nagai R, Ishizaka N (2003) Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model of hindlimb ischemia. Biochem Biophys Res Commun 302(1):138–143PubMedGoogle Scholar
  32. 32.
    Lakkisto P, Kyto V, Forsten H, Siren JM, Segersvard H, Voipio-Pulkki LM, Laine M, Pulkki K, Tikkanen I (2010) Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B. Eur J Pharmacol 635(1–3):156–164PubMedGoogle Scholar
  33. 33.
    Grochot-Przeczek A, Lach R, Mis J, Skrzypek K, Gozdecka M, Sroczynska P, Dubiel M, Rutkowski A, Kozakowska M, Zagorska A, Walczynski J, Was H, Kotlinowski J, Drukala J, Kurowski K, Kieda C, Herault Y, Dulak J, Jozkowicz A (2009) Heme oxygenase-1 accelerates cutaneous wound healing in mice. PLoS One 4(6):e5803PubMedCentralPubMedGoogle Scholar
  34. 34.
    Sunamura M, Duda DG, Ghattas MH, Lozonschi L, Motoi F, Yamauchi J, Matsuno S, Shibahara S, Abraham NG (2003) Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis 6(1):15–24PubMedGoogle Scholar
  35. 35.
    Tongers J, Knapp JM, Korf M, Kempf T, Limbourg A, Limbourg FP, Li Z, Fraccarollo D, Bauersachs J, Han X, Drexler H, Fiedler B, Wollert KC (2008) Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hindlimb ischaemia in mice. Cardiovasc Res 78(2):294–300PubMedGoogle Scholar
  36. 36.
    Miyake M, Fujimoto K, Anai S, Ohnishi S, Kuwada M, Nakai Y, Inoue T, Matsumura Y, Tomioka A, Ikeda T, Tanaka N, Hirao Y (2011) Heme oxygenase-1 promotes angiogenesis in urothelial carcinoma of the urinary bladder. Oncol Rep 25(3):653–660PubMedGoogle Scholar
  37. 37.
    Kozakowska M, Ciesla M, Stefanska A, Skrzypek K, Was H, Jazwa A, Grochot-Przeczek A, Kotlinowski J, Szymula A, Bartelik A, Mazan M, Yagensky O, Florczyk U, Lemke K, Zebzda A, Dyduch G, Nowak W, Szade K, Stepniewski J, Majka M, Derlacz R, Loboda A, Dulak J, Jozkowicz A (2012) Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. Antioxid Redox Signal 16(2):113–127PubMedGoogle Scholar
  38. 38.
    Jozkowicz A, Huk I, Nigisch A, Weigel G, Dietrich W, Motterlini R, Dulak J (2003) Heme oxygenase and angiogenic activity of endothelial cells: stimulation by carbon monoxide and inhibition by tin protoporphyrin-IX. Antioxid Redox Signal 5(2):155–162PubMedGoogle Scholar
  39. 39.
    Deshane J, Chen S, Caballero S, Grochot-Przeczek A, Was H, Li Calzi S, Lach R, Hock TD, Chen B, Hill-Kapturczak N, Siegal GP, Dulak J, Jozkowicz A, Grant MB, Agarwal A (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204(3):605–618PubMedCentralPubMedGoogle Scholar
  40. 40.
    Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573):435–439PubMedGoogle Scholar
  41. 41.
    Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573):439–442PubMedGoogle Scholar
  42. 42.
    Dulak J, Jozkowicz A, Foresti R, Kasza A, Frick M, Huk I, Green CJ, Pachinger O, Weidinger F, Motterlini R (2002) Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal 4(2):229–240PubMedGoogle Scholar
  43. 43.
    Jozkowicz A, Huk I, Nigisch A, Weigel G, Weidinger F, Dulak J (2002) Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1. Antioxid Redox Signal 4(4):577–585PubMedGoogle Scholar
  44. 44.
    Loboda A, Jazwa A, Wegiel B, Jozkowicz A, Dulak J (2005) Heme oxygenase-1-dependent and -independent regulation of angiogenic genes expression: effect of cobalt protoporphyrin and cobalt chloride on VEGF and IL-8 synthesis in human microvascular endothelial cells. Cell Mol Biol (Noisy-le-grand) 51(4):347–355PubMedCentralGoogle Scholar
  45. 45.
    Kim EH, Na HK, Surh YJ (2006) Upregulation of VEGF by 15-deoxy-Delta12,14-prostaglandin J2 via heme oxygenase-1 and ERK1/2 signaling in MCF-7 cells. Ann N Y Acad Sci 1090:375–384PubMedGoogle Scholar
  46. 46.
    Choi YK, Kim CK, Lee H, Jeoung D, Ha KS, Kwon YG, Kim KW, Kim YM (2010) Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein. J Biol Chem 285(42):32116–32125PubMedGoogle Scholar
  47. 47.
    Cisowski J, Loboda A, Jozkowicz A, Chen S, Agarwal A, Dulak J (2005) Role of heme oxygenase-1 in hydrogen peroxide-induced VEGF synthesis: effect of HO-1 knockout. Biochem Biophys Res Commun 326(3):670–676PubMedGoogle Scholar
  48. 48.
    Jazwa A, Loboda A, Golda S, Cisowski J, Szelag M, Zagorska A, Sroczynska P, Drukala J, Jozkowicz A, Dulak J (2006) Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes. Free Radic Biol Med 40(7):1250–1263PubMedCentralPubMedGoogle Scholar
  49. 49.
    Malaguarnera L, Imbesi RM, Scuto A, D'Amico F, Licata F, Messina A, Sanfilippo S (2004) Prolactin increases HO-1 expression and induces VEGF production in human macrophages. J Cell Biochem 93(1):197–206PubMedGoogle Scholar
  50. 50.
    Abdel-Aziz MT, el-Asmar MF, el-Miligy D, Atta H, Shaker O, Ghattas MH, Hosni H, Kamal N (2003) Retrovirus-mediated human heme oxygenase-1 (HO-1) gene transfer into rat endothelial cells: the effect of HO-1 inducers on the expression of cytokines. Int J Biochem Cell Biol 35(3):324–332PubMedGoogle Scholar
  51. 51.
    Angermayr B, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J, Fernandez M (2006) Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats. J Hepatol 44(6):1033–1039PubMedGoogle Scholar
  52. 52.
    Lin HH, Chen YH, Yet SF, Chau LY (2009) After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J Thromb Haemost 7(8):1401–1408PubMedGoogle Scholar
  53. 53.
    Lin HH, Chen YH, Chang PF, Lee YT, Yet SF, Chau LY (2008) Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1. J Mol Cell Cardiol 45(1):44–55PubMedGoogle Scholar
  54. 54.
    Lin HH, Lai SC, Chau LY (2011) Heme oxygenase-1/carbon monoxide induces vascular endothelial growth factor expression via p38 kinase-dependent activation of Sp1. J Biol Chem 286(5):3829–3838PubMedGoogle Scholar
  55. 55.
    Fernandez M, Bonkovsky HL (2003) Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane. Br J Pharmacol 139(3):634–640PubMedGoogle Scholar
  56. 56.
    Bussolati B, Ahmed A, Pemberton H, Landis RC, Di Carlo F, Haskard DO, Mason JC (2004) Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration. Blood 103(3):761–766PubMedGoogle Scholar
  57. 57.
    Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, Kitamura Y, Matsushima K, Yoshida N, Nishikawa S, Kishimoto T, Nagasawa T (1998) The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393(6685):591–594PubMedGoogle Scholar
  58. 58.
    Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382(6592):635–638PubMedGoogle Scholar
  59. 59.
    Lau TT, Wang DA (2011) Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine. Expert Opin Biol Ther 11(2):189–197PubMedGoogle Scholar
  60. 60.
    Wang Y, Luther K (2012) Genetically manipulated progenitor/stem cells restore function to the infarcted heart via the SDF-1alpha/CXCR4 signaling pathway. Prog Mol Biol Transl Sci 111:265–284PubMedGoogle Scholar
  61. 61.
    Hiasa K, Ishibashi M, Ohtani K, Inoue S, Zhao Q, Kitamoto S, Sata M, Ichiki T, Takeshita A, Egashira K (2004) Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization. Circulation 109(20):2454–2461PubMedGoogle Scholar
  62. 62.
    Li FY, Lam KS, Tse HF, Chen C, Wang Y, Vanhoutte PM, Xu A (2012) Endothelium-selective activation of AMP-activated protein kinase prevents diabetes mellitus-induced impairment in vascular function and reendothelialization via induction of heme oxygenase-1 in mice. Circulation 126(10):1267–1277PubMedGoogle Scholar
  63. 63.
    Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, Dzau VJ, Lee ME, Perrella MA (2001) Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 89(2):168–173PubMedGoogle Scholar
  64. 64.
    Wojakowski W, Tendera M, Cybulski W, Zuba-Surma EK, Szade K, Florczyk U, Kozakowska M, Szymula A, Krzych L, Paslawska U, Paslawski R, Milewski K, Buszman PP, Nabialek E, Kuczmik W, Janiszewski A, Dziegiel P, Buszman PE, Jozkowicz A, Dulak J (2012) Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury. Thromb Haemost 108(3):464–475PubMedGoogle Scholar
  65. 65.
    Bhang SH, Kim JH, Yang HS, La WG, Lee TJ, Sun AY, Kim GH, Lee M, Kim BS (2009) Combined delivery of heme oxygenase-1 gene and fibroblast growth factor-2 protein for therapeutic angiogenesis. Biomaterials 30(31):6247–6256PubMedGoogle Scholar
  66. 66.
    Bhang SH, Kim JH, Yang HS, La WG, Lee TJ, Kim GH, Kim HA, Lee M, Kim BS (2011) Combined gene therapy with hypoxia-inducible factor-1alpha and heme oxygenase-1 for therapeutic angiogenesis. Tissue Eng Part A 17(7–8):915–926PubMedGoogle Scholar
  67. 67.
    Jujo K, Ii M, Losordo DW (2008) Endothelial progenitor cells in neovascularization of infarcted myocardium. J Mol Cell Cardiol 45(4):530–544PubMedCentralPubMedGoogle Scholar
  68. 68.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302):964–967PubMedGoogle Scholar
  69. 69.
    Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, Isner JM (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18(14):3964–3972PubMedGoogle Scholar
  70. 70.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10(8):858–864PubMedGoogle Scholar
  71. 71.
    Kong D, Melo LG, Mangi AA, Zhang L, Lopez-Ilasaca M, Perrella MA, Liew CC, Pratt RE, Dzau VJ (2004) Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 109(14):1769–1775PubMedGoogle Scholar
  72. 72.
    Wu BJ, Midwinter RG, Cassano C, Beck K, Wang Y, Changsiri D, Gamble JR, Stocker R (2009) Heme oxygenase-1 increases endothelial progenitor cells. Arterioscler Thromb Vasc Biol 29(10):1537–1542PubMedGoogle Scholar
  73. 73.
    Krenning G, van Luyn MJ, Harmsen MC (2009) Endothelial progenitor cell-based neovascularization: implications for therapy. Trends Mol Med 15(4):180–189PubMedGoogle Scholar
  74. 74.
    Brunt KR, Wu J, Chen Z, Poeckel D, Dercho RA, Melo LG, Funk CD, Ward CA, Li RK (2012) Ex vivo Akt/HO-1 gene therapy to human endothelial progenitor cells enhances myocardial infarction recovery. Cell Transplant 21(7):1443–1461PubMedGoogle Scholar
  75. 75.
    Long J, Wang S, Zhang Y, Liu X, Zhang H (2013) The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model. J Vasc Surg 58(3):756–765, e2PubMedGoogle Scholar
  76. 76.
    Yang JJ, Yang X, Liu ZQ, Hu SY, Du ZY, Feng LL, Liu JF, Chen YD (2012) Transplantation of adipose tissue-derived stem cells overexpressing heme oxygenase-1 improves functions and remodeling of infarcted myocardium in rabbits. Tohoku J Exp Med 226(3):231–241PubMedGoogle Scholar
  77. 77.
    Jiang YB, Zhang XL, Tang YL, Ma GS, Shen CX, Wei Q, Zhu Q, Yao YY, Liu NF (2011) Effects of heme oxygenase-1 gene modulated mesenchymal stem cells on vasculogenesis in ischemic swine hearts. Chin Med J (Engl) 124(3):401–407Google Scholar
  78. 78.
    Hou C, Shen L, Huang Q, Mi J, Wu Y, Yang M, Zeng W, Li L, Chen W, Zhu C (2013) The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials 34(1):112–120PubMedGoogle Scholar
  79. 79.
    Zeng B, Lin G, Ren X, Zhang Y, Chen H (2010) Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium. J Biomed Sci 17:80PubMedGoogle Scholar
  80. 80.
    Kearns-Jonker M, Dai W, Gunthart M, Fuentes T, Yeh HY, Gerczuk P, Pera M, Mummery C, Kloner RA (2012) Genetically engineered mesenchymal stem cells influence gene expression in donor cardiomyocytes and the recipient heart. J Stem Cell Res Ther. S1.Google Scholar
  81. 81.
    Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal 9(12):2099–2117PubMedCentralPubMedGoogle Scholar
  82. 82.
    Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5(5):1107–1113PubMedGoogle Scholar
  83. 83.
    Was H, Cichon T, Smolarczyk R, Rudnicka D, Stopa M, Chevalier C, Leger JJ, Lackowska B, Grochot A, Bojkowska K, Ratajska A, Kieda C, Szala S, Dulak J, Jozkowicz A (2006) Overexpression of heme oxygenase-1 in murine melanoma: increased proliferation and viability of tumor cells, decreased survival of mice. Am J Pathol 169(6):2181–2198PubMedGoogle Scholar
  84. 84.
    Sass G, Leukel P, Schmitz V, Raskopf E, Ocker M, Neureiter D, Meissnitzer M, Tasika E, Tannapfel A, Tiegs G (2008) Inhibition of heme oxygenase 1 expression by small interfering RNA decreases orthotopic tumor growth in livers of mice. Int J Cancer 123(6):1269–1277PubMedGoogle Scholar
  85. 85.
    Birrane G, Li H, Yang S, Tachado SD, Seng S (2013) Cigarette smoke induces nuclear translocation of heme oxygenase 1 (HO-1) in prostate cancer cells: nuclear HO-1 promotes vascular endothelial growth factor secretion. Int J Oncol 42(6):1919–1928PubMedGoogle Scholar
  86. 86.
    Sengupta S, Sellers LA, Matheson HB, Fan TP (2003) Thymidine phosphorylase induces angiogenesis in vivo and in vitro: an evaluation of possible mechanisms. Br J Pharmacol 139(2):219–231PubMedGoogle Scholar
  87. 87.
    Skrzypek K, Tertil M, Golda S, Ciesla M, Weglarczyk K, Collet G, Guichard A, Kozakowska M, Boczkowski J, Was H, Gil T, Kuzdzal J, Muchova L, Vitek L, Loboda A, Jozkowicz A, Kieda C, Dulak J (2013) Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization and metastasis. Antioxid Redox Signal 19(7):644–660PubMedGoogle Scholar
  88. 88.
    Ferrando M, Gueron G, Elguero B, Giudice J, Salles A, Leskow FC, Jares-Erijman EA, Colombo L, Meiss R, Navone N, De Siervi A, Vazquez E (2011) Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis 14(4):467–479PubMedGoogle Scholar
  89. 89.
    Chan K, Lu R, Chang JC, Kan YW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93(24):13943–13948PubMedGoogle Scholar
  90. 90.
    Chan K, Kan Y (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 96(22):12731–12736PubMedGoogle Scholar
  91. 91.
    Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59(1):169–177PubMedGoogle Scholar
  92. 92.
    Ramos-Gomez M, Kwak M, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98(6):3410–3415PubMedGoogle Scholar
  93. 93.
    Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60(4):1343–1353PubMedGoogle Scholar
  94. 94.
    Afonyushkin T, Oskolkova OV, Philippova M, Resink TJ, Erne P, Binder BR, Bochkov VN (2010) Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependent mechanism: novel point of convergence between electrophilic and unfolded protein stress pathways. Arterioscler Thromb Vasc Biol 30(5):1007–1013PubMedGoogle Scholar
  95. 95.
    Kweider N, Fraqoulis A, Rosen C, Pecks U, Rath W, Pufe T, Wruck CJ (2011) Interplay between vascular endothelial growth factor (VEGF) and nuclear factor erythroid 2-related factor-2 (Nrf2): implications for preeclampsia. J Biol Chem 286(50):42863–42872PubMedGoogle Scholar
  96. 96.
    Shibuya A, Onda K, Kawahara H, Uchiyama Y, Nakayama H, Omi T, Nagaoka M, Matsui H, Hirano T (2010) Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells. Biochem Biophys Res Commun 398(3):581–584PubMedGoogle Scholar
  97. 97.
    Chao MW, Po IP, Laumbach RJ, Koslosky J, Cooper K, Gordon MK (2012) DEP induction of ROS in capillary-like endothelial tubes leads to VEGF-A expression. Toxicology 297(1–3):34–46PubMedCentralPubMedGoogle Scholar
  98. 98.
    Meng D, Wang X, Chang Q, Hitron A, Zhang Z, Xu M, Chen G, Luo J, Jiang B, Fang J, Shi X (2010) Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism. Toxicol Appl Pharmacol 244(3):291–299PubMedGoogle Scholar
  99. 99.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613PubMedCentralPubMedGoogle Scholar
  100. 100.
    Malec V, Gottschald OR, Li S, Rose F, Seeger W, Hanze J (2010) HIF-1 alpha signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells. Free Radic Biol Med 48:1626–1635PubMedGoogle Scholar
  101. 101.
    Loboda A, Stachurska A, Florczyk U, Rudnicka D, Jazwa A, Wegrzyn J, Kozakowska M, Stalinska K, Poellinger L, Levonen AL, Yla-Herttuala S, Jozkowicz A, Dulak J (2009) HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells. Antioxid Redox Signal 11(7):1501–1517PubMedGoogle Scholar
  102. 102.
    Zhang Z, Wang Q, Ma J, Yi X, Zhu Y, Xi X, Feng Y, Jin Z (2013) Reactive oxygen species regulate FSH-induced expression of vascular endothelial growth factor via Nrf2 and HIF1alpha signaling in human epithelial ovarian cancer. Oncol Rep 29(4):1429–1434PubMedGoogle Scholar
  103. 103.
    Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res 71(6):2260–2275PubMedGoogle Scholar
  104. 104.
    Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A (2012) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67(8):821–829PubMedGoogle Scholar
  105. 105.
    Wei Y, Gong J, Yoshida T, Eberhart CG, Xu Z, Kombairaju P, Sporn MB, Handa JT, Duh EJ (2011) Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury. Free Radic Biol Med 51(1):216–224PubMedGoogle Scholar
  106. 106.
    Reddy NM, Kleeberger SR, Kensler TW, Yamamoto M, Hassoun PM, Reddy SP (2009) Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice. J Immunol 182(11):7264–7271PubMedCentralPubMedGoogle Scholar
  107. 107.
    Copple IM, Goldring CE, Kitteringham NR, Park BK (2008) The Nrf2-Keap1 defence pathway: role in protection against drug-induced toxicity. Toxicology 246(1):24–33PubMedGoogle Scholar
  108. 108.
    Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26(2):175–182PubMedGoogle Scholar
  109. 109.
    Auf dem Keller U, Huber M, Beyer TA, Kumin A, Siemes C, Braun S, Bugnon P, Mitropoulos V, Johnson DA, Johnson JA, Hohl D, Werner S (2006) Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing. Mol Cell Biol 26(10):3773–3784PubMedCentralPubMedGoogle Scholar
  110. 110.
    Uno K, Prow TW, Bhutto IA, Yerrapureddy A, McLeod DS, Yamamoto M, Reddy SP, Lutty GA (2010) Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy. Exp Eye Res 90(4):493–500PubMedGoogle Scholar
  111. 111.
    Nijmeh J, Moldobaeva A, Wagner EM (2010) Role of ROS in ischemia-induced lung angiogenesis. Am J Physiol Lung Cell Mol Physiol 299(4):L535–L541PubMedGoogle Scholar
  112. 112.
    Ichihara S, Yamada Y, Liu F, Murohara T, Itoh K, Yamamoto M, Ichihara G (2010) Ablation of the transcription factor Nrf2 promotes ischemia-induced neovascularization by enhancing the inflammatory response. Arterioscler Thromb Vasc Biol 30(8):1553–1561PubMedGoogle Scholar
  113. 113.
    Merchant AA, Singh A, Matsui W, Biswal S (2011) The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood 118(25):6572–6579PubMedGoogle Scholar
  114. 114.
    Tsai JJ, Dudakov JA, Takahashi K, Shieh JH, Velardi E, Holland AM, Singer NV, West ML, Smith OM, Young LF, Shono Y, Ghosh A, Hanash AM, Tran HT, Moore MA, van den Brink MR (2013) Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol 15(3):309–316PubMedCentralPubMedGoogle Scholar
  115. 115.
    Yu X, Kensler T (2005) Nrf2 as a target for cancer chemoprevention. Mutat Res 591(1–2):93–102PubMedGoogle Scholar
  116. 116.
    Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M (2013) Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res 73(13):4158–4168PubMedGoogle Scholar
  117. 117.
    Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K, Fostel J, Yamamoto M, Kleeberger SR (2011) Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice. PLoS One 6(10):e26590PubMedCentralPubMedGoogle Scholar
  118. 118.
    Zhou S, Ye W, Zhang M, Liang J (2012) The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr 22(2):149–160PubMedGoogle Scholar
  119. 119.
    Ji XJ, Chen SH, Zhu L, Pan H, Zhou Y, Li W, You WC, Gao CC, Zhu JH, Jiang K, Wang HD (2013) Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model. Oncol Rep 30(1):157–164PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Urszula Florczyk
    • 1
  • Alicja Józkowicz
    • 1
  • Józef Dulak
    • 1
    Email author
  1. 1.Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityKrakówPoland

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