Advertisement

Ferritin und Hämoxygenase: Antioxidative Gene als „Target“ für Pentaerithrityltetranitrat

  • Stefanie Oberle
  • Petra Schwartz
  • H. Schröder
Chapter

Zusammenfassung

Bis vor kurzem galt Ferritin als Protein, dessen Hauptfunktion in der Speicherung von Eisen liegt und dem ansonsten keine Bedeutung als potentiellem Wirkort von Arzneistoffen zukommt. Verschiedene Studien, auch solche aus unserer Gruppe [1, 8, 14, 15], haben aber gezeigt, daß Ferritin bzw. neu synthetisiertes eisenfreies Apoferritin eine Schlüsselfunktion als endogener „iron scavenger“ mit cytoprotektiven Eigenschaften besitzt. Ferritin fungiert dabei als antioxidatives Protein, das dem Prozeß der Sauerstoffradikalbildung die als Katalysator essentiellen, freien cytosolischen Eisenionen (Fenton-Chemie) rasch und dauerhaft entzieht. Ferritin erhöht dadurch die Resistenz des Gewebes gegenüber zellschädigenden Einflüssen wie aktivierten Neutrophilen, Wasserstoffsuperoxid oder oxidiertem Low-density-Lipoprotein [1, 6, 14, 15]. Auch klinische Studien weisen darauf hin, daß hohe zelluläre Eisenspiegel oxidativen Streß verursachen und ein koronares Risiko darstellen [18, 21, 22]. Eine Steigerung katalytisch aktiven Eisens gefolgt von vermehrter Ferritinexpression wurde außerdem von verschiedenen Autoren in atherosklerotischen Gefäßläsionen bei Patienten mit koronarer Herzkrankheit beschrieben, ein Befund, der die In-vivo-Relevanz dieses antioxidativen Stoffwechselwegs unterstreicht [6, 16, 19].

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM (1992) Ferritin: A cytoprotective antioxidant strategem of endothelium. J Biol Chem 267: 18148–18153PubMedGoogle Scholar
  2. 2.
    Dikalov S, Fink B, Skatchkov M, Stalleicken D, Bassenge E (1998) Formation of reactive oxygen species by pentaerithrityltetranitrate and glyceryl trinitrate in vitro and development of nitrate tolerance. J Pharmacol Exp Ther 286: 938–944PubMedGoogle Scholar
  3. 3.
    Durante W, Kroll MH, Christodoulides N, Peyton KJ, Schafer AI (1997) Nitric oxide induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells. Circ Res 80: 557–564PubMedCrossRefGoogle Scholar
  4. 4.
    Eisenstein RS, Garcia-Mayol D, Pettingell W, Munro-HN (1991) Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc Natl Acad Sci USA 88: 688–692PubMedCrossRefGoogle Scholar
  5. 5.
    Harrison PM, Arosio P (1996) The ferritins: Molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1275: 161–203PubMedCrossRefGoogle Scholar
  6. 6.
    Juckett MB, Balla J, Balla G, Jessurun J, Jacob HS, Vercellotti GM (1995) Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am J Pathol 147: 782–789PubMedGoogle Scholar
  7. 7.
    Keyse SM, Tyrrell RM (1989) Herne 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: 99–103PubMedCrossRefGoogle Scholar
  8. 8.
    Kim YM, Bergonia H, Lancaster JR Jr (1995) Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett 374: 228–232PubMedCrossRefGoogle Scholar
  9. 9.
    Kojda G, Hacker A, Noack E (1998) Effects of nonintermittent treatment of rabbits with pentaerythritol tetranitrate on vascular reactivity and superoxide production. Eur J Pharmacol 355: 23–31PubMedCrossRefGoogle Scholar
  10. 10.
    Kojda G, Stein D, Kottenberg E, Schnaith EM, Noack E (1995) In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc Pharmacol 25: 763–773PubMedCrossRefGoogle Scholar
  11. 11.
    Maines MD (1997) The heme oxygenase system: A regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37: 517–554PubMedCrossRefGoogle Scholar
  12. 12.
    Motterlini R, Foresti R, Intaglietta M, Winslow RM (1996) NO-mediated activation of heme oxygenase: Endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol 270: H107 - H114PubMedGoogle Scholar
  13. 13.
    Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME (1992) Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 90: 267–270PubMedCrossRefGoogle Scholar
  14. 14.
    Oberle S, Polte T, Abate A, Podhaisky H-P, Schröder H (1998) Aspirin increases ferri-tin synthesis in endothelial cells: a novel antioxidant pathway. Circ Res 82: 1016–1020PubMedCrossRefGoogle Scholar
  15. 15.
    Oberle S, Schröder H (1997) Ferritin may mediate SIN-1-induced protection against oxidative stress. Nitric Oxide Biol Chem (Arch Biochem Biophys Part B) 1: 308–314Google Scholar
  16. 16.
    Pang JHS, Jiang MJ, Chen YL, Wang FW, Wang DL, Chu SH, Chau LY (1996) Increased ferritin gene expression in atherosclerotic lesions. J Clin Invest 97: 2204–2212PubMedCrossRefGoogle Scholar
  17. 17.
    Recalcati S, Taramelli D, Conte D, Cairo G (1998) Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: Role of selective iron regulatory protein-2 downregulation. Blood 91: 1059–1066PubMedGoogle Scholar
  18. 18.
    Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R (1992) High stored iron levels are associated with excess risk of myocardial infarction in eastern finnish men. Circulation 86: 803–811PubMedCrossRefGoogle Scholar
  19. 19.
    Smith C, Mitchinson MJ, Aruoma OI, Halliwell B (1992) Stimulation of lipid peroxidation and hydoxyl-radical generation by the contents of human atherosclerotic lesions. Biochem J 286: 803–811Google Scholar
  20. 20.
    Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235: 1043–1046PubMedCrossRefGoogle Scholar
  21. 21.
    Sullivan JL (1992) Stored iron and ischemic heart disease. Empirical support for a new paradigm. Circulation 86: 1036–1037PubMedCrossRefGoogle Scholar
  22. 22.
    Tzonou A, Lagiou P, Trichopoulou A, Tsoutsos V, Trichopoulos D (1998) Dietary iron and coronary heart disease risk: A study from Greece. Am J Epidemiol 147: 161–166PubMedCrossRefGoogle Scholar
  23. 23.
    Vile GF, Tyrrell RM (1993) Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to heme oxygenase-dependent increase in ferritin. J Biol Chem 268: 14678–14681PubMedGoogle Scholar
  24. 24.
    Yee EL, Pitt BR, Billiar TR, Kim YM (1996) Effect of nitric oxide on heme metabolism in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 271: L512 - L518Google Scholar

Copyright information

© Steinkopff Verlag, Darmstadt 1999

Authors and Affiliations

  • Stefanie Oberle
  • Petra Schwartz
  • H. Schröder

There are no affiliations available

Personalised recommendations