Log in

Short term protective effects of iron in a murine model of ischemia/reperfusion

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The role of iron in the pathogenesis of cardio-vascular disorders is still controversial. We studied the effects of iron perturbations on myocardial injury upon temporary ischemia/reperfusion. C57BL/6J male mice were injected with iron dextran for 2 weeks while controls received saline. Mice were then subjected to 30 min of myocardial ischemia and subsequent reperfusion for 6–24 h. Tissue damage was quantified histologically and by troponin T determination. The expressions of tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were investigated in non-ischemic and ischemic regions of both groups. After myocardial ischemia and reperfusion, troponin T levels, as a marker of myocardial damage, were significantly reduced in iron-treated mice as compared to control mice (P < 0.05). Under the same conditions the infarction area and damage score were significantly lower in iron-treated animals. In parallel, TNF-α and SOD expressions were increased in infarcted regions of iron-treated mice as compared to controls, whereas myocardial iNOS expression was significantly lower in iron-treated mice. Although, iron challenge increased radical formation and TNF-α expression in vivo, this did not result in myocardial damage which may be linked to the parallel induction of SOD. Importantly, iron treatment inhibited iNOS expression. Since, an increased nitric oxide (NO) formation has been linked to cardiac damage after acute myocardial infarction, iron may exert short time cardio-protective effects after induction of ischemia/reperfusion via decreasing iNOS formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adamcova M, Machackova J, Gersl V et al. (2002). Cardiac troponin T following repeated administration of pyridoxal isonicotinoyl hydrazone in rabbits. Physiol Res. 51:443–448

    PubMed  CAS  Google Scholar 

  • Baer DM, Tekawa IS, Hurley LB (1994). Iron stores are not associated with acute myocardial infarction. Circulation 89:2915–2918

    PubMed  CAS  Google Scholar 

  • Bernard M, Menasche P, Pietri S, Piwnica A, Cozzone PJ (1988). Cardioplegic arrest superimposed on evolving myocardial ischemia. Improved recovery after inhibition of hydroxyl radical generation by peroxidase or deferoxamine. A 31P nuclear resonance study. Circulation 78:164–172

    Google Scholar 

  • Bolli R, Patel BS, Jeroudi MO et al (1990). Iron-mediated radical reactions upon reperfusion contribute to myocardial “stunning”. Am J Physiol 259:H1901–H1911

    PubMed  CAS  Google Scholar 

  • Bogdan C (2001). Nitric oxide and the immune response. Nat Immunol 2:907–916

    Article  PubMed  CAS  Google Scholar 

  • Chauhan SD, Seggara G, Vo PA, Macallister RJ, Hobbs AJ, Ahluwalia A (2003). Protection against lipopolysaccharide-induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice. FASEB J 17:773–775

    PubMed  CAS  Google Scholar 

  • Dlaska M, Weiss G (1999). Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162:6171–6177

    PubMed  CAS  Google Scholar 

  • Drapier JC, Hibbs JB Jr (1988). Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol 140:2829–2838

    PubMed  CAS  Google Scholar 

  • Foster MW, McMahon TJ, Stamler JS (2003). S-nitrosylation in health and disease. Trends Mol Med 9:160–168

    Article  PubMed  CAS  Google Scholar 

  • Ferdinandy P, Schulz R (2003). Nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury and preconditioning. Br J Pharmacol 138:532–543

    Article  PubMed  CAS  Google Scholar 

  • Gaenzer H, Marschang P, Sturm W, Vogel W, Patsch J, Weiss G (2002). Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol 40:2189–2194

    Article  PubMed  CAS  Google Scholar 

  • Galinanes M, Fowler AG. (2004). Role of clinical pathologies in myocardial injury following ischaemia and reperfusion. Cardiovasc Res 61:512–521

    Article  PubMed  CAS  Google Scholar 

  • Gastl G, Spizzo G, Obrist P, Dünser M, Mikuz G (2000). Ep-CAM overexpression in breast cancer as a predictor of survival. Lancet 356:1981–1982

    Article  PubMed  CAS  Google Scholar 

  • Griendling KK, Alexander RW. (1997). Oxidative stress and cardiovascular disease. Circulation 96:3264–3265

    PubMed  CAS  Google Scholar 

  • Jones PL, Boss JM (1997). Tumor necrosis factor alpha and interleukin-1 beta regulate the murine manganese superoxide dismutase gene through a complex inotronic enhancer involving C/EBP-beta and NF-kB. Mol Cell Biol 17:6970–6981

    PubMed  CAS  Google Scholar 

  • Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F (1997). Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 96:3300–3307

    PubMed  CAS  Google Scholar 

  • Kurrelmeyer KM, Michael L, Baumgarten G, et al (2000). Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 100:5456–5461

    Article  Google Scholar 

  • Lancel S, Tissier S, Mordon S, et al (2004). Peroxynitrite decompositon catalysts prevent myocardical dysfunction and inflamamtion in endotoxemic rats. J Am Coll Cardiol 43:2348–2358

    Article  PubMed  CAS  Google Scholar 

  • Liao Y, Cooper RS, McGee DL (1994). Iron status and coronary heart disease: negative findings from the NHANES I epidemilogic follow-up study. Am J Epidemiol 139:704–712

    PubMed  CAS  Google Scholar 

  • Ludwiczek S, Theurl I, Artner-Dworzak E, Chorney M, Weiss G (2004). Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability. J Mol Med 82:373–382

    Article  PubMed  CAS  Google Scholar 

  • Melillo G, Taylor LS, Brooks A, Musso T, Cox GW, Varesio L (1997). Functional requirement of the hypoxia-responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine. J Biol Chem 272:12236–12243

    Article  PubMed  CAS  Google Scholar 

  • Metzler B, Mair J, Lercher A, Hintringer F, Pachinger O, Xu Q (2001). Mouse model of myocardial remodeling after ischemia: role of intercellular adhesion molecule-1. Cardivasc Res 49:399–407

    Article  CAS  Google Scholar 

  • Metzler B, Hammerer-Lercher A, Jehle J et al. (2002). Plasma cardiac troponin T closely correlates with infarct size in a mouse model of acute myocardial infarction. Clin Chim Acta 325:87–90

    Article  PubMed  CAS  Google Scholar 

  • Michael LH, Entman ML, Youker KA, (1995). Myocardial ischemia and reperfusion: a murine model. Am J Physiol 269:H2147–H2154

    PubMed  CAS  Google Scholar 

  • Moncada S (1997). Nitric oxide in the vasculature: physiology and pathophysiology. Ann NY Acad Sci 811:60–67

    Article  PubMed  CAS  Google Scholar 

  • Morita K, Ihnken K, Buckberg GD, Sherman MP, Young HH, Ignarro LJ (1994). Role of controlled cardiac reoxygenation in reducing nitric oxide production and cardiac oxidant damage in cyanotic infantile hearts. J Clin Invest 93:2658–2666

    Article  PubMed  CAS  Google Scholar 

  • Mungrue IM, Gros R, You X, et al. (2002). Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109:735–743

    Article  PubMed  CAS  Google Scholar 

  • Naranjan S, Dhalla S, Makino N (2000). Status of myocardial antioxidants in ischemia reperfusion injury. Cardiovasc Res 47:446–456

    Article  Google Scholar 

  • Nathan C, **e QW (1994). Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918

    Article  PubMed  CAS  Google Scholar 

  • Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S (2004). Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci USA 101:7630–7635

    Article  PubMed  CAS  Google Scholar 

  • Papanikolaou G, Pantopoulos K (2005). Iron metabolism and toxicity. Toxicol Appl Pharmacol 202:199–211

    Article  PubMed  CAS  Google Scholar 

  • Pietrangelo A (2004). Hereditary hemochromatosis – a new look at an old disease. N Engl J Med 350:2383–2397

    Article  PubMed  CAS  Google Scholar 

  • Sack MN, Smith RM, Opie LH (2000). Tumor necrosis factor in myocardial hypertrophy and ischemia – an anti-apoptotic perspective. Cardiovasc Res 3:688–695

    Article  Google Scholar 

  • Saito T, Hu F, Tayara L, Fahas L, Shennib H, Giaid A (2002). Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure. Am J Physiol Heart Circ Physiol 283:H339–H345

    PubMed  CAS  Google Scholar 

  • Schneider BD, Leibold EA (2003). Effects of iron regulatory protein regulation on iron homeostasis during hypoxia. Blood 102:3404–3411

    Article  PubMed  CAS  Google Scholar 

  • Strieter RM, Bone RC (1993). Role of tumor necrosis factor in disease states and inflammation. Crit Care Med 21:S447–S463

    Article  PubMed  CAS  Google Scholar 

  • Theurl I, Ludwiczek S, Fritsche G, Garimorth K, Bellman-Weiler R, Weiss G (2005). The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals 18:359–367

    Article  PubMed  CAS  Google Scholar 

  • Tuomainen TP, Kontula K, Nyssonen K, Lakka TA, Helio T, Salonen JT (1999). Increased risk of acute myocardial infarction in carriers of the hemochromatosis gen Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation 100:1274–1279

    PubMed  CAS  Google Scholar 

  • Turoczi T, Jun L, Cordis G et al (2003). HFE mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice. Circ Res 92:1240–1246

    Article  PubMed  CAS  Google Scholar 

  • Verma S, Fedak PW, Weisel RD et al (2002). Fundamentals of reperfusion injury for the clinical cardiologist. Circulation 100:2332–2336

    Article  Google Scholar 

  • Warner BB, Wispe JR (1996). Redox regulation of manganese superoxide dismutase. Am J Physiol 271:L150–L158

    PubMed  CAS  Google Scholar 

  • Weiss G, Goossen B, Doppler W et al (1993). Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J 12:3651–3657

    PubMed  CAS  Google Scholar 

  • Weiss G, Werner-Felmayer G, Werner ER, Grunewald K, Wachter H, Hentze MW (1994). Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med 180:969–976

    Article  PubMed  CAS  Google Scholar 

  • Zingarelli B, Salzman AL, Szabo C (1998). Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 83:85–94

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Austrian research funds FWF, project 15943 (G.W.) and by the “Joseph-Skoda-Projektförderungspreis” of the österreichische Gesellschaft für Innere Medizin (B.M).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Günter Weiss.

Additional information

Both authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Metzler, B., Jehle, J., Theurl, I. et al. Short term protective effects of iron in a murine model of ischemia/reperfusion. Biometals 20, 205–215 (2007). https://doi.org/10.1007/s10534-006-9034-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-006-9034-y

Keywords

Navigation