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Myocardial protection evoked by hyperoxic exposure involves signaling through nitric oxide and mitogen activated protein kinases

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Abstract

Background

Hyperoxic exposure in vivo (> 95% oxygen) attenuates ischemia-reperfusion injury, but the signaling mechanisms of this cardioprotection are not fully determined. We studied a possible role of nitric oxide (NO) and mitogen activated protein kinases (MAPK) in hyperoxic protection.

Methods

Mice (n = 7–9 in each group) were kept in normoxic or hyperoxic environments for 15 min prior to harvesting the heart and Langendorff perfusion with global ischemia (45 min) and reperfusion (60 min). Endpoints were cardiac function and infarct size. Additional hearts were collected to evaluate MAPK phosphorylation (immunoblot). The nitric oxide synthase inhibitor L-NAME, the ERK1/2 inhibitor PD98059 and the p38 MAPK inhibitor FR167653 were injected intraperitoneally before hyperoxia or normoxia.

Results

Hyperoxia improved postischemic functional recovery and reduced infarct size (p < 0.05). Hyperoxic exposure caused cardiac phosphorylation of the MAPK family members p38 and ERK1/2, but not JNK. L-NAME, PD98059 and FR167653 all reduced the protection afforded by hyperoxic exposure, but did not influence performance or infarction in hearts of normoxic mice. The hyperoxia-induced phosphorylation of ERK1/2 and p38 was reduced by L-NAME and both MAPK inhibitors.

Conclusion

Nitric oxide triggers hyperoxic protection, and ERK1/2 and p38 MAPK are involved in signaling of protection against ischemia-reperfusion injury.

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References

  1. Armstrong SC (2004) Protein kinase activation and myocardial ischemia/ reperfusion injury. Cardiovasc Res 61:427–436

    Article  PubMed  CAS  Google Scholar 

  2. Armstrong SC, Delacey M, Ganote CE (1999) Phosphorylation state of hsp27 and p38 MAPK during preconditioning and protein phosphatase inhibitor protection of rabbit cardiomyocytes. J Mol Cell Cardiol 31:555–567

    Article  PubMed  CAS  Google Scholar 

  3. Baines CP, Goto M, Downey JM (1997) Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol 29:207–216

    Article  PubMed  CAS  Google Scholar 

  4. Barman SA (2005) Effect of nitric oxide on mitogen-activated protein kinases in neonatal pulmonary vascular smooth muscle. Lung 183:325–335

    Article  PubMed  CAS  Google Scholar 

  5. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40

    Article  PubMed  CAS  Google Scholar 

  6. Csonka C, Szilvassy Z, Fulop F, Pali T, Blasig IE, Tosaki A, Schulz R, Ferdinandy P (1999) Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 100:2260–2266

    PubMed  CAS  Google Scholar 

  7. Dawn B, Bolli R (2002) Role of nitric oxide in myocardial preconditioning. Ann N Y Acad Sci 962:18–41

    PubMed  CAS  Google Scholar 

  8. Hiasa G, Hamada M, Ikeda S, Hiwada K (2001) Ischemic preconditioning and lipopolysaccharide attenuate nuclear factor-kappaB activation and gene expression of inflammatory cytokines in the ischemia-reperfused rat heart. Jpn Circ J 65:984–990

    Article  PubMed  CAS  Google Scholar 

  9. Li G, Tokuno S, Tahep ld P, Vaage J, Lowbeer C, Valen G (2001) Preconditioning protects the severely atherosclerotic mouse heart. Ann Thorac Surg 71:1296–1303

    Article  PubMed  CAS  Google Scholar 

  10. Lochner A, Genade S, Hattingh S, Marais E, Huisamen B, Moolman JA (2003) Comparison between ischaemic and anisomycin-induced preconditioning: role of p38 MAPK. Cardiovasc Drugs Ther 17:217–230

    Article  PubMed  CAS  Google Scholar 

  11. Lochner A, Marais E, Du Toit E, Moolman J (2002) Nitric oxide triggers classic ischemic preconditioning. Ann N Y Acad Sci 962:402–414

    Article  PubMed  CAS  Google Scholar 

  12. Lochner A, Marais E, Genade S, Moolman JA (2000) Nitric oxide: a trigger for classic preconditioning? Am J Physiol Heart Circ Physiol 279:H2752–H2765

    PubMed  CAS  Google Scholar 

  13. Maulik N, Sato M, Price BD, Das DK (1998) An essential role of NFkappaB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. FEBS Lett 429: 365–369

    Article  PubMed  CAS  Google Scholar 

  14. Maulik N, Watanabe M, Zu YL, Huang CK, Cordis GA, Schley JA, Das DK (1996) Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. FEBS Lett 396:233–237

    Article  PubMed  CAS  Google Scholar 

  15. Michel MC, Li Y, Heusch G (2001) Mitogen- activated protein kinases in the heart. Naunyn Schmiedebergs Arch Pharmacol 363:245–266

    Article  PubMed  CAS  Google Scholar 

  16. Nakano A, Liu GS, Heusch G, Downey JM, Cohen MV (2000) Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning. J Mol Cell Cardiol 32:1159–1167

    Article  PubMed  CAS  Google Scholar 

  17. Ping P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG, Bolli R (1999) PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol 276:H1468–H1481

    PubMed  CAS  Google Scholar 

  18. Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, Banerjee S, Dawn B, Balafonova Z, Bolli R (1999) Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res 84:587–604

    PubMed  CAS  Google Scholar 

  19. Rakhit RD, Kabir AN, Mockridge JW, Saurin A, Marber MS (2001) Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury. Biochem Biophys Res Commun 286:995–1002

    Article  PubMed  CAS  Google Scholar 

  20. Ravingerova T, Barancik M, Strniskova M (2003) Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol Cell Biochem 247:127–138

    Article  PubMed  CAS  Google Scholar 

  21. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344

    Article  PubMed  CAS  Google Scholar 

  22. Saurin AT, Martin JL, Heads RJ, Foley C, Mockridge JW, Wright MJ, Wang Y, Marber MS (2000) The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. Faseb J 14:2237–2246

    Article  PubMed  CAS  Google Scholar 

  23. Steenbergen C (2002) The role of p38 mitogen-activated protein kinase in myocardial ischemia/reperfusion injury; relationship to ischemic preconditioning. Basic Res Cardiol 97:276–285

    Article  PubMed  CAS  Google Scholar 

  24. Zatta AJ, Headrick JP (2005) Mediators of coronary reactive hyperaemia in isolated mouse heart. Br J Pharmacol 144:576–587

    Article  PubMed  CAS  Google Scholar 

  25. Tahepold P, Elfstrom P, Eha I, Kals J, Taal G, Talonpoika A, Valen G, Vaage J, Starkopf J (2002) Exposure of rats to hyperoxia enhances relaxation of isolated aortic rings and reduces infarct size of isolated hearts. Acta Physiol Scand 175:271–277

    Article  PubMed  CAS  Google Scholar 

  26. Tahepold P, Ruusalepp A, Li G, Vaage J, Starkopf J, Valen G (2002) Cardioprotection by breathing hyperoxic gas – relation to oxygen concentration and exposure time in rats and mice. Eur J Cardiothorac Surg 21:987–994

    Article  PubMed  CAS  Google Scholar 

  27. Tahepold P, Vaage J, Starkopf J, Valen G (2003) Hyperoxia elicits myocardial protection through a nuclear factor kappaB-dependent mechanism in the rat heart. J Thorac Cardiovasc Surg 125:650–660

    Article  PubMed  CAS  Google Scholar 

  28. Tanno M, Gorog DA, Bellahcene M, Cao X, Quinlan RA, Marber MS (2003) Tumor necrosis factor-induced protection of the murine heart is independent of p38-MAPK activation. J Mol Cell Cardiol 35:1523–1527

    Article  PubMed  CAS  Google Scholar 

  29. Toma O, Weber NC, Wolter JI, Obal D, Preckel B, Schlack W (2004) Desflurane preconditioning induces time-dependent activation of protein kinase C epsilon and extracellular signal-regulated kinase 1 and 2 in the rat heart in vivo. Anesthesiology 101:1372–1380

    Article  PubMed  CAS  Google Scholar 

  30. Valen G, Tahepold P, Starkopf J, Ruusalepp A, Vaage J (2003) Adaptation to ischemia by hyperoxia – signalling through mitogen activated protein kinases and nuclear factor kappa B. In: Dhalla N HL, Kardani E, Singal PV (eds) Signal Transduction and Cardiac hypertrophy. MA: Kluwer Academic Publications, Boston, pp 461–477

  31. Valen G, Vaage J (2005) Pre- and postconditioning during cardiac surgery. Basic Res Cardiol 100:179–186

    Article  PubMed  Google Scholar 

  32. Valen G, Yan ZQ, Hansson GK (2001) Nuclear factor kappa-B and the heart. J Am Coll Cardiol 38:307–314

    Article  PubMed  CAS  Google Scholar 

  33. Yada M, Shimamoto A, Hampton CR, Chong AJ, Takayama H, Rothnie CL, Spring DJ, Shimpo H, Yada I, Pohlman TH, Verrier ED (2004) FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg 128:588–594

    Article  PubMed  CAS  Google Scholar 

  34. Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    PubMed  CAS  Google Scholar 

  35. Ytrehus K, Liu Y, Downey JM (1994) Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol 266:H1145–1152

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Basic Medical Science, Dept. of Physiology University of Oslo, Oslo, Norway

    A. Ruusalepp, G. Czibik, T. Flatebø & G. Valen

  2. Dept. of Cardiac Surgery, Tartu University Hospital, 51014, Tartu, Estonia

    A. Ruusalepp

  3. Ullevål University Hospital, Oslo, Norway

    J. Vaage

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  1. A. Ruusalepp
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  2. G. Czibik
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  3. T. Flatebø
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  4. J. Vaage
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  5. G. Valen
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Correspondence to A. Ruusalepp.

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Ruusalepp, A., Czibik, G., Flatebø, T. et al. Myocardial protection evoked by hyperoxic exposure involves signaling through nitric oxide and mitogen activated protein kinases. Basic Res Cardiol 102, 318–326 (2007). https://doi.org/10.1007/s00395-007-0644-5

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  • DOI: https://doi.org/10.1007/s00395-007-0644-5

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