Skip to main content
SpringerLink
Log in

Comparison Between Ischaemic and Anisomycin-Induced Preconditioning: Role of p38 MAPK

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

To further evaluate the significance of p38 MAPK as trigger or mediator in ischaemic preconditioning, anisomycin and SB 203580 were used to manipulate its activation status. Special attention was given to the concentration of the drugs and protocols used.

The isolated perfused rat heart, subjected to either 25 min global ischaemia or 35 min regional ischaemia, was used as experimental model. This was preceded by anisomycin (2 or 5 μM: 3 × 5 min; 5 μM: 5 min or 10 min; 5 μM: 10 min + 10 min washout or 20 μM: 20 min) or SB 203580 (2 μM: 3 × 5 min; before and during 3 × 5 min or 1 × 5 min ischaemic preconditioning; 10 min). Endpoints were functional recovery during reperfusion and infarct size.

Anisomycin, regardless of the protocol, reduced infarct size, but did not improve functional recovery. In a number of experiments activation of JNK by anisomycin was blocked by SP 600125 (10 μM). SP 600125 had no effect on the anisomycin-induced reduction in infarct size. SB 203580 when administered for 10 min before sustained ischaemia, improved functional recovery and reduced infarct size. SB 203580 could not abolish the beneficial effects of a multi-cycle preconditioning protocol, but it significantly reduced the outcome of 1 × 5 min preconditioning. In all hearts improved functional recovery and reduction in infarct size were associated with attenuation of p38 MAPK activation during sustained ischaemia-reperfusion.

The results indicate that activation of p38 MAPK acts as a trigger of preconditioning, while attenuation of its activation is a prerequisite for improved recovery and a reduction in infarct size.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Michel MC, Li Y, Heusch G. Mitogen-activated protein kinases in the heart. Naunyn-Schmiedberg's Arch Pharmacol 2001;363:245-266.

    Google Scholar 

  2. Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G. Signal transduction in ischaemic preconditioning. Cardiovasc Res 2001;52:181-198.

    Google Scholar 

  3. Ping P, Zhang J, Huang S, et al. PKC-dependent activation of p46/54 JNKs during ischaemic preconditioning in conscious rabbits. Am J Physiol 1999;277:H1771-H1785.

    Google Scholar 

  4. Ping P; Zhang J, Cao X, et al. PKC-dependent activation of p44/p42MAPKsduring myocardial ischaemia-reperfusion in conscious rabbits. Am J Physiol 1999;276:H1468-H1481.

    Google Scholar 

  5. Marais E, Genade S, Huisamen B, Strijdom JG, Moolman JA, Lochner A. Activation of p38 MAPK induced by a multicycle ischaemic preconditioning protocol is associated with attenuated p38 MAPK activity during sustained ischaemia and reperfusion. J Mol Cell Cardiol 2001;33:769-778.

    Google Scholar 

  6. Sato M, Cordis GA, Maulik N, Das DK. SAPKs regulation of ischemic preconditioning. Am J Physiol 2000;279:H901-H907.

    Google Scholar 

  7. Sanada S, Kitakaze M, Papst P, et al. Role of phasic dynamism of p38 mitogen activated protein kinase activation in ischemic preconditioning of the canine heart. Circ Res 2001;88:175-180.

    Google Scholar 

  8. Fryer RM, Patel HH, Hsu AK, Gross GJ. Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium. Am J Physiol 2001;281:H1184-H1192.

    Google Scholar 

  9. Nakano A, Cohen MV, Critz S, Downey JM. SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts. Bas Res Cardiol 2000;95:466-471.

    Google Scholar 

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

    Google Scholar 

  11. Marais E, Genade S, Strijdom H, Moolman JA, Lochner A. p38MAPKactivation triggers pharmacologically-induced ?-adrenergic preconditioning, but not ischaemic preconditioning. J Mol Cell Cardiol 2001;33:2157-2177.

    Google Scholar 

  12. Schneider S, Chen Z, Hon J, Steenbergen C, Murphy E. Inhibition of p38 MAPK ?/? reduces ischemic injury and does not block protective effects of preconditioning. Am J Physiol 2001;280:H499-H508.

    Google Scholar 

  13. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, et al. Stimulation of the stress-activated mitogen-activated protein kinase subfamily in the perfused heart. p38/ERK mitogen-activated protein kinases and c-Jun N-terminal kinases. Circ Res 1996;79:162-173.

    Google Scholar 

  14. Ma XL, Kumar S, Gao F, et al. Inhibition of p38 mitogenactivated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 1999;99:1685-1691.

    Google Scholar 

  15. Weinbrenner C, Liu GS, Cohen MV, Downey JM. Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Mol Cell Cardiol 1997;29:2383-2391.

    Google Scholar 

  16. Nakano A, Baines CP, Kim SO, et al. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: Evidence for involvement of p38 MAPK. Circ Res 2000;86:141-151.

    Google Scholar 

  17. Maulik N, Yoshida T, Zu Y-L, Sato M, Banerjee A, Das DK. Ischemic preconditioning triggers tyrosine kinase signalling: Apotential role for MAPKAP kinase 2. Am J Physiol 1998;275:H1857-H1865.

    Google Scholar 

  18. Sakamoto K, Urushidanie T, Nagao T. Translocation of HSP27 to sarcomere induced by ischemic preconditioning in isolated rat hearts. Biochem Biophys Res Commun 2000;269:137-142.

    Google Scholar 

  19. Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA, Glembotski CC. MKK6 activates myocardial cell NF-kB and inhibits apoptosis in a p38 mitogenactivated protein kinase-dependent manner. J Biol Chem 1998;273:8232-8239.

    Google Scholar 

  20. Törócsik B, Szeberényi J. Anisomycin affects both pro-and antiapoptotic mechanisms in PC12 cells. Biochem Biophys Res Commun 2000;278:550-556.

    Google Scholar 

  21. Lochner A, Genade S, Tromp E, Podzuweit T, Moolman JA. Ischemic preconditioning and the ?-adrenergic signal transduction pathway. Circulation 1999;100:958-966.

    Google Scholar 

  22. Kannengieser GJ, Opie LH, Van der Werff TJ. Impaired cardiac work and oxygen uptake after reperfusion of regionally ischaemic myocardium. J Mol Cell Cardiol 1979;11:197-207.

    Google Scholar 

  23. Steenbergen C. The role of p38 mitogen-activated protein kinase in myocardial ischaemia/reperfusion injury; relationships to ischemic preconditioning. Bas Res Cardiol 2002;97:276-285.

    Google Scholar 

  24. Baines CP, Liu GS, Birincioglu M, Critz SD, Cohen MV, Downey JM. Ischaemic preconditioning depend on interaction between mitochondrial KATP channels and actin cytoskeleton. Am J Physiol 1999;276:H1361-1368.

    Google Scholar 

  25. Barancik M, Htun P, Schaper W. Okadaic acid and anisomycin are protective and stimulate the SAPK/JNK pathway. J Cardiovasc Pharmacol 1999;34:182-190.

    Google Scholar 

  26. Bennett BL, Sasaki DT, Murray BW, et al. SP 600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 2001;98:13681-13686.

    Google Scholar 

  27. Tong L, Pav S, White DM, et al. A highly specific inhibitor of human p38 MAPK binds in the ATP pocket. Nat Struct Biol 1997;4:311-316.

    Google Scholar 

  28. Young P, McLaughlin MM, Kumar S, et al. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J Biol Chem 1997;272:12116-12121.

    Google Scholar 

  29. Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM. The p38 MAPK inhibitor, SB 203580, abrogates ischemic preconditioning in rat heart but timing of administration is critical. Bas Res Cardiol 2000;95:472-478.

    Google Scholar 

  30. Sandhu R, Diaz RJ, Mao GD, Wilson GJ. Ischemic preconditioning. Differences in protection and susceptibility to blockade with single-cycle versus multicycle transient ischaemia. Circulation 1997;96:984-995.

    Google Scholar 

  31. Cohen MV, Barnes CP, Downey JM. Ischemic preconditioning: From adenosine receptor to KATP channel. Ann Rev Physiol 2000;62:79-109.

    Google Scholar 

  32. Barancik M, Htun P, Strohm C, Kilian S, Schaper W. Inhibition of cardiac p38 MAPK pathway by SB 203580 delays ischemic cell death. J Cardiovasc Pharmacol 2000;35:474-483.

    Google Scholar 

  33. Saurin AT, Martin JC, Heads RJ, et al. The role of differential activation of p38 mitogen-activated protein kinase in preconditioned ventricular myocytes. Faseb J 2000;14:2237-2246.

    Google Scholar 

  34. MacKay K, Mochley-Rosen D. An inhibitor of p38 mitogenactivated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 1999;274:6272-6279.

    Google Scholar 

  35. Nagarkatti DS, Sha'afi RI. Role of p38 MAPKinase in myocardial stress. J Mol Cell Cardiol 1998;30:1651-1664.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MRC Diabetes Research Group, Tygerberg, Republic of South Africa

    A. Lochner

  2. Department of Medical Physiology and Biochemistry, University of Stellenbosch Faculty of Health Science, Tygerberg, Republic of South Africa

    S. Genade, S. Hattingh, E. Marais & J. A. Moolman

  3. MRC Diabetes Research Group, Tygerberg, Republic of South Africa

    B. Huisamen

Authors
  1. A. Lochner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Genade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Hattingh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Marais
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Huisamen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. A. Moolman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lochner, A., Genade, S., Hattingh, S. et al. Comparison Between Ischaemic and Anisomycin-Induced Preconditioning: Role of p38 MAPK. Cardiovasc Drugs Ther 17, 217–230 (2003). https://doi.org/10.1023/A:1026116022552

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026116022552

Search

Navigation