Summary
The stress kinase, p38 mitogen activated protein kinase (p38 MAPK), is known to be activated by both ischaemia and reperfusion. Whether this activation is beneficial or deleterious is still a matter of debate. The aims of this study were to (i) evaluate the activation pattern of p38 MAPK during a multi-cycle preconditioning protocol, during sustained (index) ischaemia and during reperfusion (ii) use transient β-adrenergic stimulation to mimic ischaemic preconditioning and to study its effects on p38 MAPK activation and (iii) reevaluate the effects of p38 MAPK blockade by SB 203580 on cardioprotection elicited by ischaemic preconditioning as well as by β-adrenergic preconditioning. The isolated perfused working rat heart was subjected to a preconditioning protocol of 3 X 5 min global ischaemia or 5 min isoproterenol (10-7M) followed by 5 min washout. All hearts were then subjected to 25 min global ischaemia and 30 min reperfusion during which time mechanical function was monitored. Hearts were freeze-clamped at different time intervals for subsequent analysis of p38 MAPK activation using Western blotting and a p38 MAPK phospho-antibody (Thr 180/Tyr 182).
The results showed that p38 MAPK was activated transiently during a multi-cycle ischaemic preconditioning protocol and this was associated with attenuation of its kinase activity during both sustained ischaemia and reperfusion when compared with non-preconditioned hearts, β-adrenergic preconditioning induced a similar pattern of attenuated p38 MAPK activation during sustained ischaemia and reperfusion. In all cases attenuation of p38 MAPK activation during ischaemia and reperfusion was associated with improved mechanical recovery during reperfusion. Using SB 203580 it was shown that p38 MAPK activation was not required as a trigger for ischaemic preconditioning, whereas it was a prerequisite for β-adrenergic preconditioning.
Conclusions: Attenuation of p38 MAPK activation during sustained ischaemia and reperfusion is always associated with improved functional recovery during reperfusion, indicating that activation of this kinase is detrimental to the ischaemic heart.
Key words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Michel MC, Li Y, Heusch G. 2001. Mitogen-activated protein kinase in the heart. Naunyn-Schmiedeberg’s Arch Pharmacol 363:245–266.
Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G. 2001. Signal transduction in preconditioning. Cardiovasc Res 52:181–198.
Sugden PH, Clerk A. 1998. “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 83:345–352.
Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH. 1996. 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 79:162–173.
Weinbrenner C, Liu G-S, Cohen MV, Downey JM. 1997. Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Mol Cell Cardiol 29:2383–2391.
Kim SO, Baines CP, Critz SD, Pelech SL, Katz S, Downey JM, Cohen MV. 1999. Ischaemia-induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart. Biochem Cell Biol 77:559–567.
Marais E, Genade S, Huisamen B, Strijdom JG, Moolman JA, Lochner A. 2001. 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 33:769–778.
Maulik N, Yoshida T, Zu X-L, Sato M, Banerjee A, Das DK. 1998. Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. Am J Physiol 275:H1857–H1864.
Vahlhaus C, Schulz R, Post H, Onallah R, Heusch G. 1996. No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine. Circ Res 79:407–414.
Barancik M, Htun P, Strohm C, Kilian S, Schaper W. 2000. Inhibition of the cardiac p38 MAPK pathway by SB 203580 delays ischemic cell death. J Cardiovasc Pharmacol 35:474–483.
Sanada S, Kitakaze M, Papst PJ, Hatanaka K, Asanuma H et al. 2001. Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart. Circ Res 88:175–180.
Nakano A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, Critz SD. 2000. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart. Evidence for involvement of p38 MAPK. Circ Res 86:144–151.
Behrends M, Schulz R, Post H, Alexandrov A, Belosjorow S, Michel MC, Heusch G. 2000. Incosistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am J Physiol 279:H1111–H1119.
Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM. 2000. The p38 MAPK inhibitor, SB 203580, abrogates preconditioning, but timing of administration is critical. Bas Res Cardiol 95:472–478.
Saurin AT, Martin JC, Heads RJ, Foley C, Mockridge JW, Wright MJ, Wang Y, Marber S. 2000. The role of differential activation of p38 mitogen activated protein kinase in preconditioned ventricular myocytes. Faseb J 14:2237–2246.
Schneider S, Chen W, Hou J, Steenbergen C, Murphy E. 2001. Inhibition of p38 MAPK α/β reduces ischemic injury and does not block protective effects of preconditioning. Am J Physiol 280: H499–H508.
Gysembergh A, Simkhovich BZ, Kloner KA, Przyklenk K. 2001. p38 MAPK activity is not increased early during sustained coronary artery occlusion in preconditioned vs control rabbit heart. J Mol Cell Cardiol 33:681–690.
Cano E, Hazzalin CA, Mahadevan LC. 1994. Anisomycin-activated protein kinases p45 and p53 but not mitogen-activated protein kinases ERK-1 and -2 are implicated in the induction of c-fos and c-jun. Mol Cell Biol 14:7352–7362.
Cano E, Doza YN, Ben-Levy R, Cohen P, Mahadevan LC. 1996. Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. Oncogene 12:805–812.
Clerk A, Sugden PH. 1998. The p38-MAPK inhibitor, SB 203580, inhibits cardiac stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs). Febs Lett 426:93–96.
Wadsworth SA, Cavender DE, Beers SA, Lalan P et al. 1999. RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exptl Therap 291; 680–687.
Lochner A, Genade S, Tromp E, Podzuweit T, Moolman JA. 1999. Ischemic preconditioning and the β-adrenergic signal transduction pathway. Circulation 100:958–966.
Kannengieser GJ, Opie LH, Van der Werff TJ. 1979. Impaired cardiac work and oxygen uptake after reperfusion of regionally ischaemic myocardium. J Mol Cell Cardiol 11:197–207.
Bradford MM. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 71:248–254.
Schömig A, Haas M, Richard G. 1991. Catecholamine release and arrhythmias in acute myocardial ischaemia. Europ Heart Journal 12 (suppl): 38–47.
Lochner A, Marais E, Genade S, Moolman JA. 2000. Nitric oxide: a trigger for classic preconditioning. Am J Physiol 279:H2752–H2765.
Haq SEA, Clerk A, Sugden PH. 1998. Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by adenosine in the perfused heart. Febs Lett 434:305–308.
Das DK, Engelman RM, Maulik N. 1999. Oxygen free radical signalling in ischemic preconditioning. Ann NY Acad Sci 874:49–65.
Ping P, Zhang J, Huang S, Cao X, Tang X-L, Li RC et al. 1999. PKC dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. Am J Physiol 277: H1771–H1785.
Ping P, Zhang J, Cao X, Li RCX, Kong D, Tang X-L, 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.
Jennings RB, Reimer KA. 1991. The cell biology of acute myocardial ischemia. Ann Rev Med 42; 225–246.
MacKay K, Mochly-Rosen D. 1999. An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 274:6272–6279.
Yin T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, Hai T, Whelan J. 1997. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem 272:19943–19950.
Nagarkatti D, Sha’afi RI. 1998. Role of p38 MAP kinase in myocardial stress. J Mol Cell Cardiol 30:1651–1664.
Sato M, Cordis GA, Maulik N, Das DK. 2000. SAPKs regulation of ischemic preconditioning. Am J Physiol 279:H901–H907.
Zheng M, Zhang S-J, Zhu W-Z, Ziman B, Kobilka B, Ziao R-P. 2000. β2-adrenergic receptor induced p38 activation is mediated by PKA rather than by Gi or Gβα in adult mouse cardiomyocytes. J Biol Chem 275:40635–40640.
Communal C, Colucci WS, Singh K. 2000. p38 Mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against β-adrenergic receptor-stimulated apoptosis. J Biol Chem 275:19375–19400.
Asimakis GK, Inners-McBride K, Conti VR, Yang C. 1994. Transient β-adrenergic stimulation can precondition the rat heart against postischaemic contractile dysfunction. Cardiovasc Res 28:1726–1734.
Yabe K, Ishishita H, Tanonaka K, Takeo S. 1998. Pharmacologic preconditioning induced by β-adrenergic stimulation is mediated by activation of protein kinase C. J Cardiovasc Pharmacol 32:962–968.
Zhao TC, Taher MM, Valerie KC, Kukreja RC. 2001. p38 triggers late preconditioning elicited by anisomycin in the heart: involvement of NF-kappa B and iNOS. Circ Res 89:915–922.
Fryer RM, HSU AK, Gross GJ. 2001. ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. Bas Res Cardiol 96:136–142.
Cohen MV, Baines CP, Downey JM. 2000. Ischemic preconditioning: from adenosine receptor to KATP channel. Ann Rev Physiol 62:79–109.
Moolman JA, Genade S, Tromp E, Lochner A. 1996. A comparison between ischemic preconditioning and anti-adrenergic interventions: cAMP, energy metabolism and functional recovery. Bas Res Cardiol 91:219–233.
Wang Y, Huang S, Sah VP, Ross J Jr, Brown JH, Han J, Chien KR. 1998. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 273:2161–2168.
Armstrong SC, Delacy M, Ganote E. 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.
Sakamoto K, Urushidani T, Nagao T. 1998. Translocation of HSP27 to cytoskeleton by repetitive hypoxia-reoxygenation in the rat myoblast cell line, H9C2. Biochem Biophys Res Comm 251:576–579.
Bluhm WF, Martin JL, Mestril R, Dillman WH. 1998. Specific heat shock proteins protect microtubules during simulated ischemia in cardiac myocytes. Am J Physiol 275:H2243–H2249.
Kyriakis JM, Avruch J. 2001. Mammahan mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Phys Rev 81(2): 807–869.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
Lochner, A., Marais, E., Genade, S., Huisamen, B., Strijdom, H., Moolman, J.A. (2003). Ischaemic and Pharmacological Preconditioning Is Associated with Attenuation of p38 MAPK Activation During Sustained Ischaemia and Reperfusion. In: Dhalla, N.S., Takeda, N., Singh, M., Lukas, A. (eds) Myocardial Ischemia and Preconditioning. Progress in Experimental Cardiology, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0355-2_18
Download citation
DOI: https://doi.org/10.1007/978-1-4615-0355-2_18
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5036-1
Online ISBN: 978-1-4615-0355-2
eBook Packages: Springer Book Archive