A new paradigm: cross talk of protein kinases during reperfusion saves life!

Abstract

EDITORIALA new paradigm: cross talk of protein kinases during reperfusion saves life!Rainer SchulzRainer SchulzPublished Online:01 Jan 2005https://doi.org/10.1152/ajpheart.00886.2004MoreSectionsPDF (42 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat timely reperfusion after myocardial ischemia is the prerequisite to reduce irreversible tissue injury (16). However, reperfusion itself after a prolonged ischemic period may contribute to tissue damage, including reversible contractile dysfunction of viable cardiomyocytes (4, 14) as well as cardiomyocyte necrosis and apoptosis (8, 22).To reduce the consequences of ischemia-reperfusion injury, many studies have been undertaken to define its underlying mechanisms. A better understanding of the signal transduction cascade involved in irreversible tissue injury came from the analysis of triggers and mediators involved in the endogenous cardioprotective phenomenon of ischemic preconditioning. Activation of certain sarcolemmal receptors during the preconditioning ischemic period triggers and subsequent activation of protein kinases during the sustained ischemia mediates the infarct size reduction by ischemic preconditioning. Depending on the animal species, some of these kinases act in parallel as demonstrated for protein kinase C and protein tyrosine kinases; in pigs, pharmacological inhibition of neither protein kinase C nor protein tyrosine kinase alone was sufficient to block the protection of ischemic preconditioning, but combined blockade completely abolished the infarct size reduction by ischemic preconditioning (30). Similar results were subsequently obtained in rat and dog hearts as well (7, 18, 27). Within a given family of protein kinases, certain isoforms appear to be important for mediating the cardioprotection by ischemic preconditioning, i.e., protein kinase C-α and/or -ε (for a review, see Ref. 25), p38 MAPK-β (26), or p44 ERK MAPK (6), whereas other isoforms contribute to the ischemia-reperfusion-induced irreversible tissue injury, i.e., p38 ERK MAPK-α (23).Certain protein kinases that are activated during ischemia are activated to an even greater extent during the subsequent period of reperfusion. Such a pattern of activation is seen for p42/p44 ERK MAPK; ERK MAPKs are activated during ischemia (2, 3, 6, 21), but their activation is further increased early on during the subsequent reperfusion period (2, 6, 21), especially in preconditioned hearts (6). Also, many pharmacological interventions that were initiated at the time of reperfusion (for a review, see Ref. 13) and reduced infarct size activated the ERK MAPK pathway. Activated ERK MAPK phosphorylates the proapoptotic factor BAD, thereby reducing its affinity and binding to the antiapoptotic factor BCLXL. In consequence, the ratio of unbound pro- (BAD) and antiapoptotic (BCLXL) factors is altered, resulting in a reduced incidence of apoptosis (24). Indeed, in isolated rat cardiomyocytes, blockade of ERK MAPK activation by PD-98059 increased the extent of apoptosis (32).In a recent study, Hausenloy et al. (13) also assessed the time course of protein kinase phosphorylation during global ischemia and subsequent reperfusion in nonpreconditioned and preconditioned isolated rat hearts. The authors reported a decrease of phosphatidylinositol 3-kinase (PI3K) and ERK MAPK phosphorylation during the sustained ischemic period but a marked increase in the phosphorylation of both kinases during the subsequent period of reperfusion in preconditioned hearts. This increase in kinase phosphorylation during reperfusion confirms previous data obtained for ERK MAPK (6) and PI3K [see a recently published study by the same group (12)]. Such an increase in kinase phosphorylation was involved in the protection of ischemic preconditioning, because the blockade of either PI3K (using LY-29408) or ERK MAPK (using PD-98059) at the time of reperfusion abolished the infarct size reduction by ischemic preconditioning.These data are of great importance because they extend our view on ischemic preconditioning in that the mediation and execution of protection occurs to a large extent during the reperfusion period after the sustained ischemia.In a previously published study (12), the authors proposed a cross talk of PI3K and ERK MAPK, because blockade of PI3K phosphorylation increased ERK MAPK phosphorylation. Blockade of neither PI3K nor ERK MAPK phosphorylation alone was sufficient to block the phosphorylation of the downstream protein kinase target, i.e., phosphorylation of the p70S6K protein kinase, implying that both PI3K and ERK MAPK kinase acted in parallel on p70S6K protein kinase. This conclusion, however, contrasts to the data of the present study, in which blockade of either PI3K or ERK MAPK alone completely attenuated the reperfusion-induced phosphorylation of p70S6K protein kinase. However, given the fact that blockade of either p70S6K protein kinase (using rapamycin) (12) or PI3K (present study) or ERK MAPK (present study) at the time of reperfusion completely abolished the protection of ischemic preconditioning, the present findings on kinase phosphorylation appear more reasonable.As outlined above, the activation of ERK MAPK reduced cardiomyocyte apoptosis (32), a mechanism proposed by Hausenloy et al. (13) to be important for the protection observed in their experiments. However, the authors did not measure cardiomyocyte apoptosis (which might be difficult in the short time frame of reperfusion) but instead assessed a reduction in myocardial necrosis. Common cellular targets for both apoptosis and necrosis are the mitochondria. Tonic release of factors such as cytochrome c from mitochondria can induce cardiomyocyte apoptosis (20), whereas massive opening of the mitochondrial permeability transition pore (MPTP) leads to cardiomyocyte necrosis (19). Indeed, blockade of the MPTP at the time of reperfusion reduced irreversible tissue injury (5, 9–11), and ischemic preconditioning delayed opening of the MPTP during reperfusion (1).How could protein kinases mediate their cardioprotective effect? It has been suggested that antiapoptotic factors such as BCL bind to the outside of the MPTP (outer mitochondrial membrane), thereby influencing its open probability (29). Under such circumstances, increased phosphorylation of factors such as BCL by protein kinases (for example, ERK MAPK) in preconditioned hearts could keep the MPTP closed during early reperfusion, thereby reducing the release of proapoptotic factors (from the intermembrane space) and irreversible tissue injury.In conclusion, there is now good evidence that reperfusion not only salvages myocardium from irreversible tissue damage but might also be capable of inducing cell death via apoptosis and necrosis. Modification of the initial minutes of reperfusion–by application of pharmacological agents (13), by ischemic preconditioning (see present study), or even by ischemic postconditioning (15, 17, 28, 31, 33)–reduces the extent of irreversible tissue injury. The recent study as well as others published by Hausenloy and colleagues clearly demonstrate that activation of protein kinases such as PI3K, ERK MAPK, and p70S6K protein kinase plays an important role in mediating such cardioprotection (28). As previously suggested for protein kinase C and protein tyrosine kinase during ischemia (30), a cross talk might exist also for PI3K and ERK MAPK during reperfusion (12). The cellular target(s) might be located at the level of the mitochondria; however, the precise protein(s) and their interaction(s) have still to be defined.REFERENCES1 Argaud L, Gateau-Roesch O, Chalabreysse L, Gomez L, Loufouat J, Thivolet-Bejui F, Robert D, and Ovize M. Preconditioning delays Ca2+-induced mitochondrial permeability transition. Cardiovasc Res 61: 115–122, 2004.Crossref | PubMed | ISI | Google Scholar2 Barancik M, Htun P, Maeno Y, Zimmermann R, and Schaper W. Differential regulation of distinct protein kinase cascades by ischemia and ischemia/reperfusion in porcine myocardium (Abstract). Circulation 96, Suppl: I-252, 1997.Google Scholar3 Behrends M, Schulz R, Post H, Alexandrov A, Belosjorow S, Michel MC, and Heusch G. Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am J Physiol Heart Circ Physiol 279: H1111–H1119, 2000.Link | ISI | Google Scholar4 Bolli R and Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 70: 609–634, 1999.Google Scholar5 Di Lisa F, Canton M, Menabó R, Dodoni G, and Bernardi P. Mitochondria and reperfusion injury. The role of permeability transition. Basic Res Cardiol 98: 235–241, 2003.Crossref | PubMed | ISI | Google Scholar6 Fryer RM, Pratt PF, Hsu AK, and Gross G. Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther 296: 642–649, 2001.PubMed | ISI | Google Scholar7 Fryer RM, Schultz JJ, Hsu AK, and Gross GJ. Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts. Am J Physiol Heart Circ Physiol 276: H1229–H1235, 1999.Link | ISI | Google Scholar8 Garcia-Dorado D. Myocardial reperfusion injury: a new view. Cardiovasc Res 61: 363–364, 2004.Crossref | PubMed | ISI | Google Scholar9 Gillespie JP and Halestrap AP. Mitochondria and reperfusion injury–a pore death. The Bulletin 12: 4–11, 1997.Google Scholar10 Halestrap AP, Clarke SJ, and Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res 61: 372–385, 2004.Crossref | PubMed | ISI | Google Scholar11 Hausenloy DJ, Duchen MR, and Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 60: 617–625, 2003.Crossref | PubMed | ISI | Google Scholar12 Hausenloy DJ, Mocanu MM, and Yellon DM. Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res 63: 305–312, 2004.Crossref | PubMed | ISI | Google Scholar13 Hausenloy DJ and Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 61: 448–460, 2004.Crossref | PubMed | ISI | Google Scholar14 Heusch G. Stunning–great paradigmatic, but little clinical importance. Basic Res Cardiol 93: 164–166, 1998.Crossref | PubMed | ISI | Google Scholar15 Heusch G. Postconditioning: old wine in a new bottle? J Am Coll Cardiol 44: 1111–1112, 2004.Crossref | PubMed | ISI | Google Scholar16 Jennings RB and Reimer KA. Factors involved in salvaging ischemic myocardium: effect of reperfusion of arterial blood. Circulation 68, Suppl I: I-25–I-36, 1983.Google Scholar17 Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, and Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62: 74–85, 2004.Crossref | PubMed | ISI | Google Scholar18 Kitakaze M, Node K, Asanuma H, Takashima S, Sakata Y, Asakura M, Sanada S, Shinozaki Y, Mori H, Kuzuya T, and Hori M. Protein tyrosine kinase is not involved in the infarct size-limiting effect of ischemic preconditioning in canine hearts. Circ Res 87: 303–308, 2000.Crossref | PubMed | ISI | Google Scholar19 Kroemer G and Reed JC. Mitochondrial control of cell death. Nat Med 6: 513–519, 2000.Crossref | PubMed | ISI | Google Scholar20 Martinou JC, Desagher S, and Antonsson B. Cytochrome c release from mitochondria: all or nothing. Nat Cell Biol 2: E41–E43, 2000.Crossref | PubMed | ISI | Google Scholar21 Omura T, Yoshiyama M, Shimada T, Shimizu N, Kim S, Iwao H, Tekeuchi K, and Yoshikawa J. Activation of mitogen-activated protein kinases in vivo ischemia/reperfused myocardium in rats. J Mol Cell Cardiol 31: 1269–1279, 1999.Crossref | PubMed | ISI | Google Scholar22 Piper HM, Abdallah Y, and Schäfer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res 61: 365–371, 2004.Crossref | PubMed | ISI | Google Scholar23 Saurin AT, Martin JL, Heads RJ, Foley C, Mockridge JW, Wright MJ, Wang Y, and Marber MS. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB J 14: 2237–2246, 2000.Crossref | PubMed | ISI | Google Scholar24 Scheid MP, Schubert KM, and Duronio V. Regulation of bad phosphorylation and association with Bcl-xL by the MAPK/Erk kinase. J Biol Chem 274: 31108–31113, 1999.Crossref | PubMed | ISI | Google Scholar25 Schulz R, Cohen MV, Behrends M, Downey JM, and Heusch G. Signal transduction of ischemic preconditioning. Cardiovasc Res 52: 181–198, 2001.Crossref | PubMed | ISI | Google Scholar26 Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, and Heusch G. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J 17: 1355–1357, 2003.Crossref | PubMed | ISI | Google Scholar27 Tanno M, Tsuchida A, Nozawa Y, Matsumoto T, Hasegawa T, Miura T, and Shimamoto K. Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat. J Cardiovasc Pharmacol 35: 345–352, 2000.Crossref | PubMed | ISI | Google Scholar28 Tsang A, Hausenloy DJ, Mocanu MM, and Yellon DM. Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95: 230–232, 2004.Crossref | PubMed | ISI | Google Scholar29 Tsujimoto Y and Shimizu S. Bcl-2 family: life-or-death switch. FEBS Lett 466: 6–10, 2000.Crossref | PubMed | ISI | Google Scholar30 Vahlhaus C, Schulz R, Post H, Rose J, and Heusch G. Prevention of ischemic preconditioning only by combined inhibition of protein kinase C and protein tyrosine kinase in pigs. J Mol Cell Cardiol 30: 197–209, 1998.Crossref | PubMed | ISI | Google Scholar31 Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, and Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect hearts by targeting cell signaling pathways. J Am Coll Cardiol 44: 1103–1110, 2004.Crossref | PubMed | ISI | Google Scholar32 Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC, Feuerstein GZ, Thomas H, Maleeff B, and Ohlstein EH. Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 86: 692–699, 2000.Crossref | PubMed | ISI | Google Scholar33 Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, and Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285: H579–H588, 2003.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: R. Schulz, Institut für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany (E-mail: [email protected]) Download PDF Back to Top Next FiguresReferencesRelatedInformationCited ByThe PI3K-AKT-mTOR pathway activates recovery from general anesthesia19 June 2016 | Oncotarget, Vol. 7, No. 27Total Saikosaponins Attenuates Depression-Like Behaviors Induced by Chronic Unpredictable Mild Stress in Rats by Regulating the PI3K/AKT/NF-κB Signaling AxisEvidence-Based Complementary and Alternative Medicine, Vol. 2022Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning24 June 2015Molecular Basis of CardioprotectionCirculation Research, Vol. 116, No. 4Role of p38 inhibition in cardiac ischemia/reperfusion injury29 December 2011 | European Journal of Clinical Pharmacology, Vol. 68, No. 5Transient anoxia and oxyradicals induce a region-specific activation of MAPKs in the embryonic heart21 March 2010 | Molecular and Cellular Biochemistry, Vol. 340, No. 1-2Myocardial preconditioning and cardioprotection by volatile anaestheticsJournal of Cardiovascular Medicine, Vol. 7, No. 2 More from this issue > Volume 288Issue 1January 2005Pages H1-H2 Copyright & PermissionsCopyright © 2005 by the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00886.2004PubMed15598864History Published online 1 January 2005 Published in print 1 January 2005 Metrics