Download PDF
Horm Metab Res 2009; 41(1): 10-15
DOI: 10.1055/s-0028-1087171
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Ischemic Preconditioning Phosphorylates Mitogen-activated Kinases and Heat Shock Protein 27 in the Diabetic Rat Heart

D. Ebel 1 , 2 , O. Toma 1 , S. Appler 1 , K. Baumann 1 , J. Fräßdorf 3 , B. Preckel 3 , P. Rösen 4 , W. Schlack 3 , N. C. Weber 3
  • 1Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
  • 2Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • 3Department of Anaesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • 4Deutsches Diabetes Zentrum, Heinrich-Heine-Universität, Düsseldorf, Germany
Further Information

Publication History

received 25.01.2008

accepted 17.07.2008

Publication Date:
22 September 2008 (online)

Also available at
    Permissions and Reprints

Abstract

Diabetes mellitus blocks protection by ischemic preconditioning (IPC), but the mechanism is not known. We investigated the effect of ischemic preconditioning on mitogen-activated protein kinases (extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases, p38 mitogen-activated kinase) and heat shock protein 27 phosphorylation in diabetic and nondiabetic rat hearts in vivo. Two groups of anaesthetized nondiabetic and diabetic rats underwent a preconditioning protocol (3 cycles of 3 min coronary artery occlusion and 5 min of reperfusion). Two further groups served as untreated controls. Hearts were excised for protein measurements by Western blot. Four additional groups underwent 25 min of coronary occlusion followed by 2 h of reperfusion to induce myocardial infarction. In these animals, infarct size was measured. IPC reduced infarct size in the nondiabetic rats but not in the diabetic animals. In diabetic rats, IPC induced phosphorylation of the mitogen-activated protein kinases and of heat shock protein 27. We conclude that protection by IPC is blocked by diabetes mellitus in the rat heart in vivo without affecting phosphorylation of mitogen-activated protein kinases or heat shock protein 27. Therefore, the blockade mechanism of diabetes mellitus is downstream of mitogen-activated kinases and heat shock protein 27.

Key words

diabetes mellitus - myocardial infarction - infarct size - signal transduction - cardioprotection - ischemia - reperfusion

References

  • 1 Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization Monica Project: registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in 4 continents.  Circulation. 1990;  90 583-612
    PubMedGoogle Scholar
  • 2 Feskens EJ, Kromhout D. Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study.  J Clin Epidemiol. 1992;  45 1327-1334
    CrossrefPubMedGoogle Scholar
  • 3 Kannel WB, MacGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study.  Diabetes Care. 1979;  2 120-126
    CrossrefPubMedGoogle Scholar
  • 4 Jelesoff NE, Feinglos M, Granger CB, Califf RM. Outcomes of diabetic patients following acute myocardial infarction: a review of the major thrombolytic trials.  Coron Artery Dis. 1996;  7 732-743
    PubMedGoogle Scholar
  • 5 Orlander PR, Goff DC, Morrissey M, Ramsey DJ, Wear ML, Labarthe DR, Nichaman MZ. The relation of diabetes to the severity of acute myocardial infarction and post-myocardial infarction survival in Mexican-Americans and non-Hispanic whites. The Corpus Christi Heart Project.  Diabetes. 1994;  43 897-902
    PubMedGoogle Scholar
  • 6 Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, Mittleman MA. Impact of diabetes on long-term survival after acute myocardial infarction.  Diabetes Care. 2001;  24 1422-1427
    PubMedGoogle Scholar
  • 7 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.  Circulation. 1986;  74 1124-1136
    CrossrefPubMedGoogle Scholar
  • 8 Bolli R. The late phase of preconditioning.  Circ Res. 2000;  87 972-983
    PubMedGoogle Scholar
  • 9 Kersten JR, Toller WG, Gross ER, Pagel PS, Warltier DC. Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality.  Am J Physiol Heart Circ Physiol. 2000;  278 H1218-H1224
    PubMedGoogle Scholar
  • 10 Ebel D, Müllenheim J, Fräßdorf J, Heinen A, Huhn R, Bohlen T, Ferrari J, Südkamp H, Preckel B, Schlack W, Thämer V. Effect of acute hyperglycemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischemic late preconditioning in the rabbit heart in vivo.  Pflügers Arch Eur J Physiol. 2003;  446 175-182
    PubMedGoogle Scholar
  • 11 Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, Kouno Y, Umemura T. Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction.  J Am Coll Cardiol. 2001;  38 1007-1011
    CrossrefPubMedGoogle Scholar
  • 12 Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C.  Circ Res. 2000;  87 309-315
    PubMedGoogle Scholar
  • 13 Mocanu MM, Bell RM, Yellon DM. PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning.  J Mol Cell Cardiol. 2002;  34 661-668
    CrossrefPubMedGoogle Scholar
  • 14 Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart. The importance of Akt Phosphorylation.  Diabetes. 2005;  54 2360-2364
    CrossrefPubMedGoogle Scholar
  • 15 Michel MC, Li Y, Heusch G. Mitogen-activated protein kinases in the heart.  Naunyn Schmiedebergs Arch Pharmacol. 2001;  363 245-266
    CrossrefPubMedGoogle Scholar
  • 16 Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology.  Physiol Rev. 2003;  83 1113-1151
    PubMedGoogle Scholar
  • 17 Nagy N, Shiroto K, Malik G, Huang CK, Gaestel M, Abdellatif M, Tosaki A, Maulik N, Das DK. Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target.  J Mol Cell Cardiol. 2007;  42 981-990
    CrossrefPubMedGoogle Scholar
  • 18 Clerk A, Michael A, Sudgen PH. Stimulation of multiple mitogen-activated protein kinases sub-families by oxidative stress and phosphorylation of the small heat shock proteins, HSP25/27, in neonatal ventricular myocytes.  Biochem J. 1998;  333 581-589
    PubMedGoogle Scholar
  • 19 Grussner R, Nakhleh R, Grussner A, Tomadze G, Diem P, Sutherland D. Streptozotocin-induced diabetes mellitus in pigs.  Horm Metab Res. 1993;  25 199-203
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Yoshino G, Matsushita M, Maeda E, Morita M, Nagata K, Matsuba K, Tani T, Horinuki R, Kimura Y, Kazumi T. Effect of probucol on re-covery from streptozotocin diabetes in rats.  Horm Metab Res. 1992;  24 306-309
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Garcia JB, Venturino MC, Alvarez E, Fabiano de BL, Braun M, Pivetta OH, Basabe JC. Insulin secretion stimulated by allogeneic lymphocytes in an inbred strain of mice.  J Clin Invest. 1986;  77 1453-1459
    CrossrefPubMedGoogle Scholar
  • 22 Obal D, Preckel B, Scharbatke H, Müllenheim J, Höterkes F, Thämer V, Schlack W. One MAC of sevoflurane already provides protection against reperfusion injury in the rat heart in vivo.  Br J Anaesth. 2001;  87 905-911
    PubMedGoogle Scholar
  • 23 Lowry OH. Protein measurement with Folin phenol reagent.  J Biol Chem. 1951;  193 265-270
    PubMedGoogle Scholar
  • 24 Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP, MacCabe CH, Braunwald E. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning?.  Circulation. 1995;  91 37-45
    PubMedGoogle Scholar
  • 25 Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, MacCabe CH, Braunwald E. Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B.  Circulation. 1998;  97 1042-1045
    PubMedGoogle Scholar
  • 26 Ghosh S, Standen NB, Galinanes M. Failure to precondition pathological human myocardium.  J Am Coll Cardiol. 2001;  37 711-718
    CrossrefPubMedGoogle Scholar
  • 27 Cleveland  Jr  JC, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium – Two paradoxes revisited.  Circulation. 1997;  96 29-32
    CrossrefPubMedGoogle Scholar
  • 28 Kersten JR, Schmeling TJ, Orth KG, Pagel PS, Warltier DC. Acute hyperglycemia abolishes ischemic preconditioning in vivo.  Am J Physiol Heart Circ Physiol. 1998;  275 H721-H725
    PubMedGoogle Scholar
  • 29 Nieszner E, Posa I, Kocsis E, Pogatsa G, Preda I, Koltai MZ. Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits.  Exp Clin Endocrinol Diabetes. 2002;  110 212-218
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Ebel D, Redler S, Preckel B, Schlack W, Thämer V. Moderate glucose deprivation preconditions myocardium against infarction.  Horm Metab Res. 2005;  37 516-520
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update.  Am J Physiol Heart Circ Physiol. 2003;  285 H921-H930
    PubMedGoogle Scholar
  • 32 Samavati L, Monick MM, Sanlioglu S, Buettner GR, Oberley LW, Hunninghake GW. Mitochondrial KATP channel openers activate the ERK kinase by an oxidant-dependent mechanism.  Am J Physiol Cell Physiol. 2002;  283 C273-C281
    PubMedGoogle Scholar
  • 33 Smith JM, Wahler GM. ATP-sensitive potassium channels are altered in ventricular myocytes from diabetic rats.  Mol Cell Biochem. 1996;  158 43-51
    PubMedGoogle Scholar
  • 34 Kersten JR, Montgomery MW, Ghassemi T, Gross ER, Toller WG, Pagel PS, Warltier DC. Diabetes and hyperglycemia impair activation of mitochondrial KATP channels.  Am J Physiol Heart Circ Physiol. 2001;  280 H1744-H1750
    PubMedGoogle Scholar
  • 35 Tosaki A, Engelman DT, Engelman RM, Das DK. The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts.  Cardiovasc Res. 1996;  31 526-536
    CrossrefPubMedGoogle Scholar
  • 36 Lu R, Hu CP, Peng J, Deng HW, Li YJ. Role of calcitonin gene-related peptide in ischaemic preconditioning in diabetic rat hearts.  Clin Exp Pharmacol Physiol. 2001;  28 392-396
    CrossrefPubMedGoogle Scholar
  • 37 Qin Q, Downey JM, Cohen MV. Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase.  Am J Physiol Heart Circ Physiol. 2003;  284 H727-H734
    PubMedGoogle Scholar
  • 38 Loubani M, Galinanes M. Pharmacological and ischemic preconditioning of the human myocardium: mitoKATP channels are upstream and p38MAPK is downstream of PKC.  BMC Physiology. 2002;  2 10
    CrossrefPubMedGoogle Scholar
  • 39 Philipp S, Critz SD, Cui L, Solodushko V, Cohen MV, Downey JM. Localizing extracellular signal-regulated kinase (ERK) in pharmacological preconditioning's trigger pathway.  Basic Res Cardiol. 2006;  101 159-167
    CrossrefPubMedGoogle Scholar
  • 40 Wang S, Cone J, Liu Y. Dual roles of mitochondrial KATP channels in diazoxide-mediated protection in isolated rabbit hearts.  Am J Physiol Heart Circ Physiol. 2001;  280 H246-H256
    PubMedGoogle Scholar
  • 41 Strniskova M, Barancik M, Neckar J, Ravingerova T. Mitogen-activated protein kinases in the acute diabetic myocardium.  Mol Cell Biochem. 2003;  249 59-65
    CrossrefPubMedGoogle Scholar
  • 42 Tatsumi T, Matoba S, Kobara M, Keira N, Kawahara A, Tsuruyama K, Tanaka T, Katamura M, Nakagawa C, Ohta B, Yamahara Y, Asayama J, Nakagawa M. Energy metabolism after ischemic preconditioning in streptozotocin-induced diabetic rat hearts.  J Am Coll Cardiol. 1998;  31 707-715
    CrossrefPubMedGoogle Scholar
  • 43 Ravingerova T, Stetka R, Volkovova K, Pancza D, Dzurba A, Ziegelhöffer A, Styk J. Acute diabetes modulates response to ischemia in isolated rat heart.  Mol Cell Biochem. 2000;  210 143-151
    CrossrefPubMedGoogle Scholar
  • 44 Baines CP, Cohen MV, Downey JM. Signal transduction in ischemic preconditioning: The role of kinases and mitochondrial KATP channels.  J Cardiovasc Electrophysiol. 1999;  10 741-754
    CrossrefPubMedGoogle Scholar
  • 45 Kim SO, Baines CP, Critz SD, Pelech SL, Katz S, Downey JM, Cohen MV. Ischemia induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart.  Biochem Cell Biol. 1999;  77 559-567
    CrossrefPubMedGoogle Scholar
  • 46 Maulik N, Watanabe M, Zu YL, Huang CK, Cordis GA, Schley JA, Das DK. Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts.  FEBS Lett. 1996;  396 233-237
    CrossrefPubMedGoogle Scholar

Correspondence

PD Dr. D. Ebel

Department of Intensive Care Medicine

Radboud University Nijmegen Medical Center

Geert Grooteplein 10

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Phone: +31/24/36 14 17 0

Fax: +31/24/35 41 61 2

Email: D.Ebel@ic.umcn.nl

      >