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Inhibition of Ras-GTPase, but not tyrosine kinases or Ca2+/calmodulin-dependent protein kinase II, improves recovery of cardiac function in the globally ischemic heart

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Abstract

The signaling pathways involved in ischemic heart disease are not well characterized. In this study, the roles of Ras-GTPase, tyrosine kinases (TKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in global ischemia and reperfusion (I/R) in a perfused rat heart model were investigated and compared to beneficial effects produced by preconditioning (PC). A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). Hearts from male Wistar rats pre-treated with the tyrosine kinase inhibitor, genistein (1 mg/kg/day for 6 days), or the CaMKII inhibitor, KN-93 (578 ng/min for 6 days), produced detrimental effects on recovery of cardiac function and coronary hemodynamics. In contrast, pre-treatment with Ras-GTPase inhibitor FPT III (232 ng/min for 6 days) significantly enhanced cardiac recovery in terms of left ventricular contractility and coronary vascular hemodynamics. Treatment with FPT III also significantly reduced expression of the sodium-hydrogen exchanger-1 (NHE-1) which was elevated during I/R as detected by Western blotting. These data suggest that TKs and CaMKII are involved in signaling pathways leading to recovery from cardiac ischemia, whereas activation of Ras-GTPase signaling pathways are critical in the development of cardiac dysfunction due to I/R.

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References

  1. Abe J, Berk BC: Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med 8: 59-64, 1998

    Article  Google Scholar 

  2. Jennings RB, Reimer KA: The cell biology of acute myocardial ischemia. Annu Rev Med 42: 225-312, 1991

    Article  PubMed  Google Scholar 

  3. Takeishi Y, Abe J, Lee J, Kawakatsu H, Walsh RA, Berk BC: Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused guinea pig hearts. Circ Res 85: 1164-1172, 1999

    PubMed  Google Scholar 

  4. Cohen MV, Yang X, Liu GS, Heusch G, Downey JM: Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generation free radicals and opening mitochondrial KATP channels. Circ Res 89: 273-278, 2001

    PubMed  Google Scholar 

  5. Cohen MV, Baines CP, Downey JM: Ischemic preconditioning: From adenosine receptor to KATP channel. Annu Rev Physiol 62: 79-109, 2000

    Article  PubMed  Google Scholar 

  6. Osada M, Netticadan T, Kawabata K, Tamura K, Dhalla NS: Ischemic preconditioning prevents I/R-induced alterations in SR calcium-calmodulin protein kinase II. Am J Physiol 278: H1791-H1798, 2000

    Google Scholar 

  7. Abe J, Okuda M, Huang Q, Yoshizumi M, Berk BC: Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras. J Biol Chem 275: 1739-1748, 2000

    Article  PubMed  Google Scholar 

  8. Abe J, Baines PC, Berk BC: Role of mitogen-activated protein kinases in ischemia and reperfusion injury. The good and the bad. Circ Res 86: 607-609, 2000

    PubMed  Google Scholar 

  9. Ping P, Murphy E: Role of p38 mitogen-activated protein kinases in preconditioning. A detrimental factor or a protective kinase? Circ Res 86: 921-922, 2000

    PubMed  Google Scholar 

  10. Muthalif MM, Karzoun NA, Gaber L, Benter IF, Parmentier JH, Manne V, Malik KU: Angiotensin II-induced hypertension: Contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites. Hypertension 35: 457-463, 2000

    PubMed  Google Scholar 

  11. Muthalif MM, Karzoun NA, Benter IF, Gaber L, Ljuca F, Uddin MR, Khandekar Z, Estes A, Malik KU: Functional significance of activation of calcium/calmodulin-dependent protein kinase II in angiotensin II-induced vascular hyperplasia and hypertension. Hypertension 39: 704-709, 2002

    Article  PubMed  Google Scholar 

  12. Deodato B, Altavilla D, Squadrito G, Campo GM, Arlotta M, Minutoli L, Saitta A, Cucinotta D, Calapai G, Caputi AP, Miano M, Squadrito F: Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. Br J Pharmacol 128: 1683-1690, 1999

    Article  PubMed  Google Scholar 

  13. Khan I, Collins SM: Altered expression of sodium pump isoforms in the inflamed intestine of Trichinella spiralis-infected rats. Am J Physiol 264: G1160-G1168, 1993

    PubMed  Google Scholar 

  14. Khan I, Ali M: Altered expression of the Na+/H+ exchanger isoform-3 in experimental colitis: Effect of garlic. Mol Cell Biochem 200: 77-84, 1999

    Article  PubMed  Google Scholar 

  15. Khan I: Topology of the C-terminus of sodium hydrogen exchanger isoform-1: Presence of an extracellular epitope. Arch Biochem Biophys 391: 25-29, 2001

    Article  PubMed  Google Scholar 

  16. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (Lond) 227: 680-685, 1970

    Article  Google Scholar 

  17. Avkiran M, Gross G, Karmazyn M, Klein H, Murphy E, Ytrehus K: Na+/H+ exchange in ischemia. reperfusion and preconditioning. Cardiovasc Res 50: 162-166, 2001

    Article  PubMed  Google Scholar 

  18. Avkiran M, Marber MS: Na(+)/H(+) exchange inhibitors for cardio-protective therapy: Progress, problems and prospects. J Am Cell Cardiol 39: 747-753, 2002

    Article  Google Scholar 

  19. Avkiran M: Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia. Am J Cardiol 83: 10G-18G, 1999

    Article  PubMed  Google Scholar 

  20. Avkiran M: Protection of the myocardium during ischemia and reperfusion: Na+/H+ exchange inhibition vs. ischemia preconditioning. Circulation 100: 2469-2472, 1999

    PubMed  Google Scholar 

  21. Wallert MA, Frohlich O: α1-adrenergic stimulation of Na-H exchange in cardiac myocytes. Am J Physiol 517: 159-180, 1992

    Google Scholar 

  22. Gunasegaram S, Haworth RS, Hearse DJ, Avkiran M: Regulation of sarcolemmal Na+/H+ exchanger activity by angiotensin II in adult rat ventricular myocytes: Opposing actions of AT1 and AT2 receptors. Circ Res 85: 919-930, 1999

    PubMed  Google Scholar 

  23. Yasutake M, Haworth RS, King A, Avkiran M: Thrombin activates the Na+/H+ exchanger: Evidence for a receptor-mediated mechanism involving protein kinase C. Circ Res 79: 705-715, 1996

    PubMed  Google Scholar 

  24. Snabaitis AK, Yokoyama H, Avkiran M: Roles of mitogen-activated protein kinases and protein kinase C in α1A-adrenoreceptor-mediated stimulation of the sarcolemmal Na+-H+ exchanger. Circ Res 86: 214-220, 2000

    PubMed  Google Scholar 

  25. Ricciardi R, Schaffer BK, Kim RD, Shah RD, Donohue SE, Wheeler SM, Quarforst SH, Callery MP, Meyers WC, Chari RS: Protective effects of ischemic preconditioning on the cold-preserved liver are tyrosine kinase dependent. Transplantation 72: 406-412, 2001

    Article  PubMed  Google Scholar 

  26. Hawkins C, Xu A, Narayanan N: Sarcoplasmic reticulum calcium pump in cardiac and slow twitch skeletal muscle but not fast twitch skeletal muscle undergoes phosphorylation by endogenous and exogenous Ca2+/calmodulin-dependent protein kinase. Characterization of optimal conditions for calcium pump phosphorylation. J Biol Chem 269: 31198-31206, 1994

    PubMed  Google Scholar 

  27. Netticadan T, Kato K, Tappia P, Dhalla NS: Phosphorylation of cardiac Na+-K+ATPase by Ca2+/calmodulin-dependent protein kinase. Biochem Biophys Res Commun 238: 544-548, 1997

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, 13110, Kuwait

    Ibrahim F. Benter

  2. Department of Physiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, 13110, Kuwait

    Jasbir S. Juggi

  3. Department of Biochemistry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, 13110, Kuwait

    Islam Khan

  4. Centre for Genome-based Therapeutics, Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3XF, Wales, UK

    Saghir Akhtar

Authors
  1. Ibrahim F. Benter
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  2. Jasbir S. Juggi
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  3. Islam Khan
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  4. Saghir Akhtar
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Benter, I.F., Juggi, J.S., Khan, I. et al. Inhibition of Ras-GTPase, but not tyrosine kinases or Ca2+/calmodulin-dependent protein kinase II, improves recovery of cardiac function in the globally ischemic heart. Mol Cell Biochem 259, 35–42 (2004). https://doi.org/10.1023/B:MCBI.0000021342.39935.a3

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  • DOI: https://doi.org/10.1023/B:MCBI.0000021342.39935.a3

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