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Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart

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Abstract

Endogenous cardiac protection against prolonged ischemic insult can be achieved by repeated brief episodes of ischemia (hypoxia) or by cardiac adaptation to various stresses such as chronic hypoxia. Activation of phosphatidylinositol 3-kinase (PI3K)/Akt is involved in antiapoptotic effects, however, it is not clear whether it is required for overall heart salvage including protection against myocardial infarction and arrhythmias. We focussed on the potential common role of PI3K/Akt in anti-infarct protection, in the experimental settings of long-term adaptation to chronic intermittent hypobaric hypoxia (IHH; 8 h/day, 25–30 exposures, in vivo rats) and acute ischemic preconditioning (IP; Langendorff-perfused hearts). In addition, we explored the role of PI3K/Akt in susceptibility to ischemic ventricular arrhythmias. In normoxic open-chest rats, PI3K/Akt inhibitor LY294002 (LY; 0.3 mg/kg) given 5 min before test occlusion/reperfusion (I/R) did not affect infarct size (IS) normalized to the size of area at risk (AR). In hypoxic rats, LY partially attenuated IS-limiting effect of IHH (IS/AR 59.7 ± 4.1% vs. 51.8 ± 4.4% in the non-treated rats; p > 0.05) and increased IS/AR to its value in normoxic rats (64.9 ± 5.1%). In the isolated hearts, LY (5 μM) applied 15 min prior to I/R completely abolished anti-infarct protection by IP (IS/AR 55.0 ± 4.9% vs. 15.2 ± 1.2% in the non-treated hearts and 42.0 ± 5.5% in the non-preconditioned controls; p < 0.05). In the non-preconditioned hearts, PI3K/Akt inhibition did not modify IS/AR, on the other hand, it markedly suppressed arrhythmias. In the LY-treated isolated hearts, the total number of ventricular premature beats and the incidence of ventricular tachycardia (VT) was reduced from 518 ± 71 and 100% in the controls to 155 ± 15 and 12.5%, respectively (p < 0.05). Moreover, bracketing of IP with LY did not reverse antiarrhythmic effect of IP. These results suggest that activation of PI3K/Akt cascade plays a role in the IS-limiting mechanism in the rat heart, however, it is not involved in the mechanisms of antiarrhythmic protection.

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References

  1. Murphy E 2004 Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. Circ Res 94:7–16

    Article  PubMed  CAS  Google Scholar 

  2. Qin S, Chock PB 2003 Implication of phosphatidylinositol 3-kinase membrane recruitment in hydrogen peroxide-induced activation of PI3K and Akt. Biochemistry 43:2995–3003

    Article  CAS  Google Scholar 

  3. Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA 2000 Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem 275:4693–4698

    Article  PubMed  CAS  Google Scholar 

  4. Baines CP, Wang L, Cohen MV, Downey JM 1999 Myocardial protection by insulin is dependent on phosphatidylinositol 3-kinase but not protein kinase C or KATP channels in the isolated rabbit heart. Basic Res Cardiol 94:188–198

    Article  PubMed  CAS  Google Scholar 

  5. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, Koch WJ 2003 A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112:999–1007

    Article  PubMed  CAS  Google Scholar 

  6. Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, Grazette L, Michael A, Hajjar R, Force T, Molkentin JD 2001 Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103:670–677

    PubMed  CAS  Google Scholar 

  7. Matsui T, Rosenzweig A 2005 Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI3-kinase and Akt. J Mol Cell Cardiol 38:63–71

    Article  PubMed  CAS  Google Scholar 

  8. El Jamali A, Freund C, Rechner C, Scheidereit C, Dietz R, Bergmann MW 2004 Reoxygenation after severe hypoxia induces cardiomyocyte hypertrophy in vitro: activation of CREB downstream of GSK3beta. FASEB 18:1096–1098

    CAS  Google Scholar 

  9. Ostadal B, Kolar F, Pelouch V, Prochazka J, Widimsky J 1994 Intermittent high altitude and the cardiovascular system. In: Nagano M, Takeda N, Dhalla NS (eds) The Adapted Heart. Raven Press, New York, pp. 173–182

    Google Scholar 

  10. Kolar F, Ostadal B 1991 Right ventricular function in rats with hypoxic pulmonary hypertension. Pflügers Arch 419: 121–126

    Article  PubMed  CAS  Google Scholar 

  11. Neckar J, Ostadal B, Kolar F 2004 Myocardial infarct size-limiting effect of chronic hypoxia persists for five weeks of normoxic recovery. Physiol Res 53:621–628

    PubMed  CAS  Google Scholar 

  12. Pelouch V, Kolar F, Ostadal B, Milerova M, Cihak R, Widimsky J 1997 Regression of chronic hypoxia-induced pulmonary hypertension, right ventricular hypertrophy and fibrosis: Effect of enalapril. Cardiovasc Drugs Ther 11: 177–185

    Article  PubMed  CAS  Google Scholar 

  13. Kolar F, Ostadal B 2004 Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia. Physiol Res, 53(Suppl. 1): S3–S13

    PubMed  CAS  Google Scholar 

  14. Rafiee P, Shi Y, Kong X, Pritchard KA, Tweddel JS, Litwin SB, Mussatto K, Jaquiss RD, Su J, Baker JE 2002 Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection. Circulation 106:239–245

    Article  PubMed  CAS  Google Scholar 

  15. Oldenburg O, Qin Q, Krieg T, Yang XM, Philipp S, Critz SD, Cohen MV, Downey JM 2004 Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. Am J Physiol Heart Circ Physiol 286:H468–476

    Article  PubMed  CAS  Google Scholar 

  16. Nagarkatti D, Sha’afi RI 1998 Role of p38 MAPK kinase in myocardial stress. J Mol Cell Cardiol 30:1651–1664

    Article  PubMed  CAS  Google Scholar 

  17. Baxter GF, Goma FM, Yellon DM 1995 Involvement of protein kinase C in the delayed cytoprotection following sublethal ischaemia in rabbit myocardium. Br J Pharmacol. 115:222–224

    PubMed  CAS  Google Scholar 

  18. Strohm C, Barancik M, Bruhl ML, Kilian SA, Schaper W 2000 Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium. J Cardiovasc Pharmacol 36:218–229

    Article  PubMed  CAS  Google Scholar 

  19. Hausenloy DJ, Mocanu MM, Yellon DM 2004 Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res 63:305–312

    Article  PubMed  CAS  Google Scholar 

  20. Fryer RM, Hsu AK, Gross GJ 2001 ERK and p38MAP kinase activation are components of opioid induced delayed cardioprotection. Basic Res Cardiol 96:136–142

    Article  PubMed  CAS  Google Scholar 

  21. Tong H, Chen W, Steenbergen C, Murphy E 2000 Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res 87:309–315

    PubMed  CAS  Google Scholar 

  22. Kis A, Yellon DM, Baxter GF 2003 Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase. J Mol Cell Cardiol 35:1063–1071

    Article  PubMed  CAS  Google Scholar 

  23. Jezkova J, Novakova O, Kolar F, Tvrzicka E, Neckar J, Novak F 2002 Chronic hypoxia alters fatty acid composition of phospholipids in right and left ventricular myocardium. Mol Cell Biochem 232:49–56

    Article  PubMed  CAS  Google Scholar 

  24. Neckar J, Markova I, Novak F, Novakova O, Szarszoi O, Ostadal B, Kolar F 2005 Increased expression and altered subcellular distribution of PKC-δ in chronically hypoxic rat myocardium: involvement in cardioprotection. Am J Physiol 288:H1566–H1572

    CAS  Google Scholar 

  25. Strniskova M, Ravingerova T, Neckar J, Kolar F, Pastorekova S, Barancik M 2006 Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia. Gen Physiol Biophys 25:25–41

    PubMed  CAS  Google Scholar 

  26. Mocanu MM, Bell RM, Yellon DM 2002 PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. J Mol Cell Cardiol 34:661–668

    Article  PubMed  CAS  Google Scholar 

  27. Ravingerova T, Neckar J, Kolar F, Stetka R, Volkovova K, Ziegelhoffer A, Styk J 2001 Ventricular arrhythmias following coronary artery occlusion in rats: Is diabetic heart less or more sensitive to ischemia? Basic Res Cardiol 96:160–168

    Article  PubMed  CAS  Google Scholar 

  28. Neckar J, Szarszoi O, Koten L, Papousek F, Ostadal B, Grover GJ, Kolar F 2002 Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats. Cardiovasc Res 55:567–575

    Article  PubMed  CAS  Google Scholar 

  29. Walker MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon D M, Cobbe SM, Coker SJ, Harness JB, Harron DW, Higgins AJ, Julian DG, Lab MJ, Manning AS, Northover BJ, Parratt JR, Riemersma RA, Riva E, Russell DC, Sheridan DJ, Winslow E, Woodward B 1988 The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc Res 22: 447–455

    Article  PubMed  CAS  Google Scholar 

  30. Gross ER, Hsu AK, Gross AJ 2004 Opioid-induced cardioprotection occurs via glycogen synthase kinase β inhibition during reperfusion in intact rat hearts. Circ Res 94:960–966

    Article  PubMed  CAS  Google Scholar 

  31. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang M, Izumo S 2003 Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 100:12355–12360

    Article  PubMed  CAS  Google Scholar 

  32. Oudit GY, Sun H, Kerfant B-G, Crackower MA, Penninger JM, Backx PH 2004 The role of phosphoinositide 3-kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37:449–471

    Article  PubMed  CAS  Google Scholar 

  33. Davies SP, Reddy H, Caivano M, Cohen P 2000 Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    Article  PubMed  CAS  Google Scholar 

  34. Uchiyama T, Engelman RM, Maulik N, Das DK 2004 Role of Akt signaling in mitochondrial pathway triggered by hypoxic preconditioning. Circulation 24:3042–3049

    Article  CAS  Google Scholar 

  35. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A 2001 Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104:330–335

    PubMed  CAS  Google Scholar 

  36. Vittone L, Said M, Mattiazzi A 2006 Beta(2)-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart. Naunyn Schmiedebergs Arch Pharmacol 373:60–70

    Article  PubMed  CAS  Google Scholar 

  37. O’Neill T, Abel ED 2004 Akt1 in the cardiovascular system: friend or foe? J Clin Invest 115:2059–2064

    Article  CAS  Google Scholar 

  38. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K 2005 Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118

    Article  PubMed  CAS  Google Scholar 

  39. Taniyama Y, Ito M, Sato K, Kuester C, Veit K, Tremp G, Liao R, Colucci WS, Ivashcenko Y, Walsh K, Shiojima I 2005 Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy. J Mol Cell Cardiol 38:375–385

    Article  PubMed  CAS  Google Scholar 

  40. Dorn GW II, Force T 2005 Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115:527–537

    Article  PubMed  CAS  Google Scholar 

  41. Bauer B, Simkhovich BZ, Kloner RA, Przyklenk K 1999 Preconditioning-induced cardioprotection and release of the second messenger inositol (1,4,5)-trisphosphate are both abolished by neomycin in rabbit heart. Basic Res Cardiol 94:31–40

    Article  PubMed  CAS  Google Scholar 

  42. Woodcock EA, Lambert KA, Du X-J 1996 Ins(1,4,5)P3 during myocardial ischemia and its relationship to the development of arrhythmias. J Mol Cell Cardiol 28:2129–2138

    Article  PubMed  CAS  Google Scholar 

  43. Hirata A, Minamino T, Asanuma H, Sanada S, Fujita M, Tsukamoto O, Wakeno M, Myoishi M, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Tomoike H, Hori M, Kitakaze M 2005 Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther 19:33–40

    Article  PubMed  CAS  Google Scholar 

  44. Bai CX, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T 2005 Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 112:1701–1710

    Article  PubMed  CAS  Google Scholar 

  45. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, Kajstura J, Anversa P, Sussman MA 2001 Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 88:1020–1027

    PubMed  CAS  Google Scholar 

  46. Bae S, Zhang L 2005 Gender differences in cardioprotection against ischemia-reperfusion injury in adult rat hearts: focus on Akt and PKC signaling. J Pharmacol Exp Ther 315:1125–35

    Article  PubMed  CAS  Google Scholar 

  47. Trepanier-Boulay V, St-ichel C, Tremblay A, Fiset C 2001 Gender-based differences in cardiac repolarization in mouse ventricle. Circ Res 89:437–444

    PubMed  CAS  Google Scholar 

  48. Abi-Gerges N, Philp K, Pollard C, Wakefield I, Hammond TG, Valentin JP 2004 Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes. Fundam Clin Pharmacol 18:139–151

    Article  PubMed  CAS  Google Scholar 

  49. Black SC, Fagbemi SO, Chi L, Friedrichs GS, Lucchesi BR 1993 Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide. J Mol Cell Cardiol 25:1427–1438

    Article  PubMed  CAS  Google Scholar 

  50. Lundmark JL, Ramasamy R, Vulliet PR, Schaefer S 1999 Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts. Am J Physiol 277:H999–H1006

    PubMed  CAS  Google Scholar 

  51. Steinberg SF 2001 PI3King the L-type calcium channel activation mechanism. Circ Res 89:641–644

    PubMed  CAS  Google Scholar 

  52. Zhang Y, Wang H, Wang J, Han H, Nattel S, Wang Z 2003 Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity. FEBS Letters 534:125–132

    Article  PubMed  CAS  Google Scholar 

  53. Gamper N, Fillon S, Huber SM, Feng Y, Kobayashi T, Cohen P, Lang F 2002 IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflügers Arch – Eur J Physiol 443:625–634

    Article  CAS  Google Scholar 

  54. Mockridge JW, Marber MS, Heads RJ 2000 Activation of Akt during simulated ischemia/reperfusion in cardiac myocytes. Biochem Biophys Res Commun 270:947–952

    Article  PubMed  CAS  Google Scholar 

  55. Curtis MJ, Hearse DJ 1989 Ischemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: Implications for the mechanisms of initiation and maintenance of ventricular fibrillation. J Mol Cell Cardiol 21:21–40

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by VEGA SR grants No 2/5110/25, APVT 51–027404 and GACR grant No 305/04/0465.

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Authors and Affiliations

  1. Institute for Heart Research, Slovak Academy of Sciences, Dubravská cesta 9, POB 104, Bratislava, 840 05, Slovak Republic

    Táňa Ravingerová, Jana Matejíková & Eva Andelová

  2. Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic and Centre for Cardiovascular Research, Prague, Czech Republic

    Jan Neckář & František Kolář

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  1. Táňa Ravingerová
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  2. Jana Matejíková
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Correspondence to Táňa Ravingerová.

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Ravingerová, T., Matejíková, J., Neckář, J. et al. Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart. Mol Cell Biochem 297, 111–120 (2007). https://doi.org/10.1007/s11010-006-9335-z

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