Basic Research in Cardiology

, Volume 105, Issue 2, pp 193–203 | Cite as

Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation

  • Efstathios K. Iliodromitis
  • Ioanna AndreadouEmail author
  • Eftihios Prokovas
  • Anastasia Zoga
  • Dimitrios Farmakis
  • Theano Fotopoulou
  • Konstantinos Ioannidis
  • Ioannis A. Paraskevaidis
  • Dimitrios Th. Kremastinos
Original Contribution


Postconditioning (POC) reduces lethal reperfusion injury under normal conditions, but its effectiveness under certain pathological states is in dispute. In the present study, we sought to determine the effect of chronic simvastatin treatment in hyperlipidemic animals with or without POC. Anesthetized rabbits were randomized into eight groups, as follows, and were subjected to 30-min myocardial ischemia followed by 3-h reperfusion. Normally fed animals: a Control group with no additional intervention, a Sim group treated with simvastatin for 3 weeks at a dose of 3 mg kg−1, a POC group subjected to POC with eight cycles of 30-s ischemia/reperfusion, a Sim-POC group treated with simvastatin, and POC. Cholesterol fed (6 weeks) animals: a Chol group with no additional interventions, a Chol–Sim group treated with simvastatin for 3 weeks, a Chol-POC group subjected to POC, and a Chol–Sim-POC group treated with simvastatin and POC. Infarct size and plasma levels of malondialdehyde (MDA), nitrotyrosine (NT), NO x , total cholesterol, and LDL were evaluated. In a second series of experiments, heart tissue samples were taken for MDA, NT, and NO x assessment. Infarct size, circulating MDA, NT, NO x and cardiac MDA, NT, and NO x levels declined in POC and all Sim groups compared with Control, Chol, and Chol-POC (p < 0.05). Simvastatin also reduced total cholesterol and LDL plasma levels. In conclusion, a 3-week simvastatin treatment limits the infarct size and attenuates the oxidative and nitrosative stress both in normo- and in hyper-cholesterolemic rabbits subjected to ischemia–reperfusion irrespective of the presence of POC, while POC is effective only in normocholesterolemic animals.


Postconditioning Hypercholesterolemia Simvastatin Oxidative stress Nitrosative stress 



The authors are grateful to ELPEN Pharmaceutical Co. Inc. for the kind donation of simvastatin.


  1. 1.
    Akiyama K, Suzuki H, Grant P, Bing RJ (1997) Oxidation products of nitric oxide NO2 and NO3 in plasma after experimental myocardial infarction. J Mol Cell Cardiol 29:1–7CrossRefPubMedGoogle Scholar
  2. 2.
    Akiyama K, Kimura A, Suzuki H, Takeyama Y, Gluckman TL, Tarhakopian A, Katagiri T, Suh KY, Roseto J, Bing RJ (1998) Production of oxidative products of nitric oxide in infracted human heart. J Am Coll Cardiol 32:373–379CrossRefPubMedGoogle Scholar
  3. 3.
    Andreadou I, Sigala F, Iliodromitis EK, Papaefthimiou M, Sigalas C, Aligiannis N, Savvari P, Gorgoulis V, Papalambros E, Kremastinos DTh (2007) Acute doxorubicin cardiotoxicity is succesfully treated with the the phytochemical oleuropein through suppression of oxidative and nitrosative stress. J Mol Cell Cardiol 42:549–558CrossRefPubMedGoogle Scholar
  4. 4.
    Andreadou I, Iliodromitis EK, Mikros E, Bofilis E, Zoga A, Constantinou M, Tsantili-Kakoulidou A, Kremastinos DTh (2004) Melatonin does not prevent the protection of ischemic preconditioning in vivo despite its antioxidant effect against oxidative stress. Free Radic Biol Med 37:500–510CrossRefPubMedGoogle Scholar
  5. 5.
    Andreadou I, Iliodromitis EK, Mikros E, Constantinou M, Agalias A, Magiatis P, Skaltsounis AL, Kamber E, Tsantili-Kakoulidou A, Kremastinos DTh (2006) The olive constituent oleuropein exhibits anti-ischemic, antioxidative and hypolipidemic effects in anesthetized rabbits. J Nutr 136:2213–2219PubMedGoogle Scholar
  6. 6.
    Andreadou I, Iliodromitis EK, Tsovolas K, Aggeli IK, Zoga A, Gaitanaki C, Paraskevaidis IA, Markantonis SL, Beis I, Kremastinos DTh (2006) Acute administration of vitamin E triggers preconditioning via KATP channels and cyclic-GMP without inhibiting lipid peroxidation. Free Radic Biol Med 41:1092–1099CrossRefPubMedGoogle Scholar
  7. 7.
    Andreadou I, Iliodromitis EK, Koufaki M, Kremastinos DTh (2008) Pharmacological pre- and post-conditioning agents: reperfusion–injury of the heart revisited. Mini Rev Med Chem 8:952–959CrossRefPubMedGoogle Scholar
  8. 8.
    Cavallini DC, Bedani R, Bomdespacho LQ, Vendramini RC, Rossi EA (2009) Effect of probiotic bacteria, isoflavones and simvastatin on lipid profile and atherosclerosis in cholesterol fed rabbits: a randomized double-blind study. Lipid Health Dis 7:1–8CrossRefGoogle Scholar
  9. 9.
    Crisostomo PR, Wairiuko GM, Wang M, Tsai BM, Morell ED, Meldrum DR (2006) Preconditioning versus postconditioning: mechanisms and therapeutic potentials. J Am Coll Surg 202:797–812CrossRefPubMedGoogle Scholar
  10. 10.
    Descur-Smielecka E, Wykrtowicz A, Kempa M, Furmaniuk J, Wysoski H (2001) The influence of short-term treatment with simvastatin on the inflammatory profile of patients with hypercholesterolaemia. Coron Artery Dis 12:143–148CrossRefGoogle Scholar
  11. 11.
    Donato M, Dannunzio V, Berg G, Gonzalez G, Schreier L, Wilkinski MoralesC, RL GelpiRJ (2007) Ischemic postconditioning reduces infarct size by activation of A1 receptors and KATP channels in both normal and hypercholesterolemic rabbits. J Cardiovasc Pharmacol 49:287–292CrossRefPubMedGoogle Scholar
  12. 12.
    Ferdinandy P, Schulz R, Baxter G (2007) Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning and postconditioning. Pharmacol Rev 59:418–458CrossRefPubMedGoogle Scholar
  13. 13.
    Ferdinandy P, Schulz R (2003) Nitric oxide, superoxide, and peroxynitrite in myocardial ischemia reperfusion injury and preconditioning. Br J Pharmacol 138:532–543CrossRefPubMedGoogle Scholar
  14. 14.
    Gill RM, Braz JC, Jin N, Etgen GJ, Shen W (2007) Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling. Am J Physiol Heart Circ Physiol 292:2782–2790CrossRefGoogle Scholar
  15. 15.
    Gu W, Kehl F, Krolikowski JG, Pagel PS, Wartlier DC, Kersten JR (2008) Simvastatin restores ischemic preconditioning in the presence of hyperglycemia through a nitric-oxide-mediated mechanism. Anesthesiology 108:634–642CrossRefPubMedGoogle Scholar
  16. 16.
    Granfeldt A, Lefer DJ, Vinten-Johansen J (2009) Protective ischaemia in patients: preconditioning and postconditioning. Cardiovasc Res 83:234–246CrossRefPubMedGoogle Scholar
  17. 17.
    Hausenloy DJ, Yellon DM (2007) Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev 12:217–234CrossRefPubMedGoogle Scholar
  18. 18.
    Heusch G (2009) No RISK, no….cardioprotection? A critical perspective. Cardiovasc Res 84:173–175CrossRefPubMedGoogle Scholar
  19. 19.
    Iliodromitis EK, Zoga A, Vrettou A, Andreadou I, Paraskevaidis IA, Kaklamanis L, Kremastinos DTh (2006) The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits. Atherosclerosis 188:356–362CrossRefPubMedGoogle Scholar
  20. 20.
    Iliodromitis EK, Gaitanaki C, Lazou A, Aggeli IK, Gizas V, Bofilis E, Zoga A, Beis I, Kremastinos DT (2006) Oral nicorandil recaptures the waned protection from preconditioning in vivo. Basic Res Cardiol 101:327–335CrossRefPubMedGoogle Scholar
  21. 21.
    Iliodromitis EK, Georgiadis M, Cohen MV, Downey JM, Bofilis E, Kremastinos DTh (2006) Protection from post-conditioning depends on the number of short ischemic insults in anesthetized pigs. Basic Res Cardiol 101:502–507CrossRefPubMedGoogle Scholar
  22. 22.
    Kocsis GF, Pipis J, Fekete V, Kovács-Simon A, Odendaal L, Molnár E, Giricz Z, Janáky T, van Rooyen J, Csont T, Ferdinandy P (2008) Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Am J Physiol Heart Circ Physiol 294:H2406–H2409CrossRefPubMedGoogle Scholar
  23. 23.
    Kupai K, Csonka C, Bencsik P, Fodor G, Csont T, Ferdinandy P (2006) The cardioprotective effect of postconditioning is lost in cholesterol diet-induced hyperlipidemia in rats. J Mol Cell Cardiol 40:976–977 (abstract)Google Scholar
  24. 24.
    Kupai K, Csonka C, Fekete V, Odendaal L, van Rooyen J, Marais de W, Csont T, Ferdinandy P (2009) Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Am J Physiol Heart Circ Physiol 297:H1729–H1735CrossRefPubMedGoogle Scholar
  25. 25.
    Lefer AM, Campbell B, Shin YK, Scalia R, Hayward R, Lefer DJ (1999) Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 100:178–184PubMedGoogle Scholar
  26. 26.
    Levine GN, Keaney JF Jr, Vita JA (1995) Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms. N Engl J Med 332:512–521CrossRefPubMedGoogle Scholar
  27. 27.
    Miller SJ (2001) Emerging mechanisms for secondary cardioprotective effects of statins. Cardiovasc Res 52:5–7CrossRefPubMedGoogle Scholar
  28. 28.
    Miura T, Miki T (2008) Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103:501–513CrossRefPubMedGoogle Scholar
  29. 29.
    Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136PubMedGoogle Scholar
  30. 30.
    Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ (2007) Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol 102:90–100CrossRefPubMedGoogle Scholar
  31. 31.
    Na HS, Kim YI, Yoon YW, Han HC, Nahm SH, Hong SK (1996) Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia. Am Heart J 132:78–83CrossRefPubMedGoogle Scholar
  32. 32.
    Onody A, Csonka C, Giricz Z, Ferdinandy P (2003) Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts. Cardiovasc Res 58:663–670CrossRefPubMedGoogle Scholar
  33. 33.
    Osborne JA, Lento PH, Siegrfried MR, Stahl GL, Fusman B, Lefer AM (1989) Cardiovascular effects of acute hypercholesterolemia in rabbits: reversal with lovastatin treatment. J Clin Investig 83:465–473CrossRefPubMedGoogle Scholar
  34. 34.
    Parissis JT, Andreadou I, Markantonis SL, Bistola V, Louka A, Pyriochou A, Paraskevaidis I, Filippatos G, Iliodromitis EK, Kremastinos DTh (2007) Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure. Atherosclerosis 195:210–215CrossRefGoogle Scholar
  35. 35.
    Penna C, Mancardi D, Tullio F, Pagliaro P (2008) Postconditioning and intermittent bradykinin induced cardioprotection require cycloxygenase activation and prostacyclin release during reperfusion. Basic Res Cardiol 103:368–377CrossRefPubMedGoogle Scholar
  36. 36.
    Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P (2006) Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol 101:180–189CrossRefPubMedGoogle Scholar
  37. 37.
    Sanada S, Asanuma H, Minamino T, Node K, Takashima S, Okuda H, Shinozaki Y, Ogai A, Fujita M, Hirata A, Kim J, Asano Y, Mori H, Tomoike H, Kitamura S, Hori M, Kitakaze M (2004) Optimal windows of statin use for immediate infarct limitation. 5′-nucleotidase as another downstream molecule of phosphatidylinositol-3-kinase. Circulation 110:2143–2149CrossRefPubMedGoogle Scholar
  38. 38.
    Scalia R, Gooszen ME, Jones SP, Hoffmeyer M, Rimmer DM, Trocha SD, Huang PL, Smith MB, Lefer AM, Lefer DJ (2001) Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 103:2598–2603PubMedGoogle Scholar
  39. 39.
    Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483CrossRefPubMedGoogle Scholar
  40. 40.
    Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huilier I, Aupetit JF, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148CrossRefPubMedGoogle Scholar
  41. 41.
    Tilton RG, Cole PA, Zions JD, Daugherty A, Larson KB, Sutera SP, Kilo C, Williamson JR (1987) Increased ischemia reperfusion injury to the heart associated with short-term diet induced hypercholesterolemia in rabbits. Circ Res 60:551–559PubMedGoogle Scholar
  42. 42.
    Uchiyama Y, Otani H, Okada T, Uchiyama T, Ninomiya H, Kido M, Imamura H, Nakao S, Shingu K (2003) Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor. J Thorac Cardiovasc Surg 126:148–159CrossRefPubMedGoogle Scholar
  43. 43.
    Verbeuren TJ, Jordaens FH, Zoonekeyn LL, Van Hove CE, Coene MC, Herman AG (1986) Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. endothelium-dependent and endothelium independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58:552–564PubMedGoogle Scholar
  44. 44.
    Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F (2005) Postconditioning. A new link in nature’s armor against myocardial ischemia–reperfusion injury. Basic Res Cardiol 100:295–310CrossRefPubMedGoogle Scholar
  45. 45.
    Wang H, Zhang H, Guo W, Su H, Zhang K, Li QX, Yan W, Ma XL, Lopez BL, Christopher TA, Gao F (2006) Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation: role of peroxynitrite formation. Apoptosis 11:1453–1460CrossRefPubMedGoogle Scholar
  46. 46.
    Wolfrum S, Dendorfer A, Schutt M, Weidtmann B, Heep A, Tempel K, Klein HH, Dominiak P, Rischardt G (2004) Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway. J Cardiovasc Pharmacol 44:348–355CrossRefPubMedGoogle Scholar
  47. 47.
    Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. New Engl J Med 357:1121–1135CrossRefPubMedGoogle Scholar
  48. 48.
    Zhao ZQ, Corvera JS, Halkos ME, Kerrendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285:H579–H588Google Scholar
  49. 49.
    Zhao ZQ, Vinten-Johansen J (2006) Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res 70:200–211CrossRefPubMedGoogle Scholar
  50. 50.
    Zhao JL, Yang SJ, You SJ, Cui CJ, Gao RL (2007) Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res 73:137–142CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Efstathios K. Iliodromitis
    • 1
  • Ioanna Andreadou
    • 2
    Email author
  • Eftihios Prokovas
    • 1
  • Anastasia Zoga
    • 1
  • Dimitrios Farmakis
    • 1
  • Theano Fotopoulou
    • 2
  • Konstantinos Ioannidis
    • 2
  • Ioannis A. Paraskevaidis
    • 1
  • Dimitrios Th. Kremastinos
    • 1
  1. 1.Second University Department of Cardiology, Medical School, Attikon General HospitalUniversity of AthensAthensGreece
  2. 2.Department of Pharmaceutical Chemistry, School of PharmacyUniversity of AthensAthensGreece

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