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Cardiovascular Drugs and Therapy

, Volume 28, Issue 1, pp 7–17 | Cite as

Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation

  • Chung Ho Leung
  • Lixing Wang
  • Jan M. Nielsen
  • Michael B. Tropak
  • Yana Y. Fu
  • Hideyuki Kato
  • John Callahan
  • Andrew N. Redington
  • Christopher A. Caldarone
ORIGINAL ARTICLE

Abstract

Background

Coronary effluent from an isolated perfused heart undergoing ischemic preconditioning can be transferred to precondition another naïve isolated heart. We investigated the effects of this effluent on mitochondrial integrity and function following a global infarct model of ischemia/reperfusion and the role of adenosine in this model of remote preconditioning.

Methods and Results

Coronary effluent from isolated perfused rabbit hearts was collected prior to (control effluent) and during three cycles of 5-min ischemia and 10-min reperfusion (IPC effluent). Adenosine concentration was significantly increased in IPC effluent (2.6 ± 1.1 μM) versus control effluent (0.21 ± 0.06 μM, P < 0.01). Infarct size (% necrotic LV mass) after 30-min global ischemia and 90-min reperfusion was significantly reduced in hearts preconditioned with IPC effluent (IPCeff, 23 ± 7 %) and control effluent supplemented with 2.5 μM exogenous adenosine (Ceff + 2.5 μM ADO, 25 ± 10 %) when compared to control effluent perfused hearts (Ceff, 41 ± 8 %, P < 0.05). Compared to Ceff mitochondria, IPCeff mitochondria had preserved complex I/State3 and complex IV/State 3 respiration and outer membrane integrity, and reduced cytochrome c release. In contrast, Ceff + 2.5 μM ADO mitochondria had improved state 2 respiration and coupling to oxidative phosphorylation, reduced reactive oxygen species production and preserved outer membrane integrity. Administration of adenosine receptor blocker 8-(p-sulfophenyl)theophylline abolished the infarct limiting effect (46 ± 7 %) and the mitochondrial integrity and function preservation of IPC effluent.

Conclusion

Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.

Keywords

Ischemia-reperfusion injury Adenosine Mitochondria Cardioprotection Ischemic preconditioning Remote ischemic preconditioning 

Notes

Grants

This study was supported by The Leducq Foundation (grant number 06/CVD) and the Heart and Stroke Foundation of Ontario.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10557_2013_6489_Fig6_ESM.jpg (12 kb)
Supplementary Figure 1

Ions detected in the effluent by reverse phase liquid chromatography mass spectrometry. Intensity of select ions in IPC effluent (n = 2) relative to Control effluent (n = 2) is shown on the y-axis. Mass to charge (m/z) ratio for detected ions are shown on the x-axis. This ratio is a reflection of the molecular weight of the individual ions detected by the mass spectrometer (LTQ Orbitrap). (JPEG 12 kb)

10557_2013_6489_MOESM1_ESM.tif (918 kb)
High resolution (TIFF 917 kb)

References

  1. 1.
    Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol. 1997;273(4 Pt 2):H1707–12.PubMedGoogle Scholar
  3. 3.
    Pell TJ, Baxter GF, Yellon DM, Drew GM. Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol. 1998;275(5 Pt 2):H1542–7.PubMedGoogle Scholar
  4. 4.
    Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, et al. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation. 2005;79(12):1691–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Yang X, Cohen MV, Downey JM. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc Drugs Ther. 2010;24(3):225–34.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, et al. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond). 2009;117(5):191–200.CrossRefGoogle Scholar
  7. 7.
    Wang L, Oka N, Tropak M, Callahan J, Lee J, Wilson G, et al. Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg. 2008;136(2):335–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Dickson EW, Lorbar M, Porcaro WA, Fenton RA, Reinhardt CP, Gysembergh A, et al. Rabbit heart can be “preconditioned” via transfer of coronary effluent. Am J Physiol. 1999;277(6 Pt 2):H2451–7.PubMedGoogle Scholar
  9. 9.
    Serejo FC, Rodrigues Jr LF, da Silva Tavares KC, de Carvalho AC, Nascimento JH. Cardioprotective properties of humoral factors released from rat hearts subject to ischemic preconditioning. J Cardiovasc Pharmacol. 2007;49(4):214–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK. Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol. 2010;106(1):135–45.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ. Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria. Am J Physiol Cell Physiol. 2008;294(2):C460–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem. 2003;278(38):36027–31.PubMedCrossRefGoogle Scholar
  13. 13.
    Borutaite V, Jekabsone A, Morkuniene R, Brown GC. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J Mol Cell Cardiol. 2003;35(4):357–66.PubMedCrossRefGoogle Scholar
  14. 14.
    Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol. 1997;273(3 Pt 2):H1544–54.PubMedGoogle Scholar
  15. 15.
    Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004;73:87–106.PubMedCrossRefGoogle Scholar
  16. 16.
    Crestanello JA, Lingle DM, Kamelgard J, Millili J, Whitman GJ. Ischemic preconditioning decreases oxidative stress during reperfusion: a chemiluminescence study. J Surg Res. 1996;65(1):53–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Lundberg KC, Szweda LI. Preconditioning prevents loss in mitochondrial function and release of cytochrome c during prolonged cardiac ischemia/reperfusion. Arch Biochem Biophys. 2006;453(1):130–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84(1):350–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Takaoka A, Nakae I, Mitsunami K, Yabe T, Morikawa S, Inubushi T, et al. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning”. J Am Coll Cardiol. 1999;33(2):556–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Goto M, Cohen MV, van Wylen DG, Downey JM. Attenuated purine production during subsequent ischemia in preconditioned rabbit myocardium is unrelated to the mechanism of protection. J Mol Cell Cardiol. 1996;28(3):447–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol. 2007;292(1):C137–47.PubMedCrossRefGoogle Scholar
  23. 23.
    Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem. 1977;252(23):8731–9.PubMedGoogle Scholar
  24. 24.
    Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol. 2003;160(1):65–75.PubMedCrossRefGoogle Scholar
  25. 25.
    Lee AC, Zizi M, Colombini M. Beta-NADH decreases the permeability of the mitochondrial outer membrane to ADP by a factor of 6. J Biol Chem. 1994;269(49):30974–80.PubMedGoogle Scholar
  26. 26.
    Mootha VK, Wei MC, Buttle KF, Scorrano L, Panoutsakopoulou V, Mannella CA, et al. A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c. EMBO J. 2001;20(4):661–71.PubMedCrossRefGoogle Scholar
  27. 27.
    William JN. A method for the simultaneous quantitative estimation of cytochrome a, b, c1 and and c in mitochondrial. Arch Biochem Biophys. 1964;107:537–43.CrossRefGoogle Scholar
  28. 28.
    Leung CH, Wang L, Fu YY, Yuen W, Caldarone CA. Transient mitochondrial permeability transition pore opening after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg. 2011;141(4):975–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Dickson EW, Blehar DJ, Carraway RE, Heard SO, Steinberg G, Przyklenk K. Naloxone blocks transferred preconditioning in isolated rabbit hearts. J Mol Cell Cardiol. 2001;33(9):1751–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Schrader J, Haddy FJ, Gerlach E. Release of adenosine, inosine and hypoxanthine from the isolated guinea pig heart during hypoxia, flow-autoregulation and reactive hyperemia. Pflugers Arch. 1977;369(1):1–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Peart JN, Gross GJ. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol. 2003;285(1):H81–9.PubMedGoogle Scholar
  32. 32.
    Surendra H, Diaz RJ, Harvey K, Tropak M, Callahan J, Hinek A, et al. Interaction of delta and kappa opioid receptors with adenosine A1 receptors mediates cardioprotection by remote ischemic preconditioning. J Mol Cell Cardiol. 2013;60:142–50.PubMedCrossRefGoogle Scholar
  33. 33.
    Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res. 2004;61(3):372–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC, Brookes PS, et al. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J. 2005;392(Pt 2):353–62.PubMedGoogle Scholar
  35. 35.
    Yang Z, Sun W, Hu K. Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C. Biochim Biophys Acta. 2012;1823(4):950–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003;92(8):873–80.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Scorrano L, Petronilli V, Bernardi P. On the voltage dependence of the mitochondrial permeability transition pore. A critical appraisal. J Biol Chem. 1997;272(19):12295–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Dana A, Jonassen AK, Yamashita N, Yellon DM. Adenosine A(1) receptor activation induces delayed preconditioning in rats mediated by manganese superoxide dismutase. Circulation. 2000;101(24):2841–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap AP. Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res. 2008;102(9):1082–90.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kerr PM, Suleiman MS, Halestrap AP. Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am J Physiol. 1999;276(2 Pt 2):H496–502.PubMedGoogle Scholar
  41. 41.
    Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol. 2005;288(3):H1252–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, Figueredo V, et al. Preconditioning limits mitochondrial Ca(2+) during ischemia in rat hearts: role of K(ATP) channels. Am J Physiol Heart Circ Physiol. 2001;280(5):H2321–8.PubMedGoogle Scholar
  43. 43.
    Murata M, Akao M, O’Rourke B, Marban E. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection. Circ Res. 2001;89(10):891–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Fryer RM, Eells JT, Hsu AK, Henry MM, Gross GJ. Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in preservation of mitochondrial function. Am J Physiol Heart Circ Physiol. 2000;278(1):H305–12.PubMedGoogle Scholar
  45. 45.
    Koomen JM, Wilson CR, Guthrie P, Androlewicz MJ, Kobayashi R, Taegtmeyer H. Proteome analysis of isolated perfused organ effluent as a novel model for protein biomarker discovery. J Proteome Res. 2006;5(1):177–82.PubMedCrossRefGoogle Scholar
  46. 46.
    Naydenova Z, Rose JB, Coe IR. Inosine and equilibrative nucleoside transporter 2 contribute to hypoxic preconditioning in the murine cardiomyocyte HL-1 cell line. Am J Physiol Heart Circ Physiol. 2008;294(6):H2687–92.PubMedCrossRefGoogle Scholar
  47. 47.
    Jin X, Shepherd RK, Duling BR, Linden J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest. 1997;100(11):2849–57.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Peart J, Matherne GP, Cerniway RJ, Headrick JP. Cardioprotection with adenosine metabolism inhibitors in ischemic-reperfused mouse heart. Cardiovasc Res. 2001;52(1):120–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, et al. Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol. 2010;299(5):H1598–603.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chung Ho Leung
    • 1
  • Lixing Wang
    • 1
  • Jan M. Nielsen
    • 2
  • Michael B. Tropak
    • 3
  • Yana Y. Fu
    • 1
  • Hideyuki Kato
    • 1
  • John Callahan
    • 3
  • Andrew N. Redington
    • 4
  • Christopher A. Caldarone
    • 1
  1. 1.Division of Cardiovascular SurgeryHospital for Sick Children/University of TorontoTorontoCanada
  2. 2.Department of CardiologyAarhus University HospitalAarhusDenmark
  3. 3.Division of Genetics and Genome BiologyHospital for Sick ChildrenTorontoCanada
  4. 4.Division of CardiologyHospital for Sick ChildrenTorontoCanada

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