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Connexin 43 in ischemic pre- and postconditioning

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Abstract

Connexin 43 (Cx43) is the predominant protein forming gap junctions and non-junctional hemichannels in ventricular myocardium, but Cx43 is also localized at the inner membrane of cardiomyocyte mitochondria. In cardiomyocytes, Cx43 is involved in the formation of reactive oxygen species, which are central to the signal transduction cascade of ischemic preconditioning’s protection. Accordingly, genetically-induced or age-related loss of Cx43 abolishes infarct size reduction by ischemic preconditioning. Similarly, mitochondrial import inhibition of Cx43 completely blocks infarct size reduction by pharmacological preconditioning with diazoxide. In contrast to its importance for preconditioning-induced cardioprotection, Cx43 is not important for infarct size reduction by ischemic postconditioning. In summary, Cx43––especially Cx43 localized in mitochondria––appears to be one key element of the signal transduction cascade of the protection by preconditioning.

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References

  1. Sohl G, Willecke K (2004) Gap junctions and the connexin protein family. Cardiovasc Res 62:228–232

    Article  PubMed  CAS  Google Scholar 

  2. van Veen TA, van Rijen HV, Jongsma HJ (2006) Physiology of cardiovascular gap junctions. Adv Cardiol 42:18–40

    Article  PubMed  Google Scholar 

  3. Delmar M, Coombs W, Sorgen P, Duffy HS, Taffet SM (2004) Structural bases for the chemical regulation of connexin43 channels. Cardiovasc Res 62:268–275

    Article  PubMed  CAS  Google Scholar 

  4. King TJ, Lampe PD (2005) Temporal regulation of connexin phosphorylation in embryonic and adult tissues. Biochim Biophys Acta 1719:24–35

    Article  PubMed  CAS  Google Scholar 

  5. Veenstra RD, Wang HZ, Beblo DA et al (1995) Selectivity of connexin-specific gap junctions does not correlate with channel conductance. Circ Res 77:1156–1165

    PubMed  CAS  Google Scholar 

  6. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83:1359–1400

    PubMed  CAS  Google Scholar 

  7. Spray DC, Burt JM (1990) Structure-activity relations of the cardiac gap junction channel. Am J Physiol 258:C195–C205

    PubMed  CAS  Google Scholar 

  8. Quist AP, Rhee SK, Lin H, Lal R (2000) Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation. J Cell Biol 148:1063–1074

    Article  PubMed  CAS  Google Scholar 

  9. De MA, Vega VL, Contreras JE (2002) Gap junctions, homeostasis, and injury. J Cell Physiol 191:269–282

    Article  CAS  Google Scholar 

  10. Plotkin LI, Manolagas SC, Bellido T (2002) Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem 277:8648–8657

    Article  PubMed  CAS  Google Scholar 

  11. Saez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV (2005) Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta 1711:215–224

    Article  PubMed  CAS  Google Scholar 

  12. Schulz R, Heusch G (2004) Connexin 43 and ischemic preconditioning. Cardiovasc Res 62:335–344

    Article  PubMed  CAS  Google Scholar 

  13. Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF (2000) Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J Cell Biol 149:1503–1512

    Article  PubMed  CAS  Google Scholar 

  14. Bao X, Reuss L, Altenberg GA (2004) Regulation of purified and reconstituted connexin 43 hemichannels by protein kinase C-mediated phosphorylation of Serine 368. J Biol Chem 279:20058–20066

    Article  PubMed  CAS  Google Scholar 

  15. Ek-Vitorin JF, King TJ, Heyman NS, Lampe PD, Burt JM (2006) Selectivity of connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res 98:1498–1505

    Article  PubMed  CAS  Google Scholar 

  16. Giepmans BN (2004) Gap junctions and connexin-interacting proteins. Cardiovasc Res 62:233–245

    Article  PubMed  CAS  Google Scholar 

  17. Akiyama M, Ishida N, Ogawa T, Yogo K, Takeya T (2005) Molecular cloning and functional analysis of a novel Cx43 partner protein CIP150. Biochem Biophys Res Commun 335:1264–1271

    Article  PubMed  CAS  Google Scholar 

  18. Matsuda T, Fujio Y, Nariai T et al (2006) N-cadherin signals through Rac1 determine the localization of connexin 43 in cardiac myocytes. J Mol Cell Cardiol 40:495–502

    Article  PubMed  CAS  Google Scholar 

  19. Schulz R, Gres P, Skyschally A et al (2003) Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J 17:1355–1357

    PubMed  CAS  Google Scholar 

  20. John SA, Kondo R, Wang SY, Goldhaber JI, Weiss JN (1999) Connexin-43 hemichannels opened by metabolic inhibition. J Biol Chem 274:236–240

    Article  PubMed  CAS  Google Scholar 

  21. Li F, Sugishita K, Su Z, Ueda I, Barry WH (2001) Activation of connexin-43 hemichannels can elevate [Ca(2+)]i and [Na(+)]i in rabbit ventricular myocytes during metabolic inhibition. J Mol Cell Cardiol 33:2145–2155

    Article  PubMed  CAS  Google Scholar 

  22. Vetterlein F, Muhlfeld C, Cetegen C, Volkmann R, Schrader C, Hellige G (2006) Redistribution of connexin43 in regional acute ischemic myocardium: influence of ischemic preconditioning. Am J Physiol Heart Circ Physiol 291:H813–H819

    Article  PubMed  CAS  Google Scholar 

  23. Lampe PD, Cooper CD, King TJ, Burt JM (2006) Analysis of connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart. J Cell Sci 119:3435–3442

    Article  PubMed  CAS  Google Scholar 

  24. Tansey EE, Kwaku KF, Hammer PE et al (2006) Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion. Ann Thorac Surg 82:1472–1479

    Article  PubMed  Google Scholar 

  25. Beardslee MA, Lerner DL, Tadros PN et al (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    PubMed  CAS  Google Scholar 

  26. Axelsen LN, Stahlhut M, Mohammed S et al (2006) Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol 40:790–798

    Article  PubMed  CAS  Google Scholar 

  27. Miura T, Ohnuma Y, Kuno A et al (2004) Protective role of gap junctions in preconditioning against myocardial infarction. Am J Physiol Heart Circ Physiol 286:H214–H221

    Article  PubMed  CAS  Google Scholar 

  28. Jain SK, Schuessler RB, Saffitz JE (2003) Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning. Circ Res 92:1138–1144

    Article  PubMed  CAS  Google Scholar 

  29. Azzam EI, de Toledo SM, Little JB (2001) Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha-particle irradiated to nonirradiated cells. Proc Natl Acad Sci USA 98:473–478

    Article  PubMed  CAS  Google Scholar 

  30. Garcia-Dorado D, Rodriguez-Sinovas A, Ruiz-Meana M (2004) Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc Res 61:386–401

    Article  PubMed  CAS  Google Scholar 

  31. Li G, Whittaker P, Yao M, Kloner RA, Przyklenk K (2002) The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts. Cardiovasc Pathol 11:158–165

    Article  PubMed  CAS  Google Scholar 

  32. Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G (2002) No ischemic preconditioning in heterozygous connexin43-deficient mice. Am J Physiol Heart Circ Physiol 283:H1740–H1742

    PubMed  CAS  Google Scholar 

  33. Schwanke U, Li X, Schulz R, Heusch G (2003) No ischemic preconditioning in heterozygous connexin 43-deficient mice––a further in vivo study. Basic Res Cardiol 98:181–182

    PubMed  Google Scholar 

  34. Li X, Heinzel FR, Boengler K, Schulz R, Heusch G (2004) Role of connexin 43 in ischemic preconditioning does not involve intercellular communication through gap junctions. J Mol Cell Cardiol 36:161–163

    Article  PubMed  CAS  Google Scholar 

  35. Dang X, Doble BW, Kardami E (2003) The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth. Mol Cell Biochem 242:35–38

    Article  PubMed  CAS  Google Scholar 

  36. Li H, Brodsky S, Kumari S et al (2002) Paradoxical overexpression and translocation of connexin43 in homocysteine-treated endothelial cells. Am J Physiol Heart Circ Physiol 282:H2124–H2133

    PubMed  CAS  Google Scholar 

  37. Boengler K, Dodoni G, Rodriguez-Sinovas A et al (2005) Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res 67:234–244

    Article  PubMed  CAS  Google Scholar 

  38. O’Rourke B (2004) Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res 94:420–432

    Article  PubMed  CAS  Google Scholar 

  39. Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion––a target for cardioprotection. Cardiovasc Res 61:372–385

    Article  PubMed  CAS  Google Scholar 

  40. 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 

  41. Boengler K, Gres P, Cabestrero A et al (2006) Prevention of the ischemia-induced decrease in mitochondrial Tom20 content by ischemic preconditioning. J Mol Cell Cardiol 41:426–430

    Article  PubMed  CAS  Google Scholar 

  42. Rodriguez-Sinovas A, Boengler K, Cabestrero A et al (2006) Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90-dependent TOM pathway and its importance for cardioprotection. Circ Res 99:93–101

    Article  PubMed  CAS  Google Scholar 

  43. Lefer DJ, Granger DN (2000) Oxidative stress and cardiac disease. Am J Med 109:315–323

    Article  PubMed  CAS  Google Scholar 

  44. Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G (2001) Signal transduction of ischemic preconditioning. Cardiovasc Res 52:181–198

    Article  PubMed  CAS  Google Scholar 

  45. Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    PubMed  CAS  Google Scholar 

  46. Pain T, Yang XM, Critz SD et al (2000) Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 87:460–466

    PubMed  CAS  Google Scholar 

  47. Heinzel FR, Luo Y, Li X et al (2005) Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97:583–586

    Article  PubMed  CAS  Google Scholar 

  48. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM (2004) Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95:230–232

    Article  PubMed  CAS  Google Scholar 

  49. Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M (2006) PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res 69:178–185

    Article  PubMed  CAS  Google Scholar 

  50. Darling CE, Jiang R, Maynard M, Whittaker P, Vinten-Johansen J, Przyklenk K (2005) Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2. Am J Physiol Heart Circ Physiol 289:H1618–H1626

    Article  PubMed  CAS  Google Scholar 

  51. Yang XM, Philipp S, Downey JM, Cohen MV (2005) Postconditioning’s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic Res Cardiol 100:57–63

    Article  PubMed  CAS  Google Scholar 

  52. Heusch G, Buchert A, Feldhaus S, Schulz R (2006) No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic Res Cardiol 101:354–356

    Article  PubMed  CAS  Google Scholar 

  53. Kin H, Zhao ZQ, Sun HY et al (2004) Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62:74–85

    Article  PubMed  CAS  Google Scholar 

  54. Kin H, Zatta AJ, Lofye MT et al (2005) Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res 67:124–133

    Article  PubMed  CAS  Google Scholar 

  55. Tang XL, Sato H, Tiwari S et al (2006) Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 minutes. Am J Physiol Heart Circ Physiol 291:H2308–H2317

    Article  PubMed  CAS  Google Scholar 

  56. Zatta AJ, Kin H, Lee G et al (2006) Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling. Cardiovasc Res 70: 315–324

    Article  PubMed  CAS  Google Scholar 

  57. Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV (2004) Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol 44:1103–1110

    Article  PubMed  Google Scholar 

  58. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197

    Article  PubMed  CAS  Google Scholar 

  59. Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC (2005) Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology 102:102–109

    Article  PubMed  CAS  Google Scholar 

  60. Couvreur N, Lucats L, Tissier R, Bize A, Berdeaux A, Ghaleh B (2006) Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits. Am J Physiol Heart Circ Physiol 291:H1345–H1350

    Article  PubMed  CAS  Google Scholar 

  61. Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res 70:308–314

    Article  PubMed  CAS  Google Scholar 

  62. Zhao ZQ, Corvera JS, Halkos ME et al (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588

    PubMed  CAS  Google Scholar 

  63. Halkos ME, Kerendi F, Corvera JS et al (2004) Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg 78:961–969

    Article  PubMed  Google Scholar 

  64. Iliodromitis EK, Georgiadis M, Cohen MV, Downey JM, Bofilis E, Kremastinos DT (2006) Protection from postconditioning depends on the number of short ischemic insults in anesthetized pigs. Basic Res Cardiol 101:502–507

    Article  PubMed  Google Scholar 

  65. Staat P, Rioufol G, Piot C et al (2005) Postconditioning the human heart. Circulation 112:2143–2148

    Article  PubMed  Google Scholar 

  66. Valen G, Vaage J (2005) Pre- and postconditioning during cardiac surgery. Basic Res Cardiol 100:179–186

    Article  PubMed  Google Scholar 

  67. Vinten-Johansen J, Yellon DM, Opie LH (2005) Postconditioning: a simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 112:2085–2088

    Article  PubMed  Google Scholar 

  68. Kloner RA, Rezkalla SH (2006) Preconditioning, postconditioning, their application to clinical cardiology. Cardiovasc Res 70:297–307

    Article  PubMed  CAS  Google Scholar 

  69. Ramzy D, Rao V, Weisel RD (2006) Clinical applicability of preconditioning, postconditioning: the cardiothoracic surgeons’s view. Cardiovasc Res 70:174–180

    Article  PubMed  CAS  Google Scholar 

  70. Yellon DM, Opie LH (2006) Postconditioning for protection of the infarcting heart. Lancet 367:456–458

    Article  PubMed  Google Scholar 

  71. Fantinelli JC, Mosca SM (2007) Comparative effects of ischemic pre and postconditioning on ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Mol Cell Biochem 296:45–51

    Article  PubMed  CAS  Google Scholar 

  72. Heusch G (2004) Postconditioning: old wine in a new bottle? J Am Coll Cardiol 44:1111–1112

    Article  PubMed  Google Scholar 

  73. Tsang A, Hausenloy DJ, Yellon DM (2005) Myocardial postconditioning: reperfusion injury revisited. Am J Physiol Heart Circ Physiol 289:H2–H7

    Article  PubMed  CAS  Google Scholar 

  74. 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 100:295–310

    Article  PubMed  CAS  Google Scholar 

  75. Crisostomo PR, Wairiuko GM, Wang M, Tsai BM, Morrell ED, Meldrum DR (2006) Preconditioning versus postconditioning: mechanisms and therapeutic potentials. J Am Coll Surg 202:797–812

    Article  PubMed  Google Scholar 

  76. Garcia-Dorado D, Vinten-Johansen J, Piper HM (2006) Bringing preconditioning and postconditioning into focus. Cardiovasc Res 70:167–169

    Article  PubMed  CAS  Google Scholar 

  77. Schwartz LM, Lagranha CJ (2006) Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. Am J Physiol Heart Circ Physiol 290:H1011–H1018

    Article  PubMed  CAS  Google Scholar 

  78. Crisostomo PR, Wang M, Wairiuko GM, Terrell AM, Meldrum DR (2006) Postconditioning in females depends on injury severity. J Surg Res 134:342–347

    Article  PubMed  Google Scholar 

  79. Hausenloy DJ, Tsang A, Yellon DM (2005) The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15:69–75

    Article  PubMed  CAS  Google Scholar 

  80. Hausenloy DJ, Yellon DM (2006) Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70:240–253

    Article  PubMed  CAS  Google Scholar 

  81. Downey JM, Cohen MV (2005) We think we see a pattern emerging here. Circulation 111:120–121

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstr. 55, 45122, Essen, Germany

    Rainer Schulz, Kerstin Boengler, Andreas Totzeck, Yukun Luo & Gerd Heusch

  2. Servicio de Cardiologia, Hospital Universitari Vall D’Hebron, Barcelona, Spain

    David Garcia-Dorado

Authors
  1. Rainer Schulz
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  2. Kerstin Boengler
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  3. Andreas Totzeck
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  4. Yukun Luo
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  5. David Garcia-Dorado
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  6. Gerd Heusch
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Correspondence to Gerd Heusch.

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The authors’ studies were supported by the German Research Foundation (Schu843/7-1).

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Schulz, R., Boengler, K., Totzeck, A. et al. Connexin 43 in ischemic pre- and postconditioning. Heart Fail Rev 12, 261–266 (2007). https://doi.org/10.1007/s10741-007-9032-3

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