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Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways

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Abstract

A sequence of intermittent interruptions of oxygen supply (i.e., postconditioning, Postcon) at reoxygenation reduces oxidant-induced cardiomyocyte loss. This study tested the hypothesis that prevention of cardiomyocyte apoptosis by Postcon is mediated by mitogen-activated protein kinases pathways. Primary cultured neonatal rat cardiomyocytes were exposed to 3 h hypoxia followed by 6 h of reoxygenation. Cardiomyocytes were postconditioned by three cycles each of 5 min reoxygenation and 5 min hypoxia after prolonged hypoxia. Relative to hypoxia alone, reoxygenation stimulated expression of JNKs and p38 kinases, corresponding to increased activity of JNKs (phospho-c-Jun) and p38 (phospho-ATF2). The level of TNFα in cell lysates, activity of cytosolic caspases-8, -3, expression of Bax and the number of apoptotic cardiomyocytes were increased while expression of Bcl-2 was decreased with reoxygenation. Consistent with an attenuation in generation of superoxide anions detected by lucigenin-enhanced chemiluminescence at early period of reoxygenation, treatment of cardiomyocytes with Postcon further reduced expression and activity of JNKs and p38 kinases, level of TNFα, the frequency of apoptotic cells and expression of Bax. However, the inhibitory effects of Postcon on these changes were lost when its application was delayed by 5 min after the start of reoxygenation. Addition of a JNK/p38 stimulator, anisomycin into cardiomyocytes at the beginning of reoxygenation eliminated protection by Postcon. These data suggest that 1) hypoxia/reoxygenation elicits cardiomyocyte apoptosis in conjunction with expression and activation of JNK and p38 kinases, release of TNFα, activation of caspases, and an increase in imbalance of pro-/anti-apoptotic proteins; 2) Postcon attenuates cardiomyocyte apoptosis, potentially mediated by inhibiting JNKs/p-38 signaling pathways and reducing TNFα release and caspase expression.

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References

  1. Zhao Z-Q, 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) 285:579–588

    Google Scholar 

  2. Kin H, Zhao Z-Q, Sun H-Y 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 

  3. Sun H-Y, Wang N-P, Kerendi F et al (2005) Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload. Am J Phy 288:H1900–H1908

    PubMed  CAS  Google Scholar 

  4. Yang X-M, 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 Card 44:1103–1110

    Article  PubMed  Google Scholar 

  5. 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  CAS  Google Scholar 

  6. 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. Circul Res 95:230–232

    Article  PubMed  CAS  Google Scholar 

  7. Laskey WK (2005) Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study. Catheteriz Cardiovasc Interven 65:361–367

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  9. Mackay K, Mochly-Rosen D (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 274:6272–6279

    Article  PubMed  CAS  Google Scholar 

  10. Meldrum DR, Dinarello CA, Cleveland JC, Jr et al (1998) Hydrogen peroxide induces tumor necrosis factor alpha-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanmism. Surgery 124:291–297

    PubMed  CAS  Google Scholar 

  11. Klein JB, Wang GW, Zhou Z, Buridi A, Kang YJ (2002) Inhibition of tumor necrosis factor-alpha-dependent cardiomyocyte apoptosis by metallothionein. Cardiovasc Toxicol 2:209–218

    Article  PubMed  CAS  Google Scholar 

  12. Lee MW, Park SC, Yang YG, et al (2002) The involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein (MAP(kinase in TRAIL/Apo2L-induced apoptosis. FEBS Letters 512:313–318

    Article  PubMed  CAS  Google Scholar 

  13. Osone S, Hosoi H, Kuwahara Y, Matsumoto Y, Iehara T, Sugimoto T (2004) Fenretinide induces sustained-activation of JNK/p38 MAPK and apoptosis in a reactive oxygen species-dependent manner in neuroblastoma cells. Int J Cancer 112:219–224

    Article  PubMed  CAS  Google Scholar 

  14. Yoshizumi M, Tsuchiya K, Tamaki T (2001) Signal transduction of reactive oxygen species and mitogen-activated protein kinases in cardiovascular disease. J Invest Med 48:11–24

    CAS  Google Scholar 

  15. Marczin N, Bundy RE, Hoare GS, Yacoub M (2003) Redox regulation following cardiac ischemia and reperfusion. Coron Artery Dis 14:123–133

    Article  PubMed  Google Scholar 

  16. Hahn RA, MacDonald BR, Morgan E et al (1992) Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury. Journal of Pharmacol Experim Therap 260:979–989

    CAS  Google Scholar 

  17. Gao F, Yue T-L, Shi D-W, et al (2002) p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation. Cardiovasc Res 53:414–422

    Article  PubMed  CAS  Google Scholar 

  18. Clanachan AS, Jaswal JS, Gandhi M et al (2003) Effects of inhibition of myocardial extracellular-responsive kinase and p38 mitogen-activated protein kinase on mechanical function of rat hearts after prolonged hypothermic ischemia. Transplant 75:173–180

    Article  PubMed  CAS  Google Scholar 

  19. Cicconi S, Ventura N, Pastore D et al (2003) Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model. J Cell Physiol 195:27–37

    Article  PubMed  CAS  Google Scholar 

  20. Fan H, Sun B, Gu Q, Lafond-Walker A, Cao S, Becker LC (2002) Oxygen radicals trigger activation of NF-kB and AP-1 and upregulation of ICAM-1 in reperfused canine heart. Am J Physiol (Heart Circ Physiol) 282:H1778–H1786

    CAS  Google Scholar 

  21. Wang T, Zhang X, Li J-J (2002) The role of NF-κB in the regulation of cell stress responses. Intern Immunopharm 2:1509–1520

    Article  PubMed  CAS  Google Scholar 

  22. Meldrum DR (1998) Tumor necrosis factor in the heart. Am J Physiol 274:R577–R595

    PubMed  CAS  Google Scholar 

  23. Zhao Z-Q, Vinten-Johansen J (2002) Myocardial apoptosis and ischemic preconditioning. Cardiovasc Res 55:438–455

    Article  PubMed  CAS  Google Scholar 

  24. Sun H-Y, Wang N-P, Halkos ME et al (2004) Involvement of Na+/H+ exchanger in hypoxia/re-oxygenation-induced neonatal rat cardiomyocyte apoptosis. Euro J Pharmacol 486:121–131

    Article  PubMed  CAS  Google Scholar 

  25. Laderoute KR, Webster KA (1997) Hypoxia/reoxygenation stimulates jun kinase activity through redox signaling in cardiac myocytes. Circul Res 80:336–344

    PubMed  CAS  Google Scholar 

  26. Yang X-M, 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 

  27. 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 

  28. Nakano A, Cohen MV, Critz SD, Downey JM (2000) SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of iscehmic preconditioning in isolated rabbit hearts. Basic Res Cardiol 95:466–471

    Article  PubMed  CAS  Google Scholar 

  29. Weinbrenner C, Liu GS, Cohen MV, Downey JM (1997) Phosphorylation of Tyrosine 182 of p38 mitogen activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Molec Cell Cardiol 29:2383–2391

    Article  PubMed  CAS  Google Scholar 

  30. Kaiser RA, Bueno OF, Lips DJ et al (2004) Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J Biolog Chem 279:15524–15530

    Article  PubMed  CAS  Google Scholar 

  31. Ferrandi C, Ballerio R, Gaillard P et al (2004) Inhibition of c-Jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats. British J Pharmacol 142:953–960

    Article  PubMed  CAS  Google Scholar 

  32. Ballard-Croft C, White DJ, Maass DL, Hybki DP, Horton JW (2001) Role of p38 mitogen-activated protein kinase in cardiac myocyte seretion of the inflammatory cytokine TNF-alpha. Am J Physiol (Heart Circ Physiol) 280:H1970–H1981

    CAS  Google Scholar 

  33. Brown M, McGuinness M, Wright T et al (2005) Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. Am J Physiol (Heart Circ Physiol) 289:H466–H476

    Article  CAS  Google Scholar 

  34. Haunstetter A, Izumo S (1998) Apoptosis. Basic mechanisms and implications for cardiovascular disease. Circulation Research 82:1111–1129

    PubMed  CAS  Google Scholar 

  35. Ma X-L, Kumar S, Gao F, et al (1999) Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99:1685–1691

    PubMed  CAS  Google Scholar 

  36. Maekawa N, Wada H, Kanda T et al (2002) Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J Am Coll Cardiol 39:1229–1235

    Article  PubMed  CAS  Google Scholar 

  37. Chandra J, Samali A, Orrenius S (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Medi 29:323–333

    Article  CAS  Google Scholar 

  38. Esposti MD, Dive C (2003) Mitochondrial membrane permeabilisation by Bax/Bak. Biochem & Biophys Res Comm 304:455–461

    Article  CAS  Google Scholar 

  39. Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15:691–699

    Article  PubMed  CAS  Google Scholar 

  40. Halestrap AP, Kerr PM, Javadov S, Woodfield KY (1998) Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart. Biochim Biophys Acta 1366:79–94

    Article  PubMed  CAS  Google Scholar 

  41. Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem & Biophys Res Comm 304:463–470

    Article  CAS  Google Scholar 

  42. Sun K, Liu ZS, Sun Q (2004) Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning. World J Gastroenterol 10:1934–1938

    Google Scholar 

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Authors and Affiliations

  1. Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory Crawford Long Hospital, Emory University, 550 Peachtree St., NE, Atlanta, Georgia, 30308-2225

    He-Ying Sun, Ning-Ping Wang, Michael Halkos, Faraz Kerendi, Hajime Kin, Robert A. Guyton, Jakob Vinten-Johansen & Zhi-Qing Zhao

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  1. He-Ying Sun
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  2. Ning-Ping Wang
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  3. Michael Halkos
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  4. Faraz Kerendi
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Correspondence to Zhi-Qing Zhao.

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Sun, HY., Wang, NP., Halkos, M. et al. Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis 11, 1583–1593 (2006). https://doi.org/10.1007/s10495-006-9037-8

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