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Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects

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Abstract

Survivin (Surv) belongs to the inhibitor of apoptosis protein family. Its cardiac-specific deletion results in reduced cardiomyocyte number, increased cardiomyocyte size and ploidy, and development of heart failure. Its impact on cardiac electrophysiology is unknown. In vivo transvenous electrophysiological studies were carried out in adult male mice with a cardiac-specific deletion of survivin (Surv−/−; n = 12) and wild-type controls (Surv+/+; n = 12). Epicardial activation mapping (EAM) was performed in Langendorff-perfused hearts of 16 Surv−/− and 6 Surv+/+ mice. Surface-ECG showed lower heart rates in Surv−/− mice (326 ± 66 bpm vs. 440.6 ± 39 ms; P = 0.0001), accompanied by significantly prolonged P waves (20.3 ± 5.8 vs. 14.6 ± 2.0 ms; P = 0.009), PQ-(47.4 ± 8.6 vs. 41.1 ± 3.7 ms; P = 0.043), QRS- (19.5 ± 4.8 vs. 14.0 ± 1.0 ms; P = 0.002) and QT-intervals (41.6 ± 4.4 vs. 36.2 ± 3.4 ms; P = 0.003). The HV-interval was prolonged in Surv−/− mice (12.1 ± 2.4 vs. 9.3 ± 1.4 ms; P = 0.0045). We found impaired sinus-nodal function (sinus node recovery times: 310.2 ± 76.6 vs. 207.8 ± 68.6 ms; P = 0.003) and AV-nodal conduction (Wenckebach-periodicity: 105.9 ± 15.9 vs. 79.6 ± 8.1 ms; P = 0.0002). EAM showed significant slowing and heterogeneity of conduction in the myocardium of Surv−/− mice. All Surv−/− mice showed spontaneous supraventricular and ventricular ectopic beats (P < 0.0001 vs. wildtype). Quantitative immunofluorescence staining for connexin43 (Cx43) revealed a decrease in both per cardiomyocyte and single gap junction. Surv−/− mice exhibit severe global conduction attenuations in atrial and ventricular myocardium as well as the specific conduction system, accompanied by lower connexin43 levels. Lack of susceptibility to AF and VT suggests that reduced cardiomyocyte number and increased size constitute determinants of electrical stableness in the heart and counteract potentially proarrhythmogenic connexin43 loss in Surv−/−.

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References

  1. Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli GF (2004) Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. Circ Res 95:717–725. doi:10.1161/01.RES.0000144125.61927.1c

    Article  PubMed  CAS  Google Scholar 

  2. Altieri DC (2004) Molecular circuits of apoptosis regulation and cell division control: the survivin paradigm. J Cell Biochem 92:656–663. doi:10.1002/jcb.20140

    Article  PubMed  CAS  Google Scholar 

  3. Coronel R, Wilms-Schopman FJ, de Groot JR, Janse MJ, van Capelle FJ, de Bakker JM (2000) Laplacian electrograms and the interpretation of complex ventricular activation patterns during ventricular fibrillation. J Cardiovasc Electrophysiol 11:1119–1128

    Article  PubMed  CAS  Google Scholar 

  4. Danik SB, Rosner G, Lader J, Gutstein DE, Fishman GI, Morley GE (2008) Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. Faseb J 22:1204–1212. doi:10.1096/fj.07-8974com

    Article  PubMed  CAS  Google Scholar 

  5. Fan L, Lin C, Zhuo S, Chen L, Liu N, Luo Y, Fang J, Huang Z, Lin Y, Chen J (2009) Transplantation with survivin-engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial infarction. Eur J Heart Fail 11:1023–1030. doi:10.1093/eurjhf/hfp135

    Article  PubMed  CAS  Google Scholar 

  6. Formigli L, Ibba-Manneschi L, Perna AM, Pacini A, Polidori L, Nediani C, Modesti PA, Nosi D, Tani A, Celli A, Neri-Serneri GG, Quercioli F, Zecchi-Orlandini S (2003) Altered Cx43 expression during myocardial adaptation to acute and chronic volume overloading. Histol Histopathol 18:359–369

    PubMed  CAS  Google Scholar 

  7. Kinoshita H, Kuwahara K, Takano M, Arai Y, Kuwabara Y, Yasuno S, Nakagawa Y, Nakanishi M, Harada M, Fujiwara M, Murakami M, Ueshima K, Nakao K (2009) T-type Ca2+ channel blockade prevents sudden death in mice with heart failure. Circulation 120:743–752. doi:10.1161/CIRCULATIONAHA.109.857011

    Article  PubMed  CAS  Google Scholar 

  8. Kreuzberg MM, Schrickel JW, Ghanem A, Kim JS, Degen J, Janssen-Bienhold U, Lewalter T, Tiemann K, Willecke K (2006) Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node. Proc Natl Acad Sci USA 103:5959–5964. doi:10.1073/pnas.0508512103

    Article  PubMed  CAS  Google Scholar 

  9. Lammers WJ, Schalij MJ, Kirchhof CJ, Allessie MA (1990) Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol 259:H1254–H1263

    PubMed  CAS  Google Scholar 

  10. Levkau B (2011) Survivin signalling in the heart. J Mol Cell Cardiol 50:6–8. doi:10.1016/j.yjmcc.2010.10.013

    Article  PubMed  CAS  Google Scholar 

  11. Levkau B, Schafers M, Wohlschlaeger J, von Wnuck K, Keul P, Hermann S, Kawaguchi N, Kirchhof P, Fabritz L, Stypmann J, Stegger L, Flogel U, Schrader J, Fischer JW, Hsieh P, Ou YL, Mehrhof F, Tiemann K, Ghanem A, Matus M, Neumann J, Heusch G, Schmid KW, Conway EM, Baba HA (2008) Survivin determines cardiac function by controlling total cardiomyocyte number. Circulation 117:1583–1593. doi:10.1161/CIRCULATIONAHA.107.734160

    Article  PubMed  CAS  Google Scholar 

  12. Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I, Reed JC (2003) HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J 22:2729–2740. doi:10.1093/emboj/cdg263

    Article  PubMed  CAS  Google Scholar 

  13. Mitchell GF, Jeron A, Koren G (1998) Measurement of heart rate and Q-T interval in the conscious mouse. Am J Physiol 274:H747–H751

    PubMed  CAS  Google Scholar 

  14. Petrich BG, Eloff BC, Lerner DL, Kovacs A, Saffitz JE, Rosenbaum DS, Wang Y (2004) Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J Biol Chem 279:15330–15338. doi:10.1074/jbc.M314142200

    Article  PubMed  CAS  Google Scholar 

  15. Roell W, Lewalter T, Sasse P, Tallini YN, Choi BR, Breitbach M, Doran R, Becher UM, Hwang SM, Bostani T, von Maltzahn J, Hofmann A, Reining S, Eiberger B, Gabris B, Pfeifer A, Welz A, Willecke K, Salama G, Schrickel JW, Kotlikoff MI, Fleischmann BK (2007) Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450:819–824. doi:10.1038/nature06321

    Article  PubMed  CAS  Google Scholar 

  16. Schrickel JW, Bielik H, Yang A, Schimpf R, Shlevkov N, Burkhardt D, Meyer R, Grohe C, Fink K, Tiemann K, Luderitz B, Lewalter T (2002) Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing. Basic Res Cardiol 97:452–460. doi:1007/s003950200052

    Article  PubMed  Google Scholar 

  17. Schrickel JW, Brixius K, Herr C, Clemen CS, Sasse P, Reetz K, Grohe C, Meyer R, Tiemann K, Schroder R, Bloch W, Nickenig G, Fleischmann BK, Noegel AA, Schwinger RH, Lewalter T (2007) Enhanced heterogeneity of myocardial conduction and severe cardiac electrical instability in annexin A7-deficient mice. Cardiovasc Res 76:257–268. doi:1016/j.cardiores.2007.07.001

    Article  PubMed  CAS  Google Scholar 

  18. Schrickel JW, Kreuzberg MM, Ghanem A, Kim JS, Linhart M, Andrie R, Tiemann K, Nickenig G, Lewalter T, Willecke K (2009) Normal impulse propagation in the atrioventricular conduction system of Cx30.2/Cx40 double deficient mice. J Mol Cell Cardiol 46:644–652. doi:1016/j.yjmcc.2009.02.012

    Article  PubMed  CAS  Google Scholar 

  19. Song Z, Yao X, Wu M (2003) Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem 278:23130–23140. doi:0.1074/jbc.M300957200

    Article  PubMed  CAS  Google Scholar 

  20. Spach MS, Heidlage JF, Dolber PC, Barr RC (2001) Changes in anisotropic conduction caused by remodeling cell size and the cellular distribution of gap junctions and Na(+) channels. J Electrocardiol 34(Suppl):69–76

    Article  PubMed  Google Scholar 

  21. Spach MS, Heidlage JF, Barr RC, Dolber PC (2004) Cell size and communication: role in structural and electrical development and remodeling of the heart. Heart Rhythm 1:500–515. doi:10.1016/j.hrthm.2004.06.010

    Article  PubMed  Google Scholar 

  22. van Rijen HV, Eckardt D, Degen J, Theis M, Ott T, Willecke K, Jongsma HJ, Opthof T, de Bakker JM (2004) Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation 109:1048–1055. doi:1161/01.CIR.0000117402.70689.75

    Article  PubMed  Google Scholar 

  23. Vaux DL, Silke J (2005) IAPs: the ubiquitin connection. Cell Death Differ 12:1205–1207. doi:1038/sj.cdd.4401696

    Article  PubMed  CAS  Google Scholar 

  24. Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6:287–297. doi:1038/nrm1621

    Article  PubMed  CAS  Google Scholar 

  25. Xing Z, Conway EM, Kang C, Winoto A (2004) Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis. J Exp Med 199:69–80. doi:10.1084/jem.20031588

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank B. Fleischmann and P. Sasse for methodological support with the epicardial activation maps. Electrophysiological investigations were supported by an internal grant of the university Bonn (BONFOR O-109.0008) to JWS.

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None of the authors has any disclosures to state regarding the work on this manuscript.

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Authors and Affiliations

  1. Department of Medicine-Cardiology, University of Bonn, Sigmund Freud Strasse 25, 53105, Bonn, Germany

    Jan Wilko Schrickel, Lars Lickfett & Georg Nickenig

  2. Isar Heartcenter, Munich, Germany

    Thorsten Lewalter & Klaus Tiemann

  3. Institute of Pathophysiology, University Duisburg-Essen, Essen, Germany

    Hideo Baba

  4. Institute of Neuropathology and Pathology, University Duisburg-Essen, Essen, Germany

    Gerd Heusch & Bodo Levkau

  5. Institute of Physiology, University of Giessen, Giessen, Germany

    Rainer Schulz

Authors
  1. Jan Wilko Schrickel
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  2. Lars Lickfett
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  3. Thorsten Lewalter
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  4. Klaus Tiemann
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  5. Georg Nickenig
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  6. Hideo Baba
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  7. Gerd Heusch
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  8. Rainer Schulz
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  9. Bodo Levkau
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Corresponding author

Correspondence to Jan Wilko Schrickel.

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M. Boggrefe, Mannheim, Germany served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution.

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Schrickel, J.W., Lickfett, L., Lewalter, T. et al. Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects. Basic Res Cardiol 107, 299 (2012). https://doi.org/10.1007/s00395-012-0299-8

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  • DOI: https://doi.org/10.1007/s00395-012-0299-8

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