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Mathematical Simulations of Sphingosine-1-Phosphate Actions on Mammalian Ventricular Myofibroblasts and Myocytes

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Cardiac Fibrosis and Heart Failure: Cause or Effect?

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 13))

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Abstract

Mathematical modeling has been used to explore the consequences of the actions of sphingosine-1-phosphate (S-1-P) within the ventricular myocardium. Electrophysiological data obtained from rabbit cultured myofibroblasts [1] provided the basis for formulation of our model of electrotonic coupling between ventricular myocytes and fibroblasts [2]. Specifically, our in silico fibroblast/myocyte hybrid model was modified to account for the electrophysiological properties that are characteristic of the myofibroblast (the wound healing phenotype of the fibroblast). In addition, equations describing an S-1-P-induced current that can be activated in the myofibroblast were added.

The sets of simulations that constitute this paper demonstrate that S-1-P can cause a significant depolarization of the resting membrane potential in both the myofibroblast and myocyte . When the myocyte to fibroblast coupling ratio is 1:1, this concentration-dependent effect is due to ligand-gated current in the myofibroblast depolarizing the myocyte through heterotypic connexin-mediated intercellular junctions. In addition to changing the resting potential in the myocyte, the S-1-P induced current resulted in significant changes in action potential waveform.

A second set of simulations was done for the purpose of exploring the effects of S-1-P on myocytes that have some of the main electrophysiological properties of those from the failing heart. In these computations, the ten Tusscher model of the human ventricular myocyte was modified by reducing parameters as follows: cell capacitance, inward rectifier K + current, delayed-rectifier K + currents (IKs and IKr), and transient outward K + current. In combination, these changes (each of which is associated with heart failure), resulted in prolongation of action potential duration. Simulations of electrotonic coupling between this model ‘failing’ myocyte and myofibroblasts demonstrated that the resting potential and APD in the failing myocyte is more susceptible to modulation by electrotonic influences from S-1-P-stimulated myofibroblasts when a ‘failing’ electrophysiological phenotype in the ventricular myocyte is introduced.

In summary, our simulations draw attention to important effects of S-1-P on the ventricular myocardium even when this paracrine substance acts only on the fibroblast cell population. These cell-specific S-1-P effects alter the myocyte action potential via electrotonic coupling. It is apparent that myofibroblasts can have significant effects on myocyte action potentials; and that these effects would be expected to be more pronounced in the presence of ligand-gated effects on the myofibroblast . The general setting that we have attempted to replicate with this first order model has some similarities to acute or sterile inflammation in the myocardium wherein S-1-P concentrations in the interstitium are relatively high.

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References

  1. Chilton L, Giles WR, Smith GL (2007) Evidence of intercellular coupling between co-cultured adult rabbit ventricular myocytes and myofibroblasts. J Physiol 583(Pt 1):225–236.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. MacCannell KA, Bazzazi H, Chilton L, Shibukawa Y, Clark RB, Giles WR (2007) A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts. Biophys J 92(11):4121–4132.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Pyne S, Pyne NJ (2000) Sphingosine 1-phosphate signalling in mammalian cells. Biochem J 349(Pt 2):385–402

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Peters SL, Alewijnse AE (2007) Sphingosine-1-phosphate signaling in the cardiovascular system. Curr Opin Pharmacol 7(2):186–192.

    Article  CAS  PubMed  Google Scholar 

  5. Sun Y, Kiani MF, Postlethwaite AE, Weber KT (2002) Infarct scar as living tissue. Basic Res Cardiol 97(5):343–347.

    Article  PubMed  Google Scholar 

  6. ten Tusscher KH, Noble D, Noble PJ, Panfilov AV (2004) A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286(4):H1573–1589.

    Article  PubMed  Google Scholar 

  7. Kohl P, Kamkin AG, Kiseleva IS, Noble D (1994) Mechanosensitive fibroblasts in the sino-atrial node region of rat heart: interaction with cardiomyocytes and possible role. Exp Physiol 79(6):943–956

    Article  CAS  PubMed  Google Scholar 

  8. Camelliti P, Green CR, LeGrice I, Kohl P (2004) Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogeneous and heterogeneous cell coupling. Circ Res 94(6):828–835.

    Article  CAS  PubMed  Google Scholar 

  9. Camelliti P, Devlin GP, Matthews KG, Kohl P, Green CR (2004) Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction. Cardiovasc Res 62(2):415–425.

    Article  CAS  PubMed  Google Scholar 

  10. Gaudesius G, Miragoli M, Thomas SP, Rohr S (2003) Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res 93(5):421–428.

    Article  CAS  PubMed  Google Scholar 

  11. Hachiro T, Kawahara K, Sato R, Yamauchi Y, Matsuyama D (2007) Changes in the fluctuation of the contraction rhythm of spontaneously beating cardiac myocytes in cultures with and without cardiac fibroblasts. Bio Syst 90(3):707–715.

    Google Scholar 

  12. Kizana E, Ginn SL, Smyth CM, Boyd A, Thomas SP, Allen DG, Ross DL, Alexander IE (2006) Fibroblasts modulate cardiomyocyte excitability: implications for cardiac gene therapy. Gene Ther 13(22):1611–1615.

    Article  CAS  PubMed  Google Scholar 

  13. Miragoli M, Gaudesius G, Rohr S (2006) Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ Res 98(6):801–810.

    Article  CAS  PubMed  Google Scholar 

  14. Rook MB, van Ginneken AC, de Jonge B, el Aoumari A, Gros D, Jongsma HJ (1992) Differences in gap junction channels between cardiac myocytes, fibroblasts, and heterologous pairs. Am J Physiol 263(5 Pt 1):C959–977

    CAS  PubMed  Google Scholar 

  15. Driesen RB, Dispersyn GD, Verheyen FK, van den Eijnde SM, Hofstra L, Thone F, Dijkstra P, Debie W, Borgers M, Ramaekers FC (2005) Partial cell fusion: a newly recognized type of communication between dedifferentiating cardiomyocytes and fibroblasts. Cardiovasc Res 68(1):37–46.

    Article  CAS  PubMed  Google Scholar 

  16. He J, Conklin MW, Foell JD, Wolff MR, Haworth RA, Coronado R, Kamp TJ (2001) Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure. Cardiovasc Res 49(2):298–307

    Article  CAS  PubMed  Google Scholar 

  17. Armoundas AA, Wu R, Juang G, Marban E, Tomaselli GF (2001) Electrical and structural remodeling of the failing ventricle. Pharmacol Ther 92(2–3):213–230

    Article  CAS  PubMed  Google Scholar 

  18. Beuckelmann DJ, Nabauer M, Erdmann E (1993) Alterations of K + currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73(2):379–385

    Article  CAS  PubMed  Google Scholar 

  19. Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61(2):208–217

    Article  CAS  PubMed  Google Scholar 

  20. Kaab S, Nuss HB, Chiamvimonvat N, O’Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF (1996) Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 78(2):262–273

    Article  CAS  PubMed  Google Scholar 

  21. Kaye DM, Hoshijima M, Chien KR (2008) Reversing advanced heart failure by targeting Ca2 + cycling. Annu Rev Med 59:13–28.

    Article  CAS  PubMed  Google Scholar 

  22. Li GR, Lau CP, Ducharme A, Tardif JC, Nattel S (2002) Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283(3):H1031–1041.

    Article  CAS  PubMed  Google Scholar 

  23. Jacquemet V, Henriquez CS (2007) Modelling cardiac fibroblasts: interactions with myocytes and their impact on impulse propagation. Europace: European pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 9(Suppl 6):vi29–37.

    Google Scholar 

  24. Sachse FB, Moreno AP, Abildskov JA (2008) Electrophysiological modeling of fibroblasts and their interaction with myocytes. Ann Biomed Eng 36(1):41–56.

    Article  PubMed  Google Scholar 

  25. Vasquez C, Siddiqui RA, Moreno AP, Berbari EJ (2002) A fibroblast-myocyte model which accounts for slow conduction and fractionated electrograms in infarct border zones. Comp Cardiol 29::245–248

    Google Scholar 

  26. Wang YJ, Sung RJ, Lin MW, Wu SN (2006) Contribution of BK(Ca)-channel activity in human cardiac fibroblasts to electrical coupling of cardiomyocytes-fibroblasts. J Membr Biol 213(3):175–185.

    Article  PubMed  Google Scholar 

  27. Chilton L, Ohya S, Freed D, George E, Drobic V, Shibukawa Y, Maccannell KA, Imaizumi Y, Clark RB, Dixon IM, Giles WR (2005) K + currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. Am J Physiol Heart Circ Physiol 288(6):H2931–2939.

    Article  CAS  PubMed  Google Scholar 

  28. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363.

    Article  CAS  PubMed  Google Scholar 

  29. Alvarez SE, Milstien S, Spiegel S (2007) Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab: TEM 18(8):300–307

    Article  CAS  PubMed  Google Scholar 

  30. Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nature Rev Immunol 5(7):560–570.

    Article  CAS  Google Scholar 

  31. MacDonell KL, Severson DL, Giles WR (1998) Depression of excitability by sphingosine 1-phosphate in rat ventricular myocytes. Am J Physiol 275(6 Pt 2):H2291–2299

    CAS  PubMed  Google Scholar 

  32. McDonough PM, Yasui K, Betto R, Salviati G, Glembotski CC, Palade PT, Sabbadini RA (1994) Control of cardiac Ca2 + levels. Inhibitory actions of sphingosine on Ca2 + transients and L-type Ca2 + channel conductance. Circ Res 75(6):981–989

    Article  CAS  PubMed  Google Scholar 

  33. Nattel S, Maguy A, Le Bouter S, Yeh YH (2007) Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87(2):425–456.

    Article  CAS  PubMed  Google Scholar 

  34. Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42(2):270–283

    Article  CAS  PubMed  Google Scholar 

  35. Bassani RA (2006) Transient outward potassium current and Ca2 + homeostasis in the heart: beyond the action potential. Braz J Med Biol Res = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica 39(3):393–403.

    CAS  Google Scholar 

  36. Roden DM, Balser JR, George AL, Jr., Anderson ME (2002) Cardiac ion channels. Ann Rev Physiol 64:431–475.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (WRG), the Heart and Stroke Foundation of Canada (WRG, LC), the Alberta Heritage Foundation for Medical Research, now Alberta Innovates - Health Solutions (WRG, LC) and the British Heart Foundation (GLS).

Author information

Authors and Affiliations

  1. Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, T2N 1N4, Calgary, AB, Canada

    Dr. W. R. Giles

  2. Worldwide Research and Development Pfizer Inc., Cambridge, MA, USA

    K. A. MacCannell

  3. College of Public Health, Medical & Veterinary Science, James Cook University, Townsville, Australia

    L. Chilton

  4. Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK

    G. L. Smith

Authors
  1. K. A. MacCannell
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  2. L. Chilton
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  3. G. L. Smith
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  4. Dr. W. R. Giles
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Corresponding author

Correspondence to W. R. Giles .

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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada

    Ian M.C. Dixon

  2. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

    Jeffrey T. Wigle

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MacCannell, K., Chilton, L., Smith, G., Giles, W. (2015). Mathematical Simulations of Sphingosine-1-Phosphate Actions on Mammalian Ventricular Myofibroblasts and Myocytes. In: Dixon, I., Wigle, J. (eds) Cardiac Fibrosis and Heart Failure: Cause or Effect?. Advances in Biochemistry in Health and Disease, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-17437-2_16

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