The Journal of Physiological Sciences

, Volume 68, Issue 4, pp 503–520 | Cite as

Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways

  • Ali Khalilimeybodi
  • Alireza DaneshmehrEmail author
  • Babak Sharif-Kashani
Original Paper


The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.


β-Adrenergic signaling Non-classical pathways Gi/PI3K/Akt/GSK3β pathway Gi/Ras/Raf/MEK/ERK pathway CREB transcription factor GATA4 transcription factor 



We convey our thanks to Dr. T. Jamali and Dr. M. Dehghani for their great help.

Compliance with ethical standards


There was no funding for this work.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

12576_2017_557_MOESM1_ESM.docx (330 kb)
Supplementary material 1 (DOCX 329 kb)


  1. 1.
    Aass H, Skomedal T, Osnes J-B (1988) Increase of cyclic AMP in subcellular fractions of rat heart muscle after β-adrenergic stimulation: prenalterol and isoprenaline caused different distribution of bound cyclic AMP. J Mol Cell Cardiol 20:847–860CrossRefGoogle Scholar
  2. 2.
    Amanfu RK, Saucerman JJ (2014) Modeling the effects of β1-adrenergic receptor blockers and polymorphisms on cardiac myocyte Ca2+ handling. Mol Pharmacol 86:222–230CrossRefGoogle Scholar
  3. 3.
    Anguelova M, Karlsson J, Jirstrand M (2012) Minimal output sets for identifiability. Math Biosci 239:139–153CrossRefGoogle Scholar
  4. 4.
    Barki-Harrington L, Perrino C, Rockman HA (2004) Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res 63:391–402CrossRefGoogle Scholar
  5. 5.
    Beavo JA, Bechtel P, Krebs E (1974) Activation of protein kinase by physiological concentrations of cyclic AMP. Proc Natl Acad Sci 71:3580–3583CrossRefGoogle Scholar
  6. 6.
    Bers DM (2001) Excitation-contraction coupling and cardiac contractile force, 2nd edn. Kluwer Academic, Dordrecht, p 427CrossRefGoogle Scholar
  7. 7.
    Bogoyevitch MA, Andersson MB, Gillespie-Brown J, Clerk A, Glennon PE, Fuller SJ, Sugden PH (1996) Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 314:115–121CrossRefGoogle Scholar
  8. 8.
    Böhm M, Kouchi I, Schnabel P, Zolk O (1999) Transition from hypertrophy to failure—β-adrenergic desensitization of the heart. Heart Fail Rev 4:329–351CrossRefGoogle Scholar
  9. 9.
    Bondarenko VE (2014) A compartmentalized mathematical model of the β 1-adrenergic signaling system in mouse ventricular myocytes. PLoS One 9:e89113CrossRefGoogle Scholar
  10. 10.
    Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S (1986) Beta 1-and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 59:297–309CrossRefGoogle Scholar
  11. 11.
    Brodde O-E (1991) Beta 1-and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 43:203–242PubMedGoogle Scholar
  12. 12.
    Bullock BP, Habener JF (1998) Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA-binding affinity, conformation, and increases net charge. Biochemistry 37:3795–3809CrossRefGoogle Scholar
  13. 13.
    Chesley A, Lundberg MS, Asai T, Xiao R-P, Ohtani S, Lakatta EG, Crow MT (2000) The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase. Circ Res 87:1172–1179CrossRefGoogle Scholar
  14. 14.
    Chiş O, Banga JR, Balsa-Canto E (2011) GenSSI: a software toolbox for structural identifiability analysis of biological models. Bioinformatics 27:2610–2611PubMedPubMedCentralGoogle Scholar
  15. 15.
    Choi D-J, Rockman HA (1999) β-Adrenergic receptor desensitization in cardiac hypertrophy and heart failure. Cell Biochem Biophys 31:321–329CrossRefGoogle Scholar
  16. 16.
    Chruscinski AJ, Singh H, Chan SM, Utz PJ (2013) Broad-scale phosphoprotein profiling of beta adrenergic receptor (β-AR) signaling reveals novel phosphorylation and dephosphorylation events. PLoS One 8:e82164CrossRefGoogle Scholar
  17. 17.
    Crampin EJ, Halstead M, Hunter P, Nielsen P, Noble D, Smith N, Tawhai M (2004) Computational physiology and the physiome project. Exp Physiol 89:1–26CrossRefGoogle Scholar
  18. 18.
    De Arcangelis V, Liu S, Zhang D, Soto D, Xiang YK (2010) Equilibrium between adenylyl cyclase and phosphodiesterase patterns adrenergic agonist dose-dependent spatiotemporal cAMP/protein kinase A activities in cardiomyocytes. Mol Pharmacol 78:340–349CrossRefGoogle Scholar
  19. 19.
    Doggrell SA, Brown L (1998) Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 39:89–105CrossRefGoogle Scholar
  20. 20.
    Feldman DS, Carnes CA, Abraham WT, Bristow MR (2005) Mechanisms of disease: β-adrenergic receptors—alterations in signal transduction and pharmacogenomics in heart failure. Nature Clin Pract Cardiovasc Med 2:475–483CrossRefGoogle Scholar
  21. 21.
    Freedman NJ, Liggett SB, Drachman DE, Pei G, Caron MG, Lefkowitz RJ (1995) Phosphorylation and desensitization of the human-adrenergic receptor Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase. J Biol Chem 270:17953–17961CrossRefGoogle Scholar
  22. 22.
    Freedman NJ, Lefkowitz RJ (2004) Anti–β 1-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Investig 113:1379–1382CrossRefGoogle Scholar
  23. 23.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S (2014) Heart disease and stroke statistics--2014 update: a report from the American heart association. Circulation 129(3). doi: 10.1161/01.cir.0000441139.02102.80
  24. 24.
    Grimes CA, Jope RS (2001) CREB DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium. J Neurochem 78:1219–1232CrossRefGoogle Scholar
  25. 25.
    Hatakeyama M, Kimura S, Takashi N, Kawasaki T, Yumoto N, Ichikawa M, Jae-Hoon K, Saito K, Saeki M, Shirouzu M (2003) A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. Biochem J 373:451–463CrossRefGoogle Scholar
  26. 26.
    Heijman J, Volders PG, Westra RL, Rudy Y (2011) Local control of β-adrenergic stimulation: effects on ventricular myocyte electrophysiology and Ca2+-transient. J Mol Cell Cardiol 50:863–871CrossRefGoogle Scholar
  27. 27.
    Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600CrossRefGoogle Scholar
  28. 28.
    Hu S-T, Shen Y-F, Liu G-S, Lei C-H, Tang Y, Wang J-F, Yang Y-J (2010) Altered intracellular Ca2+ regulation in chronic rat heart failure. J Physiol Sci 60:85–94CrossRefGoogle Scholar
  29. 29.
    Iancu RV, Jones SW, Harvey RD (2007) Compartmentation of cAMP signaling in cardiac myocytes: a computational study. Biophys J 92:3317–3331CrossRefGoogle Scholar
  30. 30.
    Kamide T, Okumura S, Ghosh S, Shinoda Y, Mototani Y, Ohnuki Y, Jin H, Cai W, Suita K, Sato I (2015) Oscillation of cAMP and Ca2+ in cardiac myocytes: a systems biology approach. J Physiol Sci 65:195–200CrossRefGoogle Scholar
  31. 31.
    Kawano F, Tanihata J, Sato S, Nomura S, Shiraishi A, Tachiyashiki K, Imaizumi K (2009) Effects of dexamethasone on the expression of β1-, β2-and β3-adrenoceptor mRNAs in skeletal and left ventricle muscles in rats. J Physiol Sci 59:383–390CrossRefGoogle Scholar
  32. 32.
    Kuzumoto M, Takeuchi A, Nakai H, Oka C, Noma A, Matsuoka S (2008) Simulation analysis of intracellular Na+ and Cl homeostasis during β1-adrenergic stimulation of cardiac myocyte. Prog Biophys Mol Biol 96:171–186CrossRefGoogle Scholar
  33. 33.
    Lemire I, Allen BG, Rindt H, Hebert TE (1998) Cardiac-specific overexpression of α 1B AR regulates β AR activity via molecular crosstalk. J Mol Cell Cardiol 30:1827–1839CrossRefGoogle Scholar
  34. 34.
    Li C, Li J, Cai X, Sun H, Jiao J, Bai T, Zhou XW, Chen X, Gill DL, Tang XD (2011) Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors. J Biol Chem 286:40782–40791CrossRefGoogle Scholar
  35. 35.
    Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE, Molkentin JD (2001) The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem 276:30245–30253CrossRefGoogle Scholar
  36. 36.
    Lohse M, Benovic JL, Caron MG, Lefkowitz RJ (1990) Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors. J Biol Chem 265:3202–3211PubMedGoogle Scholar
  37. 37.
    Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of β-adrenergic signaling in heart failure? Circ Res 93:896–906CrossRefGoogle Scholar
  38. 38.
    Luttrell L, Ferguson S, Daaka Y, Miller W, Maudsley S, Della Rocca G, Lin F-T, Kawakatsu H, Owada K, Luttrell D (1999) β-Arrestin-dependent formation of β2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661CrossRefGoogle Scholar
  39. 39.
    Luttrell LM, Hawes BE, van Biesen T, Luttrell DK, Lansing TJ, Lefkowitz RJ (1996) Role of c-Src tyrosine kinase in G protein-coupled receptor and Gβγ subunit-mediated activation of mitogen-activated protein kinases. J Biol Chem 271:19443–19450CrossRefGoogle Scholar
  40. 40.
    Ma Y-C, Huang J, Ali S, Lowry W, Huang X-Y (2000) Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635–646CrossRefGoogle Scholar
  41. 41.
    Morisco C, Zebrowski D, Condorelli G, Tsichlis P, Vatner SF, Sadoshima J (2000) The Akt-glycogen synthase kinase 3β pathway regulates transcription of atrial natriuretic factor induced by β-adrenergic receptor stimulation in cardiac myocytes. J Biol Chem 275:14466–14475CrossRefGoogle Scholar
  42. 42.
    Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J (2001) Glycogen synthase kinase 3β regulates GATA4 in cardiac myocytes. J Biol Chem 276:28586–28597CrossRefGoogle Scholar
  43. 43.
    Morisco C, Zebrowski DC, Vatner DE, Vatner SF, Sadoshima J (2001) β-Adrenergic cardiac hypertrophy is mediated primarily by the β 1-subtype in the rat heart. J Mol Cell Cardiol 33:561–573CrossRefGoogle Scholar
  44. 44.
    O’Connell TD, Ni YG, Lin K-M, Han H, Yan Z (2003) Isolation and culture of adult mouse cardiac myocytes for signaling studies. AFCS Res Rep 1:1–9Google Scholar
  45. 45.
    Opazo P, Watabe AM, Grant SG, O’Dell TJ (2003) Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. J Neurosci 23:3679–3688CrossRefGoogle Scholar
  46. 46.
    Rochais F, Abi-Gerges A, Horner K, Lefebvre F, Cooper DM, Conti M, Fischmeister R, Vandecasteele G (2006) A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res 98:1081–1088CrossRefGoogle Scholar
  47. 47.
    Rockman HA, Koch WJ, Lefkowitz RJ (2002) Seven-transmembrane-spanning receptors and heart function. Nature 415:206–212CrossRefGoogle Scholar
  48. 48.
    Ryall KA, Holland DO, Delaney KA, Kraeutler MJ, Parker AJ, Saucerman JJ (2012) Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling. J Biol Chem 287:42259–42268CrossRefGoogle Scholar
  49. 49.
    Ryall KA, Saucerman JJ (2012) Automated imaging reveals a concentration dependent delay in reversibility of cardiac myocyte hypertrophy. J Mol Cell Cardiol 53:282–290CrossRefGoogle Scholar
  50. 50.
    Sato S, Shirato K, Mitsuhashi R, Inoue D, Kizaki T, Ohno H, Tachiyashiki K, Imaizumi K (2013) Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise. J Physiol Sci 63:211–218CrossRefGoogle Scholar
  51. 51.
    Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD (2003) Modeling β-adrenergic control of cardiac myocyte contractility in silico. J Biol Chem 278:47997–48003CrossRefGoogle Scholar
  52. 52.
    Saucerman JJ, McCulloch AD (2006) Cardiac β-adrenergic signaling. Ann N Y Acad Sci 1080:348–361CrossRefGoogle Scholar
  53. 53.
    Schäfer M, Frischkopf K, Taimor G, Piper HM, Schlüter K-D (2000) Hypertrophic effect of selective β1-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat. Am J Physiol Cell Physiol 279:C495–C503CrossRefGoogle Scholar
  54. 54.
    Schmitt JM, Stork PJ (2000) β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf. J Biol Chem 275:25342–25350CrossRefGoogle Scholar
  55. 55.
    Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ (2006) β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor. J Biol Chem 281:1261–1273CrossRefGoogle Scholar
  56. 56.
    Shin S-Y, Kim T, Lee H-S, Kang JH, Lee JY, Cho K-H (2014) The switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes. Nature Commun 5:5777Google Scholar
  57. 57.
    Shizukuda Y, Buttrick PM (2002) Subtype specific roles of β-adrenergic receptors in apoptosis of adult rat ventricular myocytes. J Mol Cell Cardiol 34:823–831CrossRefGoogle Scholar
  58. 58.
    Steinberg SF (1999) The molecular basis for distinct β-adrenergic receptor subtype actions in cardiomyocytes. Circ Res 85:1101–1111CrossRefGoogle Scholar
  59. 59.
    Tepe NM, Liggett SB (1999) Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of β-adrenergic receptor dysfunction in the Gαq overexpressing mouse. FEBS Lett 458:236–240CrossRefGoogle Scholar
  60. 60.
    Tomida T (2015) Visualization of the spatial and temporal dynamics of MAPK signaling using fluorescence imaging techniques. J Physiol Sci 65:37–49CrossRefGoogle Scholar
  61. 61.
    Treinys R, Bogdelis A, Rimkutė L, Jurevičius J, Skeberdis VA (2016) Differences in the control of basal L-type Ca2+ current by the cyclic AMP signaling cascade in frog, rat, and human cardiac myocytes. J Physiol Sci 66:327–336CrossRefGoogle Scholar
  62. 62.
    Vayttaden SJ, Friedman J, Tran TM, Rich TC, Dessauer CW, Clark RB (2010) Quantitative modeling of GRK-mediated β2AR regulation. PLoS Comput Biol 6:e1000647CrossRefGoogle Scholar
  63. 63.
    Violin JD, DiPilato LM, Yildirim N, Elston TC, Zhang J, Lefkowitz RJ (2008) β2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real-time cAMP dynamics. J Biol Chem 283:2949–2961CrossRefGoogle Scholar
  64. 64.
    Woo AYH, R-p Xiao (2012) β-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin 33:335–341CrossRefGoogle Scholar
  65. 65.
    Yan L, Jia Z, Cui J, Yang H, Yang H, Zhang Y, Zhou C (2011) Beta-adrenergic signals regulate cardiac differentiation of mouse embryonic stem cells via mitogen-activated protein kinase pathways. Dev Growth Differ 53:772–779CrossRefGoogle Scholar
  66. 66.
    Yang JH, Polanowska-Grabowska RK, Smith JS, Shields CW, Saucerman JJ (2014) PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling. J Mol Cell Cardiol 66:83–93CrossRefGoogle Scholar
  67. 67.
    Yano N, Ianus V, Zhao TC, Tseng A, Padbury JF, Tseng Y-T (2007) A novel signaling pathway for β-adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes. Am J Physiol Heart Circ Physiol 293:H385–H393CrossRefGoogle Scholar
  68. 68.
    Zhang W, Yano N, Deng M, Mao Q, Shaw SK, Tseng Y-T (2011) β-Adrenergic receptor-PI3K signaling crosstalk in mouse heart: elucidation of immediate downstream signaling cascades. PLoS One 6:e26581CrossRefGoogle Scholar
  69. 69.
    Zou Y, Komuro I, Yamazaki T, Kudoh S, Uozumi H, Kadowaki T, Yazaki Y (1999) Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. J Biol Chem 274:9760–9770CrossRefGoogle Scholar
  70. 70.
    Zou Y, Yao A, Zhu W, Kudoh S, Hiroi Y, Shimoyama M, Uozumi H, Kohmoto O, Takahashi T, Shibasaki F (2001) Isoproterenol activates extracellular signal–regulated protein kinases in cardiomyocytes through calcineurin. Circulation 104:102–108CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK 2017

Authors and Affiliations

  • Ali Khalilimeybodi
    • 1
  • Alireza Daneshmehr
    • 1
    Email author
  • Babak Sharif-Kashani
    • 2
  1. 1.Department of Mechanical EngineeringCollege of Engineering, University of TehranTehranIran
  2. 2.Department of CardiologyMassih-Daneshvari Hospital, Shahid Beheshti University of Medical SciencesTehranIran

Personalised recommendations