Catecholamines and cardiac growth

  • Mahesh P. Gupta
  • Madhu Gupta
  • Smilja Jakovcic
  • Radovan Zak
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 19)


The present knowledge concerning the α- and β-adrenergic systems in the regulation of cardiac growth and gene expression is reviewed. To investigate the mechanism by which cAMP regulates the expression of cardiac genes we have used cultured myocytes derived from fetal rat hearts. We have shown previously that the addition of Br cAMP to the culture medium produced an increase in a-myosin heavy chain (α-MHC) mRNA level, in its rate of transcription as well as in the amount of VI isomyosin. To characterize the promoter element(s) involved in cAMP responsive regulation of α-MHC expression we performed transient transfection analysis with a series of α-MHC gene promoter-CAT constructs. We have identified a 13 bp E-box/M-CAT hybrid motif (EM element) which conferred a basal muscle specific and cAMP inducible expression of the α-MHC gene. Using mobility shift assay we have documented that one of the EM element binding protein is TEF-1. Moreover, by incubating cardiac nuclear extracts with the catalytic subunit of PK-A we have found that factor(s) binding to the EM element is a substrate for cAMP dependent phosphorylation.

Key words

adrenergic system control of gene expression α-myosin heavy chain 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Komuro I, Yazaki Y: Control of cardiac gene expression by mechanical stress. Ann Rev Physiol 55: 55–75, 1993CrossRefGoogle Scholar
  2. 2.
    Sachs F: Mechanical transduction by membrane ion channels. Mol Cell Biochem 104: 57–60, 1991PubMedCrossRefGoogle Scholar
  3. 3.
    Laks MM, Morardy F, Swan HJC: Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 64: 75–78, 1973PubMedCrossRefGoogle Scholar
  4. 4.
    Ostman-Smith I: Cardiac sympathetic nerves as the final common pathway in the induction of adaptive cardiac hypertrophy. Clin Sci 61: 265–272, 1981PubMedGoogle Scholar
  5. 5.
    Simpson PC: Molecular mechanisms in myocardial hypertrophy. Heart Failure 5: 113–129, 1989Google Scholar
  6. 6.
    Saito K, Kurihara M, Cruciana R, Potter WZ, Saavedra JM: Characterization of α1,- and β2-adrenoceptor subtypes in the rat atrioventricular node by quantitative autoradiography. Circ Res 62: 173–177, 1988PubMedGoogle Scholar
  7. 7.
    Gaus JH, Cater MR: Norepinephrine induces cardiac hypertrophy in dogs. Life Sci 9: 731–740, 1970CrossRefGoogle Scholar
  8. 8.
    King BD, Sack D, Kichuk MR, Hintze TH: Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs. Hypertension 9: 582–590, 1987PubMedGoogle Scholar
  9. 9.
    Zierhut W, Zimmer HG: Significance of myocardial α- and β-adrenoceptors in catecholamine-induced cardiac hypertrophy. Circ Res 65: 1417–1425, 1989PubMedGoogle Scholar
  10. 10.
    Xenophontos XP, Watson PA, Chua BHL, Haneda T, Morgan HE: Increased cyclic AMP content accelerates protein synthesis in rat heart. Circ Res 65: 647–656, 1989PubMedGoogle Scholar
  11. 11.
    Fuller SJ, Gaitanaki CJ, Sugden PH: Effects of catecholamines on protein synthesis in cardiac myocytes and perfused hearts isolated from adult rats. Biochem J 266: 727–736, 1990PubMedGoogle Scholar
  12. 12.
    Halle W, Wollenberger A: Differentiation and behavior of isolated embryonic and neonatal heart cells in a chemically defined medium. Am J Cardiol 25: 292–299, 1970PubMedCrossRefGoogle Scholar
  13. 13.
    Simpson PC, Kariya K, Karns LR, Long CS, Karliner JS: Adrenergic hormones and control of cardiac myocyte growth. Mol Cell Biochem 104:35–41, 1991PubMedCrossRefGoogle Scholar
  14. 14.
    Simpson P: Stimulation of hypertrophy of cultured neonatal rat heart cells through an α1-adrenergic receptor and induction of beating through and α1- and β1,-adrenergic receptor interaction: Evidence of independent regulation of growth and beating. Circ Res 56: 884–894, 1985PubMedGoogle Scholar
  15. 15.
    Meideil RS, Sen A, Henderson SA, Slahetka MF, Chien KR: α1 Adrenergic stimulation of rat myocardial cells increases protein synthesis. Am J Physiol 251 (Heart Circ Physiol 20): H1076–H1084, 1986Google Scholar
  16. 16.
    Schiuter KD, Piper HM: Trophic effects of catecholamines and parathyroid hormone on adult ventricular cardiomyocytes. Am J Physiol 263:H1739–H1746, 1992Google Scholar
  17. 17.
    Pinson A, Schiuter KD, Zhou XJ, Schwartz P, Kessler-Igerson G, Piper HM: Alpha- and beta-adrenergic stimulation of protein synthesis in cultured adult ventricular cardiomyocytes. J Mol Cell Cardiol 25: 477–490, 1993PubMedCrossRefGoogle Scholar
  18. 18.
    Clark WA, Rudnick SJ, LaPres JJ, Andersen LC, LaPointe MC: Regulation of hypertrophy and atrophy in cultured adult heart cells. Circ Res 73: 1163–1176, 1993PubMedGoogle Scholar
  19. 19.
    Cooper G IV, Kent RL, Uboh CE, Thompson EW, Marino TA: Hemodynamic versus adrenergic control of cat right hypertrophy. J Clin Invest 75: 1403–1414, 1985PubMedCrossRefGoogle Scholar
  20. 20.
    Tomanek RJ, Bhatnager RK, Schmid P, Brody MJ: Role of catecholamines in myocardial cell hypertrophy in hypertensive rats. Am J Physiol 242: H1015–H1021, 1982PubMedGoogle Scholar
  21. 21.
    Zimmer HG, Peffer H: Metabolic aspects of the development of experimental cardiac hypertrophy. Basic Res Cardiol 81 (Suppl 1): 127–137, 1986PubMedGoogle Scholar
  22. 22.
    Sen S, Tarazi RC: Regression of myocardial hypertrophy and influence of adrenergic system. Am J Physiol 244: H97–H101, 1983PubMedGoogle Scholar
  23. 23.
    Tomanek RJ, Davis JW, Anderson SC: The effects of a methyldopa on cardiac hypertrophy in spontaneously hypertensive rats: Ultrastructural, stereological and morphometric analysis. Cardiovasc Res 13: 173–182,1979PubMedCrossRefGoogle Scholar
  24. 24.
    Cutilletta AF, Erinoff L, Heller A, Low J, Oparil S: Development of left ventricular hypertrophy in young spontaneously hypertensive rats after peripheral sympathectomy. Circ Res 40: 428–434, 1977PubMedGoogle Scholar
  25. 25.
    Oparil S, Cutilletta AF: Hypertrophy in the denervated heart: A comparison of central sympatholytic treatment with 6-hydroxydopamine and peripheral sympathectomy with nerve growth factor antiserum. Am J Cardiol 44: 970–978, 1979PubMedCrossRefGoogle Scholar
  26. 26.
    Abdel-Latif AA: Calcium mobilizing receptors, polyphosphoinositides, and the generation of second messengers. Pharmacol Rev 38: 227–272, 1986PubMedGoogle Scholar
  27. 27.
    Nosek TM, Williams MF, Zeigler ST, Godt RE: Inositol trisphosphate enhances calcium release in skinned cardiac and skeletal muscle. Am J Physiol 250: C807–C811, 1986PubMedGoogle Scholar
  28. 28.
    van Bilsen M, Chien KR: Growth and hypertrophy of the heart: towards an understanding of cardiac specific and inducible gene expression. Cardiovasc Res 27: 1140–1149, 1993PubMedCrossRefGoogle Scholar
  29. 29.
    Henrich CJ, Simpson PC: Differential acute and chronic responses of protein kinase C in cultured neonatal rat heart myocytes to α1-adrenergic and phorbol ester stimulation. J Mol Cell Cardiol 20: 1081–1085, 1988PubMedCrossRefGoogle Scholar
  30. 30.
    Kariya K, Karns LR, Simson PC. Expression of a constitutively activated mutant of the beta-isozyme of protein kinase C in cardiac myocytes stimulates the promoter of the beta-myosin heavy chain isogene. J Biol Chem 266: 10023–10026, 1991PubMedGoogle Scholar
  31. 31.
    Gillespie-Brown J, Fuller SJ, Bogoyevitch, MA, Cowley S, Sugden PH: The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes. J Biol Chem 270: 28092–28096, 1995PubMedCrossRefGoogle Scholar
  32. 32.
    Byus CV, Chubb JM, Huxtable RJ, Russell DH: Increase in type I adenosine 3′,5′-monophosphate-dependent protein kinase during iso-proterenol-induced cardiac hypertrophy. Biochem Biophys Res Commun 73: 694–702, 1976PubMedCrossRefGoogle Scholar
  33. 33.
    Schreiber SS, Klein IL, Oratz M, Rothschild MA: Adenyl cyclase activity and cyclic AMP in acute cardiac overload: A method for measuring cyclic AMP production based on ATP specific activity. J Mol Cell Cardiol 2: 55–65, 1971PubMedCrossRefGoogle Scholar
  34. 34.
    Calderone A, Takahashi N, Izzo NJ, Thaik CM, Colucci WS: Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circ 92: 2385–2390, 1995Google Scholar
  35. 35.
    Chien KR, Knowlton KU, Zhu H, Chien S: Regulation of cardiac gene expression during myocardial growth and hypertrophy: Molecular studies of an adaptive physiological response. FASEB J 5: 3037–3046, 1991PubMedGoogle Scholar
  36. 36.
    Nagai R, Zarain-Herzberg A, Brandi CJ, Fujii J, Tada M, MacLennan DH, Alpert NR, Periasamy M: Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proc Natl Acad Sci USA 86: 2966–2970, 1989PubMedCrossRefGoogle Scholar
  37. 37.
    Everett AW, Clark WA, Chizzonite RA, Zak R: Change in synthesis rates of α- and β-myosin heavy chains in rabbit heart after treatment with thyroid hormone. J Biol Chem 258: 2421–2425, 1983PubMedGoogle Scholar
  38. 38.
    Advani SV, Geenen D, Malhotra A, Factor SM, Scheuer J: Swimming causes myosin adaptations in the rat cardiac isograft. Circ Res 67: 780–783, 1990PubMedGoogle Scholar
  39. 39.
    Buttrick PM, Malhotra A, Factor S, Geener D, Scheuer J: Effects of chronic dobutamine administration on hearts of normal and hypertensive rats. Circ Res 63: 173–181, 1988PubMedGoogle Scholar
  40. 40.
    Gupta MP, Gupta M, Stewart A, Zak R: Activation of a-myosin heavy chain gene expression by cAMP in cultured fetal rat heart myocyctes. Biochem Biophys Res Commun 174: 1196–1703, 1991PubMedCrossRefGoogle Scholar
  41. 41.
    Iwaki K, Sukhatme VP, Shubeita HE, Chien KR: α- and β-adrenergic stimulation induces dintinct patterns of immediate early gene expression in neonatal rat myocardial cells. J Biol Chem 265: 13809–13817, 1990PubMedGoogle Scholar
  42. 42.
    Gupta MP, Gupta M, Zak R, Sukhatme VP: Erg-1, a serum inducible zinc finger protein, regulates transcription of the rat cardiac α-myosin heavy chain gene. J Biol Chem 266: 12813–12816, 1991PubMedGoogle Scholar
  43. 43.
    Gupta MP, Gupta M, Zak R: An E-box/M-CAT hybrid motif and cog-nate binding protein(s) regulate the basal muscle-specific and cAMP-inducible expression of the rat cardiac α-myosin heavy chain gene. J Biol Chem 269: 29677–29687, 1994PubMedGoogle Scholar
  44. 44.
    Murre C, McCaw PC, Baltimore D: A new DNA binding and dimerization motif in immunoglobulin enhancer binding daughterless MyoD, and myc proteins. Cell 56: 777–783, 1989PubMedCrossRefGoogle Scholar
  45. 45.
    Edmonson DG, Olson EN: Helix-loop-helix proteins as regulators of muscle-specific transcription. J Biol Chem 268: 755–758, 1993Google Scholar
  46. 46.
    Lassar AB, Buskin JN, Lockshon D, Davis RL, Apone S, Hauschka SD, Weintraub H: MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to muscle creatine kinase enhancer. Cell 58: 823–831, 1989PubMedCrossRefGoogle Scholar
  47. 47.
    Molkentin JM, Brogan RS, Jobe SM, Markham BE: Expression of α-myosin heavy chain gene in the heart is regulated in part by an E-box-dependent mechanism. J Biol Chem 268: 2602–2609, 1993PubMedGoogle Scholar
  48. 48.
    Mar JH, Ordahl CP: A conserved CATTCCT motif is required for skeletal muscle-specific activity of the cardiac troponin T gene promoter. Proc Natl Acad Sci 85: 6404–6408, 1988PubMedCrossRefGoogle Scholar
  49. 49.
    Farrance IKG, Mar JH, Ordahl CP: M-CAT binding factor is related to the SV40 enhancer binding factor, TEF-1. J Biol Chem 267: 17234–17240, 1992PubMedGoogle Scholar
  50. 50.
    Boxer LM, Prywes R, Roeder RG, Kedes L: The sarcomeric actin CArG-binding factor is indistinguishable from the c-fos serum response factor. Mol Cell Biol 9: 515–522, 1989PubMedGoogle Scholar
  51. 51.
    Grichnik JM, French BA, Schwartz RJ: The chicken skeletal α-actin gene promoter region exhibits partial dyad symetry and a capacity to drive bidirectional transcription. Mol Cell Biol 8: 4587–4597, 1988PubMedGoogle Scholar
  52. 52.
    Yu YT, Breitbart RE, Smoot LB, Lee Y, Mahdavi V, Nadal-Ginard B: Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes and Dev 6: 1783–1798, 1992PubMedCrossRefGoogle Scholar
  53. 53.
    Gossett LA, Kelvin DJ, Sternberg EA, Olson EN: A new myocyte specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes. Mol Cell Biol 9: 5022–5033, 1989PubMedGoogle Scholar
  54. 54.
    Pollock R, Treisman R: Human SRF-related proteins: DNA binding properties and potential regulatory targets. Genes and Dev 5: 2327–2341, 1991PubMedCrossRefGoogle Scholar
  55. 55.
    Zou Y, Chien KR: EFIA/YB-1 is a component of cardiac HF-1A binding activity and positively regulates transcription of the myosin light-chain 2v gene. Mol Cell Biol 15: 2972–2982, 1995PubMedGoogle Scholar
  56. 56.
    Goswami S, Qasba P, Ghatpande S, Carlton S, Desphande AK, Baig M, Siddiqui MAQ: Differential expression of the myocyte enhancer factor 2 family of transcription factors in development: The cardiac factor BBF-1 is an early marker for cardiogenesis. Mol Cell Biol 14: 5130–5138, 1994PubMedGoogle Scholar
  57. 57.
    Didiere DK, Schiffenbauer J, Wolfe SL, Zacheis M, Schwartz BD: Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class II Y box. Proc Natl Acad Sci 85: 7322–7326, 1988CrossRefGoogle Scholar
  58. 58.
    Faber M, Sealy L: Rous sarcoma virus enhancer factor I is a ubiquitous CCAAT transcription factor highly related to CBF and NF-Y. J Biol Chem 265: 22243–22154, 1990PubMedGoogle Scholar
  59. 59.
    Ozer J, Faber M, Chalkley R, Sealy L: Isolation and characterization of a cDNA clone for the CCAAT transcription factor EF 1A reveals a novel structural motif. J Biol Chem 265: 22143–22152, 1990PubMedGoogle Scholar
  60. 60.
    Bassel-Duby R, Hernandes MD, Yang Q, Rochelle JM, Scidin MF, Williams RS: Myocyte nuclear factor, a novel winged-helix transcription factor under both developmental and neural regulation in striated myocytes. Mol Cell Biol 14: 4596–4605, 1994PubMedGoogle Scholar
  61. 61.
    Lai E, Prezioso VR, Tao W, Chen WS, Darnell Jr JE: Hepatocyte nuclear factor 3α belongs to a gene family in mammals that is homologous to the Drosphila homeotic gene fork head. Genes and Dev 5: 416–427, 1991PubMedCrossRefGoogle Scholar
  62. 62.
    Ip HS, Wilson DB, Heikinhelmo M, Tang Z, Ting CN, Simon MC, Leiden JM, Parmacek MS: The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells. Mol Cell Biol 14: 7517–7526, 1994PubMedGoogle Scholar
  63. 63.
    Kariya KI, Karns LR, Simpson PC: An enhancer core element mediates stimulation of the rat β-myosin heavy chain promoter by an α1-adrenergic agonist and activated β-protein kinase C in hypertrophy of cardiac myocytes. J Biol Chem 269: 3775–3782, 1994PubMedGoogle Scholar
  64. 64.
    Ishizuka N, Kawana M, Taira A, Ueda M, Hatsumi M, Hokari T, Kimata S, Hosoda S: Isozymic changes in myosin of rabbit ventricular myocardium induced by isoproterenol. Jpn Circ J 53: 905, 1989.Google Scholar
  65. 65.
    Kimata S, Kawana M, Hosoda S: The change in expression of cardiac myosin isozymes by the stimuli of the sympathetic nerve and thyroxine. In: M. Nagano, N. Takeda and N. S. Dhalla (eds). The Adapted Heart. Raven Press, New York, 1995, pp 393–401Google Scholar
  66. 66.
    Wallukat G, Nemecz G, Farkas T, Kuehn H, Wollenberger A: Modulation of the beta-adrenergic response in cultured rat heart cells. I. Beta-adrenergic supersensitivity is induced by lactate via a phospholipase A2 and 15-lipoxygenase involving pathway. Mol Cell Biochem 102: 35–47, 1991PubMedGoogle Scholar
  67. 67.
    Jacob R: The functional ambivalence of adaptive processes — Considerations based on the example of the hemodynamically overloaded heart. Basic Res Cardiol 86 (Suppl 3): 3, 1991PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Mahesh P. Gupta
    • 1
    • 2
    • 3
  • Madhu Gupta
    • 4
  • Smilja Jakovcic
    • 1
    • 2
    • 3
  • Radovan Zak
    • 1
    • 2
    • 3
  1. 1.Department of Medicine (Section of Cardiology)The University of ChicagoChicagoUSA
  2. 2.Department of Pharmacological and Physiological SciencesThe University of ChicagoUSA
  3. 3.Department of Organismal Biology and AnatomyThe University of ChicagoUSA
  4. 4.The Heart Institute for Children and Christ Hospital Medical CenterOak LawnUSA

Personalised recommendations