Molecular mechanisms of cardiac gene expression

  • Bernardo Nadal-Ginard
  • V. Mahdavi


Although the physiological properties of the myocardium and their dynamic character have been the focus of intense research during the past three decades, the biochemical and molecular correlates underlying cardiac development and performance have, until recently, remained poorly understood. The development of modern cellular and molecular biology has provided the necessary tools to undertake the study of the mechanisms involved in cardiac development and to understand the basis for important clinical and experimental problems in cardiovascular physiology. Most of the gene encoding contractile proteins have been cloned and characterized.The availability of molecular probes and the ability to introduce genes into individual cell types and tissues of living animals, are the most important breakthroughs of molecular and cell biology This permits not only to analyze basic mechanisms of gene expression but has also significant practical applications for gene therapy. It is now possible to analyze the role of different regulatory gene sequences and identify their corresponding trans-active factors. In addition, direct gene injection makes it possible to study gene expression in a natural context, under conditions that are physiologically relevant and controlable.

Key word

Gene regulation α-, β-myosin heavy chain transcription factors cardiac development and hypertrophy thyroid hormones in vitro and in vivo gene transfer 


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  1. 1.
    Acsadi G, Jiao S, Agnes J, Duke D, Williams P, Chong W, Wolff JA (1991) Direct gene transfer and expression into rat heart in vivo. New Biologist 3: 71–81PubMedGoogle Scholar
  2. 2.
    Barany M (1967) ATPase activity of myosin correlated with speed of muscle shortening. J Gen Physiol 50:suppl: 197–218Google Scholar
  3. 3.
    Cserjesi P, Olson EN (1991) Myogenin induces the myocytes-specific enhancer binding factor MEF–2 independently of other muscle-specific gene products. Mol Cell Biol 11: 4854 - 4862PubMedGoogle Scholar
  4. 4.
    DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Pausha E, Livingston DM (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54: 275–283PubMedCrossRefGoogle Scholar
  5. 5.
    Edmondson DG, Cheng T-C, Cserjesi P, Chakraborty T, Olson EN (1992) Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2. Mol Cell Biol 12: 3665–3677PubMedGoogle Scholar
  6. 6.
    Endo T, Nadal-Ginard B (1989) Sv 40 large T-antigen induces re-entry of terminally differentiated myotubes into the cell cycle. In Kedes LH, Stockdale FE (ed) Cellular and Molecular Biology of Muscle Development, UCLA Symposia on Molecular and Cellular Biology New Series vol 93; AR Liss New York, p 95–104Google Scholar
  7. 7.
    Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science 240: 889–895PubMedCrossRefGoogle Scholar
  8. 8.
    Field LJ (1988) Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science 239: 1029–1032PubMedCrossRefGoogle Scholar
  9. 9.
    Gossett LA, Kelvin DJ, Sternberg EA, Olson EN (1989) A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes. Mol Cell Biol 9: 5022–5033PubMedGoogle Scholar
  10. 10.
    Grossman W (1980) Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med 69: 576–584PubMedCrossRefGoogle Scholar
  11. 11.
    Izumo S, Mahdavi V, Nadal-Ginard B (1986) All members of the MHC multigene family respond to thyroid hormone in a highly tissue-specific manner. Science 231: 597–600PubMedCrossRefGoogle Scholar
  12. 12.
    Izumo S, Lompre A-M, Matsuoka R, Koren G, Schwartz K, Nadal-Ginard B, Mahdavi V (1987) Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy: Interaction between hemodynamic and thryroid hormone-induced signals. J Clin Invest 79: 970–977Google Scholar
  13. 13.
    Izumo S, Mahdavi V (1988) Thyroid hormone receptor isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature 334: 539–542PubMedCrossRefGoogle Scholar
  14. 14.
    Izumo S, Mahdavi V, Nadal-Ginard B (1988) Protooncogene induction and reprogramm- ing of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA 85: 339–343PubMedCrossRefGoogle Scholar
  15. 15.
    Lompre A-M, Schwartz K, d’Albis A, Lacombe G, Thiem NV, Swynghedauw B (1979) Myosin isoenzyme redistribution in chronic heart overload. Nature 282: 105–107PubMedCrossRefGoogle Scholar
  16. 16.
    Lompre A-M, Mahdavi V, Nadal-Ginard B (1984) Expression of the cardiac ventricular α and β myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem 259: 6437–6446PubMedGoogle Scholar
  17. 17.
    Mahdavi V, Chambers AP, Nadal-Ginard B (1984) Cardiac α and β myosin heavy chain genes are organized in tandem. Proc Natl Acad Sci USA 81: 2626–2630PubMedCrossRefGoogle Scholar
  18. 18.
    Mahdavi V, Koren G, Michaud S, Pinset C, Izumo S (1989) Identification of the sequences responsible for the tissue-specific and hormonal regulation of the cardiac myosin heavy chain genes. In: Kedes LH, Stockdale FE (ed) Cellular and Molecular Biology of Muscle Development, UCLA Symposia on Molecular and Cellular Biology New Series vol 93; AR Liss New York, pp 369–379Google Scholar
  19. 19.
    Mercadier JJ, Bouveret P, Gorza L, Schiaffino S, Clark WA, Swynghdauw B, Schwartz K (1983) Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res 53: 52–62PubMedGoogle Scholar
  20. 20.
    O’Brien TX, Hunter JJ, Dyson E, Chien KR (1991) Heart-to-Heart, new approaches for gene transfer in the myocardium. Circulation 86: 2133–2136Google Scholar
  21. 21.
    Olson EN (1990) MyoD Family. A paradigm for development? Genes & Dev 4: 1454–1461CrossRefGoogle Scholar
  22. 22.
    Parker TG, Schneider MD (1991) Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu rev Physiol 53: 179–200PubMedCrossRefGoogle Scholar
  23. 23.
    Simpson P (1983) Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an αl Adrenergic Response. J Clin Invest 72: 732–738PubMedCrossRefGoogle Scholar
  24. 24.
    Swynghedauw B (1986) Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev 66: 710–771PubMedGoogle Scholar
  25. 25.
    Thompson WR, Koren G, Izumo S, Mahdavi V, Nadal-Ginard B (1990) Molecular regulation of myosin heavy chain switches: A model for study of cardiac gene expression. In: Clark EB and Takao A (ed) Developmental Cardiology: Morphogenesis and Function; Mount Kisko NY pp 13–25Google Scholar
  26. 26.
    Thompson WR, Mahdavi V, Nadal-Ginard B (1992) A MyoDl-independent muscle-specific enhancer controls the expression of the beta-myosin heavy chain gene in skeletal and cardiac muscle cells. J Biol Chem 266: 22678–22688Google Scholar
  27. 27.
    von Harsdorf R, Schott RJ, Shen Y-T, Vatner SF, Mahdavi V, Nadal-Ginard B (1993) Gene injection onto canine myocardium as a useful model for studying gene expression in the heart of large mammals. Circ Res 72: 688–695Google Scholar
  28. 28.
    Weintraub H, Davis RL, Tapscott SJ, Thayer MJ, Krause M, Benezta R, Blackwell TK, Turner D, Rupp R, Hollenberg S, Zhuang Y, Lassar A (1991) The MyoD gene family: Nodal point during specification of the muscle cell lineage. Science 251: 761–766PubMedCrossRefGoogle Scholar
  29. 29.
    White P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E (1988) Association between a oncogene and anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334: 124–129CrossRefGoogle Scholar
  30. 30.
    Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Feigner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 247: 1465–1468PubMedCrossRefGoogle Scholar
  31. 31.
    Yu Y-T, Breitbart RE, Smoot LB, Lee Y, Mahdavi V, Nadal-Ginard B (1992) Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MAD box transcription factors. Genes & Dev 6: 1783–1798CrossRefGoogle Scholar
  32. 32.
    Zak R (1974) Development and proliferative capacity of cardiac muscle cells. Circ Res 35:suppl 11: 17–26Google Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt 1993

Authors and Affiliations

  • Bernardo Nadal-Ginard
    • 1
    • 2
    • 3
    • 4
  • V. Mahdavi
    • 1
    • 2
    • 3
    • 4
  1. 1.Laboratory of Molecular and Cellular CardiologyHoward Hughes Medical InstituteBostonUSA
  2. 2.Department of CardiologyHarvard Medical SchoolBostonUSA
  3. 3.Children’s HospitalHarvard Medical SchoolBostonUSA
  4. 4.Department of PediatricsHarvard Medical SchoolBostonUSA

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