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. 1996 Oct 15;98(8):1737–1744. doi: 10.1172/JCI118972

Triiodothyronine induces over-expression of alpha-smooth muscle actin, restricts myofibrillar expansion and is permissive for the action of basic fibroblast growth factor and insulin-like growth factor I in adult rat cardiomyocytes.

M A Gosteli-Peter 1, B A Harder 1, H M Eppenberger 1, J Zapf 1, M C Schaub 1
PMCID: PMC507611  PMID: 8878423

Abstract

Effects of triiodothyronine (T3) on the expression of cytoskeletal and myofibrillar proteins in adult rat cardiomyocytes (ARC) were followed during two weeks of culture in the presence of 20% T3-depleted (stripped) FCS. Control cultures expressed mainly beta-myosin heavy chain (MHC) mRNA. T3 caused a switch to alpha-MHC expression and a dose-dependent increase of alpha-smooth muscle (alpha-sm) actin mRNA and protein. In parallel, the number of alpha-sm actin immunoreactive cells increased from 1% in controls to 29 and 62% in ARC treated with 5 and 100 nM T3. In the presence of T3, cells exhibited a higher beating rate than controls. The distribution of myofibrils in T3-treated cells was restricted to the perinuclear area with a sharp boundary. Only 5% of the control cells but 30 and 62% of the T3-treated (5 and 100 nM) ARC showed this restricted myofibrillar phenotype. Basic fibroblast growth factor (bFGF) which restricts myofibrillar growth and upregulates alpha-sm actin in ARC cultured with normal FCS had no effect on alpha-sm actin in ARC cultured in stripped FCS, but potentiated the effect of T3. In contrast, insulin-like growth factor I (IGF I), which suppresses alpha-sm actin and stimulates myofibrillogenesis in the presence of normal FCS suppressed T3-induced alpha-sm actin expression in stripped FCS. Thus, T3 appears to be permissive for the action of bFGF and IGF I on alpha-sm actin expression.

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Selected References

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  1. Amidi M., Leon D. F., DeGroot W. J., Kroetz F. W., Leonard J. J. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation. 1968 Aug;38(2):229–239. doi: 10.1161/01.cir.38.2.229. [DOI] [PubMed] [Google Scholar]
  2. Bahouth S. W. Thyroid hormones transcriptionally regulate the beta 1-adrenergic receptor gene in cultured ventricular myocytes. J Biol Chem. 1991 Aug 25;266(24):15863–15869. [PubMed] [Google Scholar]
  3. Bedotto J. B., Gay R. G., Graham S. D., Morkin E., Goldman S. Cardiac hypertrophy induced by thyroid hormone is independent of loading conditions and beta adrenoceptor blockade. J Pharmacol Exp Ther. 1989 Feb;248(2):632–636. [PubMed] [Google Scholar]
  4. Bilezikian J. P., Loeb J. N. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Endocr Rev. 1983 Fall;4(4):378–388. doi: 10.1210/edrv-4-4-378. [DOI] [PubMed] [Google Scholar]
  5. Black F. M., Packer S. E., Parker T. G., Michael L. H., Roberts R., Schwartz R. J., Schneider M. D. The vascular smooth muscle alpha-actin gene is reactivated during cardiac hypertrophy provoked by load. J Clin Invest. 1991 Nov;88(5):1581–1588. doi: 10.1172/JCI115470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bouvagnet P., Leger J., Pons F., Dechesne C., Leger J. J. Fiber types and myosin types in human atrial and ventricular myocardium. An anatomical description. Circ Res. 1984 Dec;55(6):794–804. doi: 10.1161/01.res.55.6.794. [DOI] [PubMed] [Google Scholar]
  7. Brent G. A., Moore D. D., Larsen P. R. Thyroid hormone regulation of gene expression. Annu Rev Physiol. 1991;53:17–35. doi: 10.1146/annurev.ph.53.030191.000313. [DOI] [PubMed] [Google Scholar]
  8. Bähler M., Moser H., Eppenberger H. M., Wallimann T. Heart C-protein is transiently expressed during skeletal muscle development in the embryo, but persists in cultured myogenic cells. Dev Biol. 1985 Dec;112(2):345–352. doi: 10.1016/0012-1606(85)90405-1. [DOI] [PubMed] [Google Scholar]
  9. Davis P. J., Davis F. B. Hyperthyroidism in patients over the age of 60 years. Clinical features in 85 patients. Medicine (Baltimore) 1974 May;53(3):161–181. doi: 10.1097/00005792-197405000-00001. [DOI] [PubMed] [Google Scholar]
  10. Donath M. Y., Zapf J., Eppenberger-Eberhardt M., Froesch E. R., Eppenberger H. M. Insulin-like growth factor I stimulates myofibril development and decreases smooth muscle alpha-actin of adult cardiomyocytes. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1686–1690. doi: 10.1073/pnas.91.5.1686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dubus I., Mercadier A., Lucas O., Contard F., Nallet O., Oliviero P., Rappaport L., Samuel J. L. Alpha-, beta-MHC mRNA quantification in adult cardiomyocytes by in situhybridization: effect of thyroid hormone. Am J Physiol. 1993 Jul;265(1 Pt 1):C62–C71. doi: 10.1152/ajpcell.1993.265.1.C62. [DOI] [PubMed] [Google Scholar]
  12. Eppenberger-Eberhardt M., Flamme I., Kurer V., Eppenberger H. M. Reexpression of alpha-smooth muscle actin isoform in cultured adult rat cardiomyocytes. Dev Biol. 1990 Jun;139(2):269–278. doi: 10.1016/0012-1606(90)90296-u. [DOI] [PubMed] [Google Scholar]
  13. Eppenberger M. E., Hauser I., Baechi T., Schaub M. C., Brunner U. T., Dechesne C. A., Eppenberger H. M. Immunocytochemical analysis of the regeneration of myofibrils in long-term cultures of adult cardiomyocytes of the rat. Dev Biol. 1988 Nov;130(1):1–15. doi: 10.1016/0012-1606(88)90408-3. [DOI] [PubMed] [Google Scholar]
  14. Feldman T., Borow K. M., Sarne D. H., Neumann A., Lang R. M. Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state. J Am Coll Cardiol. 1986 May;7(5):967–974. doi: 10.1016/s0735-1097(86)80213-3. [DOI] [PubMed] [Google Scholar]
  15. Florini J. R., Magri K. A. Effects of growth factors on myogenic differentiation. Am J Physiol. 1989 Apr;256(4 Pt 1):C701–C711. doi: 10.1152/ajpcell.1989.256.4.C701. [DOI] [PubMed] [Google Scholar]
  16. Forfar J. C., Matthews D. M., Toft A. D. Delayed recovery of left ventricular function after antithyroid treatment. Further evidence for reversible abnormalities of contractility in hyperthyroidism. Br Heart J. 1984 Aug;52(2):215–222. doi: 10.1136/hrt.52.2.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Friedman M. J., Okada R. D., Ewy G. A., Hellman D. J. Left ventricular systolic and diastolic function in hyperthyroidism. Am Heart J. 1982 Dec;104(6):1303–1308. doi: 10.1016/0002-8703(82)90160-0. [DOI] [PubMed] [Google Scholar]
  18. GRAETTINGER J. S., MUENSTER J. J., CHECCHIA C. S., GRISSOM R. L., CAMPBELL J. A. A correlation of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest. 1958 Apr;37(4):502–510. doi: 10.1172/JCI103631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gillespie-Brown J., Fuller S. J., Bogoyevitch M. A., Cowley S., Sugden P. H. 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. 1995 Nov 24;270(47):28092–28096. doi: 10.1074/jbc.270.47.28092. [DOI] [PubMed] [Google Scholar]
  20. Grove B. K., Kurer V., Lehner C., Doetschman T. C., Perriard J. C., Eppenberger H. M. A new 185,000-dalton skeletal muscle protein detected by monoclonal antibodies. J Cell Biol. 1984 Feb;98(2):518–524. doi: 10.1083/jcb.98.2.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gustafson T. A., Markham B. E., Morkin E. Analysis of thyroid hormone effects on myosin heavy chain gene expression in cardiac and soleus muscles using a novel dot-blot mRNA assay. Biochem Biophys Res Commun. 1985 Aug 15;130(3):1161–1167. doi: 10.1016/0006-291x(85)91737-1. [DOI] [PubMed] [Google Scholar]
  22. Harder B. A., Schaub M. C., Eppenberger H. M., Eppenberger-Eberhardt M. Influence of fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I) on cytoskeletal and contractile structures and on atrial natriuretic factor (ANF) expression in adult rat ventricular cardiomyocytes in culture. J Mol Cell Cardiol. 1996 Jan;28(1):19–31. doi: 10.1006/jmcc.1996.0003. [DOI] [PubMed] [Google Scholar]
  23. Ichikawa K., Hashizume K. Thyroid hormone action in the cell. Endocr J. 1995 Apr;42(2):131–140. doi: 10.1507/endocrj.42.131. [DOI] [PubMed] [Google Scholar]
  24. Isenberg G., Klockner U. Calcium tolerant ventricular myocytes prepared by preincubation in a "KB medium". Pflugers Arch. 1982 Oct;395(1):6–18. doi: 10.1007/BF00584963. [DOI] [PubMed] [Google Scholar]
  25. Khaleeli A. A., Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinical, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473–476. doi: 10.1136/pgmj.58.682.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ladenson P. W., Sherman S. I., Baughman K. L., Ray P. E., Feldman A. M. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5251–5255. doi: 10.1073/pnas.89.12.5251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  28. Messerli J. M., Eppenberger-Eberhardt M. E., Rutishauser B. M., Schwarb P., von Arx P., Koch-Schneidemann S., Eppenberger H. M., Perriard J. C. Remodelling of cardiomyocyte cytoarchitecture visualized by three-dimensional (3D) confocal microscopy. Histochemistry. 1993 Sep;100(3):193–202. doi: 10.1007/BF00269092. [DOI] [PubMed] [Google Scholar]
  29. Nag A. C., Cheng M. Biochemical evidence for cellular dedifferentiation in adult rat cardiac muscle cells in culture: expression of myosin isozymes. Biochem Biophys Res Commun. 1986 Jun 13;137(2):855–862. doi: 10.1016/0006-291x(86)91158-7. [DOI] [PubMed] [Google Scholar]
  30. Parker T. G., Packer S. E., Schneider M. D. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990 Feb;85(2):507–514. doi: 10.1172/JCI114466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Polikar R., Burger A. G., Scherrer U., Nicod P. The thyroid and the heart. Circulation. 1993 May;87(5):1435–1441. doi: 10.1161/01.cir.87.5.1435. [DOI] [PubMed] [Google Scholar]
  32. Polikar R., Kennedy B., Maisel A., Ziegler M., Smith J., Dittrich H., Nicod P. Decreased adrenergic sensitivity in patients with hypothyroidism. J Am Coll Cardiol. 1990 Jan;15(1):94–98. doi: 10.1016/0735-1097(90)90182-o. [DOI] [PubMed] [Google Scholar]
  33. Samuels H. H., Stanley F., Casanova J. Depletion of L-3,5,3'-triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone. Endocrinology. 1979 Jul;105(1):80–85. doi: 10.1210/endo-105-1-80. [DOI] [PubMed] [Google Scholar]
  34. Schmid C., Steiner T., Froesch E. R. Preferential enhancement of myoblast differentiation by insulin-like growth factors (IGF I and IGF II) in primary cultures of chicken embryonic cells. FEBS Lett. 1983 Sep 5;161(1):117–121. doi: 10.1016/0014-5793(83)80742-x. [DOI] [PubMed] [Google Scholar]
  35. Schneider M. D., Parker T. G. Cardiac myocytes as targets for the action of peptide growth factors. Circulation. 1990 May;81(5):1443–1456. doi: 10.1161/01.cir.81.5.1443. [DOI] [PubMed] [Google Scholar]
  36. Speir E., Tanner V., Gonzalez A. M., Farris J., Baird A., Casscells W. Acidic and basic fibroblast growth factors in adult rat heart myocytes. Localization, regulation in culture, and effects on DNA synthesis. Circ Res. 1992 Aug;71(2):251–259. doi: 10.1161/01.res.71.2.251. [DOI] [PubMed] [Google Scholar]
  37. Swynghedauw B. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev. 1986 Jul;66(3):710–771. doi: 10.1152/physrev.1986.66.3.710. [DOI] [PubMed] [Google Scholar]
  38. Volz A., Piper H. M., Siegmund B., Schwartz P. Longevity of adult ventricular rat heart muscle cells in serum-free primary culture. J Mol Cell Cardiol. 1991 Feb;23(2):161–173. doi: 10.1016/0022-2828(91)90103-s. [DOI] [PubMed] [Google Scholar]
  39. Weiner H. L., Swain J. L. Acidic fibroblast growth factor mRNA is expressed by cardiac myocytes in culture and the protein is localized to the extracellular matrix. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2683–2687. doi: 10.1073/pnas.86.8.2683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Woodcock-Mitchell J., Mitchell J. J., Low R. B., Kieny M., Sengel P., Rubbia L., Skalli O., Jackson B., Gabbiani G. Alpha-smooth muscle actin is transiently expressed in embryonic rat cardiac and skeletal muscles. Differentiation. 1988 Dec;39(3):161–166. doi: 10.1111/j.1432-0436.1988.tb00091.x. [DOI] [PubMed] [Google Scholar]
  41. Zimmer H. G., Irlbeck M., Kolbeck-Rühmkorff C. K. Response of the rat heart to catecholamines and thyroid hormones. Mol Cell Biochem. 1995 Jun 7;147(1-2):105–114. doi: 10.1007/BF00944790. [DOI] [PubMed] [Google Scholar]
  42. van Bilsen M., Chien K. R. Growth and hypertrophy of the heart: towards an understanding of cardiac specific and inducible gene expression. Cardiovasc Res. 1993 Jul;27(7):1140–1149. doi: 10.1093/cvr/27.7.1140. [DOI] [PubMed] [Google Scholar]

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