, Volume 9, Issue 1, pp 45–55 | Cite as

Phenylephrine, endothelin, prostaglandin F, and leukemia inhibitory factor induce different cardiac hypertrophy phenotypes in vitro, and leukemia inhibitory factor induce different cardiac hypertrophy phenotypes in vitro

  • Kathleen L. King
  • Jane Winer
  • David M. Phillips
  • James Quach
  • P. Mickey Williams
  • Jennie P. Mather


In these studies, we show that endothelin (ET), leukemia inhibitory factor (LIF), phenylephrine (PE), and prostaglandin F(PGF), which are all hypertrophic for neonatal rat cardiac myocytes in culture, induce distinct morphological, physiological, and genetic changes after a 48-h treatment. Transmission electron microscopy revealed differences in myofibril organization, with ET-treated cells containing the most mature-looking myofibrils and PGF — and LIF-treated cells the least. ET- and PE-treated cultures contained the same number of beating cells as control, but LIF and PGF treatment increased the number of beating cells 180%. Treatment with LIF, PE, and PGF increased the beat rate to 3.3 times that of control. After exposure to the β-adrenergic agonist isoproterenol, the beat rate increased 50% for PGF, 54% for PE, 84% for LIF, and 125% for control. ET treatment did not increase the beat rate, nor did these cells respond to isoproterenol. ET, LIF, and PE increased the production of atrial natriuretic peptide (ANP) by three-fold and PGF by 18-fold over nontreated cells. Brain natriuretic peptide (BNP) was increased fourfold by ET and PE, 16-fold by LIF, and 29-fold by PGF. Interestingly, on a pmol/L basis, only LIF induced more BNP than ANP. Treatment with all agents led to a similar pattern of gene induction: increased expression of the embryonic genes for ANP and skeletal α-actin, and less than a twofold change in the constitutively expressed gene myosin light chain-2, with the exception that LIF did not induce skeletal α-actin. Each agent, however, induced ANP mRNA with a different time-course. We conclude that at least four distinct cardiac myocyte hypertrophy response programs can be induced in vitro. Further studies are necessary to determine whether these correlate to the different types of cardiac hypertrophy seen in vivo.

Key Words

Phenylephrine prostaglandin PGF endothelin leukemia inhibitory factor cardiac hypertrophy 


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  1. 1.
    Morkin, E. (1970). Science 167, 1499–1501.CrossRefPubMedGoogle Scholar
  2. 2.
    Anversa, P., Olivetti, G., Melssari, M., and Loud, A. V. (1980). J. Mol. Cell. Cardiol. 12, 781–795.CrossRefPubMedGoogle Scholar
  3. 3.
    Anversa, P., Levicky, V., Beghi, C., McDonald, S. L., and Kikkawa, Y. (1983). Circ. Res. 52, 57–64.PubMedGoogle Scholar
  4. 4.
    Gerdes, A. M., Campbell, S. E., and Hilbelink, D. R. (1988). Lab. Invest. 59, 857–861.PubMedGoogle Scholar
  5. 5.
    Simpson, P., McGrath, A., and Savion, S. (1982). Circ. Res. 51, 787–801.PubMedGoogle Scholar
  6. 6.
    Chien, K. R., Knowlton, K. U., Zhu, H., and Chien, S. (1991). FASEB J. 5, 3037–3046.PubMedGoogle Scholar
  7. 7.
    Glembotski, C. C., Irons, C. E., Krown, K. A., Murray, S. F., Sprenkle, A. B., and Sei, C. A. (1993). J. Biol. Chem. 27, 20,646–20,652.Google Scholar
  8. 8.
    Pennica, D., King, K.L., Shaw, K. J., Luis, E., Rullamas, J., Luoh, S.-M., et al. (1995). Proc. Nat. Acad. Sci. USA 92, 1142–1146.CrossRefPubMedGoogle Scholar
  9. 9.
    Shubieta, H. E., McDonough, P. M., Harris, A. N., Knowlton, K. U., Glembotski, C. C., Brown, J. H., and Chien, K. R. (1990). J. Biol. Chem. 265, 20,555–20,562.Google Scholar
  10. 10.
    Ito, H., Hirata, Y., Hiroe, M., Tsujino, M., Adachi, S., Takamoto, T., et al. (1991). Circ. Res. 69, 209–215.PubMedGoogle Scholar
  11. 11.
    Suzuki, T., Hoshi, H., Sasaki, H., and Mitsui, Y. (1991) J. Cardiovasc. Pharmacol. 17(Suppl. 7), S182-S186.PubMedCrossRefGoogle Scholar
  12. 12.
    King, K. L., Lai, J., Winer, J., Luis, E., Yen, R., Hooley, J., et al. (1996) Endocrine 5, 85–93.Google Scholar
  13. 13.
    Adams, J. W., Migita, D. S., Yu, M., Young, R., Hellickson, M. S., Castro-Vargas, F. E., et al. (1996). J. Biol. Chem. 271, 1179–1186.CrossRefPubMedGoogle Scholar
  14. 14.
    Lai, J., Winer, J., Yen, R., Li, W., King, K. L., Jin, H., et al. (1996). Am. J. Physiol. 271, H2197-H2208.PubMedGoogle Scholar
  15. 15.
    Brodde, O.-E., Michel, M. C., and Zerkowski, H.-R. (1995). Cardiovasc. Res. 30, 570–584.CrossRefPubMedGoogle Scholar
  16. 16.
    Gibson, U. E. M., Heid, C. A., and Williams, P. M. (1996). Genome Res. 6, 995–1001.CrossRefPubMedGoogle Scholar
  17. 17.
    Rhee, D., Sanger, J. M., and Sanger J. W. (1994). Cell Motil. Cytoskel. 28, 1–24.CrossRefGoogle Scholar
  18. 18.
    Forbes, M. S. and Sperelakis, N. (1989). In: Physiology and Pathophysiology of the Heart. Sperelakis, N. (ed.) Kluwer: Boston. pp. 3–41.Google Scholar
  19. 19.
    Sperelakis, N. and Lemkuhl, D. (1964). J. Gen. Physiol. 47, 895–927.CrossRefPubMedGoogle Scholar
  20. 20.
    Mukoyama, M., Nakao, K., Hosoda, K., Suga, S., Saito, Y., Ogawa, Y., et al. (1991). J. Clin. Invest. 87, 1402–1412.PubMedGoogle Scholar
  21. 21.
    Nakao, K., Ogawa, Y., Suga, S., and Imura, H. (1992). J. Hypertension 10, 907–912.Google Scholar
  22. 22.
    Horio, T., Kohno, M., and Takeda, T. (1993). Metabolism 42, 94–96.CrossRefPubMedGoogle Scholar
  23. 23.
    Nakagawa, O., Itoh, H., Harada, M., Komatsu, Y., Yoshimasa, T., and Nakao, K. (1995). Clin. Exp. Pharmacol. Physiol. Suppl. 1, S183-S185.Google Scholar
  24. 24.
    Wollert, K. C., Taga, T., Saito, M., Narazaki, M., Kishimoto, T., Glembotski, C. C., et al. (1996). J. Biol. Chem. 271, 9535–9545.CrossRefPubMedGoogle Scholar
  25. 25.
    Boheler, K. R. and Schwartz K. (1992). TCM 2, 176–182.Google Scholar
  26. 26.
    Calderone, A., Takahashi, N., Izzo, N. J., Thaik, C. M., and Colucci, W.S. (1995). Circulation 92, 2385–2390.PubMedGoogle Scholar
  27. 27.
    Ito, H., Hiroe, M., Hirata, Y., Fujisaki, H., Adachi, S., Akimoto, H., et al. (1994). Circulation 89, 2198–2203.PubMedGoogle Scholar
  28. 28.
    Schwartz, K., de la Bastie, D., Bouveret, P., Oliviero, P., Alonso, S., and Buckingham, M. E. (1986). Circ. Res. 59, 551–555.PubMedGoogle Scholar
  29. 29.
    Izumo, S., Nadal-Ginard, B., and Mahdavi, V. (1988). Proc. Natl. Acad. Sci. USA 85, 339–343.CrossRefPubMedGoogle Scholar
  30. 30.
    Boheler, K. R., Carrier, L., de la Bastie, D., Allen P. D., Komajda, M., Mercadier, J. J., et al. (1991). J. Clin. Invest. 88, 323–330.PubMedCrossRefGoogle Scholar
  31. 31.
    Yorekane, R., Sakai, S., Miyauchi, T., Sakurai, T., and Goto, K. (1994). Arnzneimittel-Forschung 44, 412–415.Google Scholar
  32. 32.
    Moravic, C. S., Keller, E., and Bond, M. (1995). J. Mol. Cell. Cardiol. 27, 2101–2109.CrossRefGoogle Scholar
  33. 33.
    Nishikimi, T., Yoshihara, F., Morimoto, A., Ishikawa, T., Saito, Y., Kangawa, K., et al. (1996). Hypertension 28, 22–30.PubMedGoogle Scholar
  34. 34.
    Bogoyevitch, M. A. and Sugden, P. H. (1996). Int. J. Biochem. Cell Biol. 28, 1–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Watanabe, T., Nakao, A., Emerling, D., Hashimoto, Y., Tsukamoto, K., Horie, Y., et al. (1994). J. Biol. Chem. 26, 17,619–17,625.Google Scholar
  36. 36.
    Boder, G. B., Harley, R. J., and Johnson, I. S. (1971). Nature 231, 531–532.CrossRefPubMedGoogle Scholar
  37. 37.
    Heid, C. A., Stevens, J., Livak, K. J., and Williams, P. M. (1996). Genome Res. 6, 986–994.CrossRefPubMedGoogle Scholar
  38. 38.
    Winer, J. and Williams, P. M. (1998) manuscript submitted.Google Scholar

Copyright information

© Humana Press Inc. 1998

Authors and Affiliations

  • Kathleen L. King
    • 1
  • Jane Winer
    • 1
  • David M. Phillips
    • 2
  • James Quach
    • 1
  • P. Mickey Williams
    • 1
  • Jennie P. Mather
    • 1
  1. 1.Genetech, Inc.South San Francisco
  2. 2.The Population CouncilNew York

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