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European Heart Journal 1999 20(8):604-611; doi:10.1053/euhj.1998.1231
Copyright © 1999 by the European Society of Cardiology.
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Cyclin-dependent kinase inhibitor expression in human heart failure. A comparison with fetal development

P.B.J. Burton, M.H. Yacoub and P.J.R. Bartonf1

Cardiothoracic Surgery, Imperial College of School of Medicine, National Heart and Lung Institute, London, U.K.

revised July 3, 1998; accepted July 12, 1998

Abstract

Aims

Terminal differentiation of cardiac myocyte is associated with their permanent withdrawal from the cell cycle. In adult end-stage heart failure, significant numbers of myocytes express proliferating cell nuclear antigen yet fail to progress to cell division. Cyclin dependent kinase inhibitors are powerful inhibitors of the cell cycle and may play a direct role both in myocyte development and in preventing cell division in the adult.

Methods and Results

The expression of the CIP/KIP cyclin dependent kinase inhibitors p21, p27, p57 and the retinoblastoma protein was examined in acute (seen in brain dead transplant donors) and end-stage heart failure by Western blot analysis and compared to that seen in human and rat cardiac development. The expression of p21 showed a gradual increase during development in both rat and man, becoming maximal in adulthood. p27 levels showed an initial rise with subsequent continual expression throughout life. p57 expression was detectable at only early stages in rat but persisted throughout life in man. In both acute and end-stage heart failure the levels of p21, p27 and p57 reverted to a pattern similar to that observed in human fetal heart: p21 and p27 declined while p57 expression was significantly increased. In contrast, retinoblast protein levels declined during human heart development but were unaltered in heart failure.

Conclusions

The expression of p21, but not p27 or p57, is consistent with a role in the gradual withdrawal of cardiac myocytes from cell cycle during development. In adult heart failure cyclin dependent kinase inhibitor expression reverts to the fetal pattern but is insufficient to initiate cell cycle activation.

Key Words: Cyclin dependent kinase inhibitors, heart failure, human, cardiac development

f1 Correspondence: Paul J. R. Barton, Cardiothoracic Surgery, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, U.K.

References

  1. Zak R. Cell proliferation during cardiac growth. Am J Cardiol. 1973;31:211–219[CrossRef][ISI][Medline]
  2. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991;5:3037–3046[Abstract]
  3. Sadoshima J, Jahn L, Takahashi T, Kulik TJ, Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992;267:10551–10560[Abstract/Free Full Text]
  4. Rozich JD, Barnes MA, Schmid PG, Zile MR, McDermott PJ, Cooper G IVth. Load effects on gene expression during cardiac hypertrophy. J Mol Cell Cardiol. 1995;27:485–499[ISI][Medline]
  5. Yamazaki T, Komuro I, Yazaki Y. Molecular mechanism of cardiac cellular hypertrophy by mechanical stress. J Mol Cell Cardiol. 1995;27:133–140[ISI][Medline]
  6. Maass A, Grohe C, Kubisch C, Wollnik B, Vetter H, Neyses L. Hormonal induction of an immediate-early gene response in myogenic cell lines—a paradigm for heart growth. Eur Heart J. 1995;16:12–14
  7. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557–1562[Abstract]
  8. McGill CJ, Brooks G. Cell cycle control mechanisms and their role in cardiac growth. Cardiovasc Res. 1995;30:557–569[CrossRef][ISI][Medline]
  9. Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994;79:573–582[CrossRef][ISI][Medline]
  10. Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79:551–555[CrossRef][ISI][Medline]
  11. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–1163[Free Full Text]
  12. Martin K, Trouche D, Hagemeier C, Kouzarides T. Regulation of transcription by E2F1/DP1. J Cell Sci (Suppl). 1995;19:91–94[Medline]
  13. Brooks G, Poolman RA, McGill CJ, Li JM. Expression and activities of cyclins and cyclin-dependent kinases in developing rat ventricular myocytes. J Mol Cell Cardiol. 1997;29:2261–2271[CrossRef][ISI][Medline]
  14. Kelman Z. PCNA. Structure, functions and interactions. Oncogene. 1997;14:629–640[CrossRef][ISI][Medline]
  15. Harper JW. Cyclin dependent kinase inhibitors. Cancer Surv. 1997;29:91–107[ISI][Medline]
  16. Quaini F, Cigola E, Lagrasta C. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ Res. 1994;75:1050–1063[Abstract/Free Full Text]
  17. Liu Y, Cigola E, Cheng W. Myocyte nuclear mitotic division and programmed myocyte cell death characterises the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest. 1995;73:771–787[ISI][Medline]
  18. Legato MJ. Cellular mechanisms of normal growth in the mammalian heart. I. Qualitative and quantitative features of ventricular architecture in the dog from birth to five months of age. Circ Res. 1979;44:250–262[Abstract/Free Full Text]
  19. Raff MC. Size control: the regulation of cell numbers in animal development. Cell. 1996;86:173–175[CrossRef][ISI][Medline]
  20. Barres BA, Raff MC. Control of oligodendrocyte number in the developing rat optic nerve. Neuron. 1994;12:935–942[CrossRef][ISI][Medline]
  21. Rumyantsev PP. DNA synthesis and mototic division of myocytes from ventricles, atria and conductive system of the heart during myocardial development in mammals. Tsitologiya. 1978;20:132–142
  22. Flink IL, Oana S, Maitra N, Bahl JJ, Morkin E. Changes in E2F complexes containing retinoblastoma protein family members and increased cyclin-dependent kinase inhibitor activities during terminal differentiation of cardiomyocytes. J Mol Cell Cardiol. 1998;30:563–578[CrossRef][ISI][Medline]
  23. Poolman RA, Brooks G. Expression of the Cip/Kip family of the cyclin dependent kinase inhibitors during cardiac development (Abstr). Circulation. 1996;94:I-157
  24. Koh KN, Kang MJ, FrithTerhune A. Persistent and heterogenous expression of the cyclin-dependent kinase inhibitor, p27 (KIP1), in rat hearts during development. J Mol Cell Cardiol. 1998;30:463–474[CrossRef][ISI][Medline]
  25. Zhang P, Liegeois NJ, Wong C. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwick-Wiedemann syndrome. Nature. 1997;387:151–158[CrossRef][Medline]
  26. Yan Y, Frisen J, Lee MH, Massague J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997;11:973–983[Abstract/Free Full Text]
  27. de-Nooij JC, Letendre MA, Hariharan IK. A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell. 1996;87:1237–1247[CrossRef][ISI][Medline]
  28. Lane ME, Sauer K, Wallace K, Jan YN, Lehner CF, Vaessin H. Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell. 1996;87:1225–1235[CrossRef][ISI][Medline]
  29. Fero ML, Rivkin M, Tasch M. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell. 1996;85:733–744[CrossRef][ISI][Medline]
  30. Kiyokawa H, Kineman RD, Manova-Todorova KO. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996;85:721–732[CrossRef][ISI][Medline]
  31. Nakayama K, Ishida N, Shirane M. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996;85:707–720[CrossRef][ISI][Medline]
  32. Kim KK, Soonpaa MH, Daud AI, Koh GY, Kim JS, Field LJ. Tumor suppressor gene expression during normal and pathologic myocardial growth. J Biol Chem. 1994;9; 269:22607–22613
  33. Martin XJ, Wynne DG, Glennon PE, Moorman AF, Boheler KR. Regulation of expression of contractile proteins with cardiac hypertrophy and failure. Mol Cell Biochem. 1996;157:181–189[CrossRef][ISI][Medline]
  34. Wong K, Boheler KR, Petrou M, Yacoub MH. Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular matrix, and gene expression. Circulation. 1997;96:2239–2246[Abstract/Free Full Text]
  35. Li JM, Brooks G. Downregulation of cyclin-dependent kinase inhibitors p21 and p27 in pressure-overload hypertrophy. Am J Physiol. 1997;273:H1358–1367[ISI][Medline]
  36. Liu Y, Kitsis RN. Induction of DNA synthesis and apoptosis in cardiac myocytes by E1A oncoprotein. J Cell Biol. 1996;133:325–334[Abstract/Free Full Text]
  37. Kirshenbaum LA, Schneider MD. Adenovirus E1A repress cardiac gene transcription and reactivates DNA synthesis in ventricular myocytes, via alternative pocket protein- and p300-binding domains. J Biol Chem. 1995;270:7791–7794[Abstract/Free Full Text]
  38. MacLellan WR, Schneider MD. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res. 1997;81:137–144[Abstract/Free Full Text]

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