Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle

Valeria Di Stefano, Mauro Giacca, Maurizio C. Capogrossi, Marco Crescenzi, Fabio Martelli

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Proliferation of mammalian cardiomyocytes stops rapidly after birth and injured hearts do not regenerate adequately. High cyclin-dependent kinase inhibitor (CKI) levels have been observed in cardiomyocytes, but their role in maintaining cardiomyocytes in a post-mitotic state is still unknown. In this report, it was investigated whether CKI knockdown by RNA interference induced cardiomyocyte proliferation. We found that triple transfection with p21 Waf1, p27Kip1, and p57Kip2 siRNAs induced both neonatal and adult cardiomyocyte to enter S phase and increased the nuclei/cardiomyocyte ratio; furthermore, a subpopulation of cardiomyocytes progressed beyond karyokynesis, as assessed by the detection of mid-body structures and by straight cardiomyocyte counting. Intriguingly, cardiomyocyte proliferation occurred in the absence of overt DNA damage and aberrant mitotic figures. Finally, CKI knockdown and DNA synthesis reactivation correlated with a dramatic change in adult cardiomyocyte morphology that may be a prerequisite for cell division. In conclusion, CKI expression plays an active role in maintaining cardiomyocyte withdrawal from the cell cycle.

Original languageEnglish
Pages (from-to)8644-8654
Number of pages11
JournalJournal of Biological Chemistry
Issue number10
Publication statusPublished - Mar 11 2011

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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