title: Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle.
abstract: 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), p27(Kip1), and p57(Kip2) 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.
authors.affiliation: From the Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Stefano
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Vascular Pathology Laboratory, Istituto Dermopatico dell'Immacolata-IRCCS, 00167 Rome, Italy, and.
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: the Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.affiliation: Vascular Pathology Laboratory, Istituto Dermopatico dell'Immacolata-IRCCS, 00167 Rome, Italy, and. Electronic address: f.martelli@idi.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D055785:Gene Knockdown Techniques; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D009124:Muscle Proteins