Reactivation of the mitosis-promoting factor in postmitotic cardiomyocytes

Cardiomyocytes cease to divide shortly after birth and an
irreversible cell cycle arrest is evident accompanied by the
downregulation of cyclin-dependent kinase activities. To get a
better understanding of the cardiac cell cycle and its regulation,
the effect of functional recovery of the mitosis-promoting factor
(MPF) consisting of cyclin B1 and the cyclin-dependent kinase Cdc2
was assessed in primary cultures of postmitotic ventricular adult
rat cardiomyocytes ( ARC). Gene transfer into ARC was achieved
using the adenovirus-enhanced transferrinfection system that was
characterized by the absence of cytotoxic events. Simultaneous
ectopic expression of wild-type versions of cyclin B1 and Cdc2 was
sufficient to induce MPF activity. Reestablished MPF resulted in a
mitotic phenotype, marked by an abnormal condensation of the
nuclei, histone H3 phosphorylation and variable degree of decay of
the contractile apparatus. Although a complete cell division was
not observed, the results provided conclusive evidence that cell
cycle-related events in postmitotic cardiomyocytes could be
triggered by genetic intervention downstream of the G1/S
checkpoint. This will be of importance to design novel strategies
to overcome the proliferation arrest in adult cardiomyocytes.