Reactivation of the Mitosis-Promoting Factor in Postmitotic Cardiomyocytes

Abstract

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.

Manipulating myocyte cell cycle control for cardiac repair

“…Furthermore, cyclin A2 induced cardiomyocyte mitosis (H3P), increased myocardial proliferation, and improved heart function after MI, 19,20 while ectopic expression of cyclin B1 and Cdk2 induced mitosis-promoting factor (MPF) activity in adult cardiomyocytes, which resulted in a mitotic phenotype, but no complete cell division. 21 Taken together, the data in the current study further confirm that manipulation of cell cycle regulation might offer reasonable strategies for cardiac regeneration and treatment of ischaemic heart failure. The significance of the induced myocyte proliferation is strengthened by the observed protection against cardiac dysfunction and heart failure in an ischaemia/reperfusion-induced acute MI model.…”

Notch activates cell cycle reentry and progression in quiescent cardiomyocytes

“…S2, D -F). Interestingly, once the nuclear membrane Several studies have shown that manipulation of cell cycle proteins can induce NRVCs to reenter the cell cycle (e.g., Agah et al, 1997 ;Huh et al, 2001 ;Datwyler et al, 2003 ;Tamamori-Adachi et al, 2003 ;Engel et al, 2005 ;Jung et al, 2005 ;Tseng et al, 2006 ). These studies used reagents (e.g., BrdU incorporation or Ki67 immunostaining) that refl ect entry into the cell cycle or S phase but not entry into mitosis or cell division.…”

Notch activates cell cycle reentry and progression in quiescent cardiomyocytes

“…S2, D -F). Interestingly, once the nuclear membrane Several studies have shown that manipulation of cell cycle proteins can induce NRVCs to reenter the cell cycle (e.g., Agah et al, 1997 ;Huh et al, 2001 ;Datwyler et al, 2003 ;TamamoriAdachi et al, 2003 ;Engel et al, 2005 ;Jung et al, 2005 ;Tseng et al, 2006 ). These studies used reagents (e.g., BrdU incorporation or Ki67 immunostaining) that refl ect entry into the cell cycle or S phase but not entry into mitosis or cell division.…”