E2F-1 overexpression in cardiomyocytes induces downregulation of p21(CIP1)and p27(KIP1) and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I

The heart is a postmitotic organ unable to regenerate after injury. The mec hanisms controlling cell cycle arrest in cardiomyocytes are still unknown. Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an i ncrease in the expression of key cell cycle activators and apoptosis in >90 % of the cells. However, insulin-like growth factor I (IGF-I) rescued cardi omyocytes from E2F-1-induced apoptosis. Furthermore, overexpression of E2F- 1 in the presence of IGF-I induced the specific downregulation of total p21 (CIP1) and p27(KIP1) protein levels and their dissociation from cyclin-depe ndent kinases (cdks). In contrast, p16(INK4) and p57(KIP2) protein levels a nd their association with cdks remained unaltered. The dissociation of p21( CIP1) and p27(KIP1) from their cdk complexes correlated well with the activ ation of cdk2, cdk4, and cdk6 and the release from cell cycle arrest. Under these circumstances, the number of cardiomyocytes in S phase rose from 1.2 % to 23%. These results indicate that IGF-I renders cardiomyocytes permissi ve for cell cycle reentry. Finally, the specific downregulation of p21(CIP1 ) and p27(KIP1) further suggests their key role in the maintenance of cell cycle arrest in cardiomyocytes.