Affiliation:
1. From the Department of Cardiology (R.v.H., L.H., F.M., U.W., R.D.), Franz Volhard Clinic, Humboldt University; the Max Delbrück Center for Molecular Medicine (M.C.C.), Berlin, Germany.
Abstract
Abstract
—The heart is a postmitotic organ unable to regenerate after injury. The mechanisms controlling cell cycle arrest in cardiomyocytes are still unknown. Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an increase in the expression of key cell cycle activators and apoptosis in >90% of the cells. However, insulin-like growth factor I (IGF-I) rescued cardiomyocytes 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-dependent kinases (cdks). In contrast, p16
INK4
and p57
KIP2
protein levels and their association with cdks remained unaltered. The dissociation of p21
CIP1
and p27
KIP1
from their cdk complexes correlated well with the activation 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 permissive 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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
73 articles.
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