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(Circulation Research. 2005;96:509.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Divergent Siblings

E2F2 and E2F4 but not E2F1 and E2F3 Induce DNA Synthesis in Cardiomyocytes Without Activation of Apoptosis

Henning Ebelt, Nadine Hufnagel, Petra Neuhaus, Herbert Neuhaus, Praveen Gajawada, Andreas Simm, Ursula Müller-Werdan, Karl Werdan, Thomas Braun

From the Institute of Physiological Chemistry (H.E., N.H., P.N., H.N., P.G., T.B.) and Departments of Medicine III (H.E., U.M.-W., K.W.) and Cardio-Thoracic Surgery (A.S.), University of Halle-Wittenberg, Germany; and the Max-Planck-Institute for Heart and Lung Research (T.B.), Bad Nauheim, Germany.

Correspondence to Thomas Braun, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany. E-mail thomas.braun{at}kerckhoff.mpg.de

Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.

Key Words: E2F • cardiomyocyte • cell cycle • proliferation

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