Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 15, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn194
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"E2F2 expression induces proliferation of terminally differentiated cardiomyocytes in vivo"
1 Department of Medicine III, 61231 Bad Nauheim, Parkstrasse 1, Germany
2 University of Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097 Halle, Germany, and Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Parkstrasse 1, Germany
Author for correspondence Henning Ebelt, MD; Department of Medicine III, Martin-Luther-University, Ernst-Grube-Str. 40, 06097 Halle, Germany; email: henning.ebelt{at}medizin.uni-halle.de; phone +49-345-5572113; fax +49-345-5572684
Aims: In previous experiments we have demonstrated that expression of the transcription factors E2F2 and E2F4 is sufficient to induce proliferation of isolated primary cardiomyocytes from newborn rats and mice. We now wanted to analyze whether E2F2 or E2F4 are also able to promote cell cycle progression of adult cardiomyocytes in vivo, which unlike cardiomyocytes from newborn rodents lack the ability to undergo cell proliferation.
Methods: E2F2 or E2F4 were expressed in hearts of mice at different developmental stages using adenoviral vectors. Effects regarding proliferation, hypertrophy, and apoptosis were analyzed on histological sections, and quantitative assessment of cell cycle regulatory genes was performed by real-time PCR and Western blot.
Results: We found that both E2F2 and E2F4 can stimulate hypertrophic cell growth of cardiomyocytes. However, only directed expression of E2F2 but not of E2F4 was sufficient to induce proliferation of cardiomyocytes. Expression of E2F2 in vivo did not increase the percentage of apoptotic cardiomyocytes but down-regulated the expression of the pro-apoptotic genes caspase-6 and apaf-1. Further analysis of the cell cycle regulatory machinery revealed that expression of E2F2 caused a strong induction of cyclin A and E while the expression of cyclin dependent kinase-inhibitors (CKIs) such as p21 was not affected.
Conclusion: We conclude that a limited induction of cardiomyocyte cell proliferation can be achieved by E2F2 mediated stimulation of cyclin A and E expression without a reduction of CKIs.
Time for primary review: 16 days