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RESEARCH PAPER
1 Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA; 2 Molecular Biology Institute, Department of Anesthesiology and Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; 3 Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06410, USA
Adult mammalian cardiomyocytes are considered terminally differentiated and incapable of proliferation. Consequently, acutely injured mammalian hearts do not regenerate, they scar. Here, we show that adult mammalian cardiomyocytes can divide. One important mechanism used by mammalian cardiomyocytes to control cell cycle is p38 MAP kinase activity. p38 regulates expression of genes required for mitosis in cardiomyocytes, including cyclin A and cyclin B. p38 activity is inversely correlated with cardiac growth during development, and its overexpression blocks fetal cardiomyocyte proliferation. Activation of p38 in vivo by MKK3bE reduces BrdU incorporation in fetal cardiomyocytes by 17.6%. In contrast, cardiac-specific p38
knockout mice show a 92.3% increase in neonatal cardiomyocyte mitoses. Furthermore, inhibition of p38 in adult cardiomyocytes promotes cytokinesis. Finally, mitosis in adult cardiomyocytes is associated with transient dedifferentiation of the contractile apparatus. Our findings establish p38 as a key negative regulator of cardiomyocyte proliferation and indicate that adult cardiomyocytes can divide.
[Keywords: p38 MAP kinase; cytokinesis; cardiomyocytes; dedifferentiation; regeneration; proliferation]
Received February 15, 2005; revised version accepted April 4, 2005.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1306705.
E-MAIL mkeating{at}enders.tch.harvard.edu; FAX (617) 730-8317.
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