p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes.
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 p38alpha 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.
Engel
Felix B
FB
Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Schebesta
Michael
M
Duong
Mychelle T
MT
Lu
Gang
G
Ren
Shuxun
S
Madwed
Jeffery B
JB
Jiang
Huiping
H
Wang
Yibin
Y
Keating
Mark T
MT
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D019925:Cyclin A; D019926:Cyclin B; D048051:p38 Mitogen-Activated Protein Kinases