p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes.
By Felix B. Engel, M. Schebesta, Mychelle T Duong, G. Lu, Shuxun Ren, Jeffery B Madwed, Huiping Jiang, Yibin Wang, M. Keating. Genes & Development, 2005
615 citations recorded by the source corpus.
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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/6f2a26a54276d48206357e5da9daef864d4c64eb
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Citations in the corpus
- Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. (2009, neutral): “Two have been previously identified: fibroblast growth factor1 (FGF1; Engel et al., 2005) and periostin (Kuhn et al., 2007).”
- p38 MAP-kinases pathway regulation, function and role in human diseases. (2007, background): “Knockout mice for p38α have been generated, but they die at midgestation [74–76], whereas tissue-specific knockouts have implicated p38α in cardiomyocyte proliferation and survival [77,78].”
- FGF/FGFR signaling in health and disease (2020, background): “These results imply that FGF1 might promote the survival of newly generated cardiomyocytes through the enhancement of angiogenesis.(439) Even so, the combination of FGF1 stimulation and p38 inhibition may have therapeutic effect by improving human cardiac regeneration.”
- Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. (2010, background): “(112) have demonstrated in vivo p38 activity in the developing rat heart is biphasic; however, they only examined this during the later stages of gestation (E12-E21).”
- Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration (2011, background): “Together, these findings suggest that a combination of FGF1 stimulation and p38 MAPK inhibition can induce mammalian cardiomyocytes to dedifferentiate and to disassemble their contractile apparatus before proliferatin”
- The Origin of Fibroblasts and Mechanism of Cardiac Fibrosis (2010, background): “CF produce factors such as FGF and periostin which were shown to induce adult myocyte proliferation in vitro as well as in vivo (Engel et al., 2005; Kuhn et al., 2007).”
- Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair (2007, background): “Although modification of intrinsic cell-cycle regulation can increase cell-cycle activity of differentiated cardiomyocyte”
- Signal integration by JNK and p38 MAPK pathways in cancer development (2009, background): “Interestingly, negative regulation of proliferation is emerging as a highly conserved and important function of p38α in various types of primary cells, including cardiomyocytes, hepatocytes, fibroblasts, haematopoietic cells and lung cell”