Abstract 14873: Increased Tbx20 Expression Promotes Cardiomyocyte Cell Cycle Progression in Adult Mice
During heart development cardiomyocytes (CMs) are highly proliferative, but adult CMs are relatively nonproliferative, thus contributing to the severity of myocardial injury and restricted cardiac repair in vivo. The T-box transcription factor Tbx20 is required for CM proliferation during mouse development and Tbx20 expression also is increased during cardiac regeneration in zebrafish. The ability of Tbx20 to promote CM proliferation in fetal and adult CMs was examined using a conditional gain-of-function approach in mice. We hypothesize that increased Tbx20 promotes CM proliferation through upregulation of Nmyc1 gene expression and Bmp-Smad1/5/8 signaling. β-myosin heavy chain (MHC) driven Cre was used to induce Tbx20 expression in fetal and adult CMs. Prior to birth, βMHC-Cre;Tbx20 double transgenic (DTG) mice have increased fetal CM proliferation with induction of Nmyc1 and increased Bmp-Smad1/5/8 signaling. In neotnatal (N) hearts, βMHC-Cre mediated overexpression of Tbx20 results in increased percentage of phospho-histone H3 (pHH3) positive CMs (2.3% in N1 and 0.56% in N8) compared to littermate controls (1.33% in N1 and 0.25% in N8). In adults, the percentage of pHH3;α-actinin positive CMs is increased in DTG hearts (0.15%) compared to littermate controls (0.01%). In isolated CMs from adult DTG mice, the percentage of pHH3;α-actinin cells is increased, as is the percentage of mono-nucleated CMs (39% versus 13%) relative to bi-nucleated CMs (59% versus 84%). In addition, adenovirus-mediated Tbx20 overexpression in neonatal rat CM leads to increased expression of Ki-67, Cyclin A, and Aurora B kinase, with decreased expression of p27 and phospho-p38, relative to β-gal infected controls, indicative of increased cell cycle activity and cytokinesis. Increased Tbx20 expression also results in increased Nmyc1 and Bmp2 gene expression, as well as increased phosphorylation of Smad1/5/8, in both adult DTG hearts and isolated CM. Together, these data demonstrate that Tbx20 overexpression promotes CM cell cycle progression and activates fetal cardiac proliferative pathways in adult hearts in vivo. Thus the manipulation of Tbx20 and BMP-Smad1/5/8 signaling has potential as a new therapeutic approach to promote myocardial regeneration or repair.
- © 2012 by American Heart Association, Inc.