HHS Public Access Author manuscript Author Manuscript
Circulation. Author manuscript; available in PMC 2017 March 15. Published in final edited form as: Circulation. 2016 March 15; 133(11): 1081–1092. doi:10.1161/CIRCULATIONAHA.115.019357.
Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction Fu-li Xiang, MD, PhD1, Minzhe Guo, PhD2, and Katherine E. Yutzey, PhD1 1The
Heart Institute, Cincinnati Children’s Medical Center, Cincinnati, OH
Author Manuscript
2Department
of Electrical Engineering and Computing Systems, University of Cincinnati, Cincinnati, OH
Abstract Background—Adult mammalian cardiomyocytes (CM) have the potential to proliferate, but this is not sufficient to generate adequate CMs after myocardial infarction (MI). The transcription factor Tbx20 is required for CM proliferation during development and adult CM homeostasis. The ability of Tbx20 overexpression (Tbx20OE) to promote adult CM proliferation and improve cardiac function after MI was examined.
Author Manuscript
Methods and Results—Tbx20OE was induced specifically in adult mouse differentiated CMs. Increased CM proliferation and fetal-like characteristics were found in Tbx20OE hearts, compared to controls, without causing pathology 4 weeks after Tbx20OE at baseline. Moreover, Tbx20OE in adult CM after MI significantly improved survival, cardiac function, and infarct size 4 weeks postMI. Improved cardiac repair, as indicated by increased CM proliferation and capillary density, was observed in the MI border zone of Tbx20OE hearts compared to controls. Expression of proliferation activator (cyclin D1, E1, and IGF1) and fetal contractile protein (ssTNI, βMHC) mRNA was increased, while negative cell-cycle regulators (p21, Meis1) were decreased, in Tbx20OE hearts, compared to controls, under both baseline and MI conditions. Tbx20OE in adult hearts activates multiple pro-proliferation pathways including Akt, YAP and BMP. Interestingly, p21, Meis1, and a novel cell-cycle inhibitory gene Btg2, are directly bound and repressed by Tbx20 with induction of proliferation in neonatal CM.
Author Manuscript
Conclusions—Tbx20OE specifically in adult CM activates multiple cardiac proliferative pathways, directly represses cell-cycle inhibitory genes p21, Meis1 and Btg2, promotes adult CM proliferation, and preserves cardiac performance post-MI. Keywords myocardial infarction; remodeling; myocytes; molecular biology
Correspondence: Katherine E. Yutzey, PhD, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Medical Center ML 7020, 240 Albert Sabin Way, Cincinnati, OH 45229, Phone: 513-636-8340, Fax: 513-636-5958, [email protected]. Disclosures: None.
Xiang et al.
Page 2
Author Manuscript
Introduction
Author Manuscript
Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. Due to a limited proliferative ability2, endogenous adult cardiomyocyte (CM) regeneration is inadequate to compensate for the massive loss of functional CMs after myocardial infarction (MI), which contributes significantly to HF development in mammals3. In the fetal heart, CMs are proliferative, contributing to heart growth4. After birth, the vast majority of CMs withdraw from the cell-cycle, express adult contractile protein isoforms5, induce cell senescence markers, and lose the ability to fully regenerate after myocardial injury6. Adult mammalian CMs harbor measurable but limited proliferative activities (
Circulation. Author manuscript; available in PMC 2017 March 15. Published in final edited form as: Circulation. 2016 March 15; 133(11): 1081–1092. doi:10.1161/CIRCULATIONAHA.115.019357.
Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction Fu-li Xiang, MD, PhD1, Minzhe Guo, PhD2, and Katherine E. Yutzey, PhD1 1The
Heart Institute, Cincinnati Children’s Medical Center, Cincinnati, OH
Author Manuscript
2Department
of Electrical Engineering and Computing Systems, University of Cincinnati, Cincinnati, OH
Abstract Background—Adult mammalian cardiomyocytes (CM) have the potential to proliferate, but this is not sufficient to generate adequate CMs after myocardial infarction (MI). The transcription factor Tbx20 is required for CM proliferation during development and adult CM homeostasis. The ability of Tbx20 overexpression (Tbx20OE) to promote adult CM proliferation and improve cardiac function after MI was examined.
Author Manuscript
Methods and Results—Tbx20OE was induced specifically in adult mouse differentiated CMs. Increased CM proliferation and fetal-like characteristics were found in Tbx20OE hearts, compared to controls, without causing pathology 4 weeks after Tbx20OE at baseline. Moreover, Tbx20OE in adult CM after MI significantly improved survival, cardiac function, and infarct size 4 weeks postMI. Improved cardiac repair, as indicated by increased CM proliferation and capillary density, was observed in the MI border zone of Tbx20OE hearts compared to controls. Expression of proliferation activator (cyclin D1, E1, and IGF1) and fetal contractile protein (ssTNI, βMHC) mRNA was increased, while negative cell-cycle regulators (p21, Meis1) were decreased, in Tbx20OE hearts, compared to controls, under both baseline and MI conditions. Tbx20OE in adult hearts activates multiple pro-proliferation pathways including Akt, YAP and BMP. Interestingly, p21, Meis1, and a novel cell-cycle inhibitory gene Btg2, are directly bound and repressed by Tbx20 with induction of proliferation in neonatal CM.
Author Manuscript
Conclusions—Tbx20OE specifically in adult CM activates multiple cardiac proliferative pathways, directly represses cell-cycle inhibitory genes p21, Meis1 and Btg2, promotes adult CM proliferation, and preserves cardiac performance post-MI. Keywords myocardial infarction; remodeling; myocytes; molecular biology
Correspondence: Katherine E. Yutzey, PhD, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Medical Center ML 7020, 240 Albert Sabin Way, Cincinnati, OH 45229, Phone: 513-636-8340, Fax: 513-636-5958, [email protected]. Disclosures: None.
Xiang et al.
Page 2
Author Manuscript
Introduction
Author Manuscript
Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. Due to a limited proliferative ability2, endogenous adult cardiomyocyte (CM) regeneration is inadequate to compensate for the massive loss of functional CMs after myocardial infarction (MI), which contributes significantly to HF development in mammals3. In the fetal heart, CMs are proliferative, contributing to heart growth4. After birth, the vast majority of CMs withdraw from the cell-cycle, express adult contractile protein isoforms5, induce cell senescence markers, and lose the ability to fully regenerate after myocardial injury6. Adult mammalian CMs harbor measurable but limited proliferative activities (
