Overexpression of Tbx20 in Adult Cardiomyocyte Promotes Myocyte Proliferation and Improves Cardiac Function post Myocardial Infarction

Abstract

BackgroundAdult mammalian cardiomyocytes (CM) have the potential to proliferate, but this is not sufficient to compensate for the massive loss of functional CMs after myocardial infarction (MI). During embryonic heart development, the transcription factor Tbx20 is required for CM proliferation, and Tbx20 overexpression (Tbx20OE) promotes fetal characteristics in adult CMs when initiated before birth in mice. We hypothesize that Tbx20OE, when induced in adult CMs after injury, improves cardiac function and repair via dedifferentiation and cell cycle re‐entry of CMs.Methods and ResultsTbx20OE was induced in inducible CM‐specific Tbx20 overexpressing adult mice via tamoxifen. Increased CM proliferation and fetal characteristics were found in Tbx20OE hearts compared to controls without affecting cardiac function and morphology 4 weeks after Tbx20 overexpression at baseline. However, Tbx20OE in adult CM after MI significantly improved cardiac function and infarct size, and decreased myocardial hypertrophy 4 weeks post‐MI. Improved cardiac repair as indicated by increased capillary density and CM proliferation was also observed in border zone of Tbx20OE hearts compared to controls. Expression of proliferation activators (cyclin D1, E1, and IGF1) and fetal contractile proteins (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. Interestingly, multiple pro‐proliferation pathways including Akt, YAP and BMP signaling were activated in Tbx20OE adult heart at baseline. And we found p21, Meis1 and Btg2, act as direct downstream targets of Tbx20 in CM proliferation.Conclusion(sIn conclusion, Tbx20OE in adult CM promotes cell proliferation via regulating multiple pro‐proliferation pathways and directly impair cell‐cycle repressor gene p21, Meis1 and Btg2. Overexpressing of Tbx20 in adult CM improves cardiac function and repair in mice when induced post‐MI.Support or Funding InformationAmerican Heart Association postdoc fellowship 15POST22060001