Abstract 163: Regulation of Adult Cardiomyocyte Proliferation and Repair by Tbx20

Abstract

Background: In the adult heart, there is increasing evidence that cardiomyocytes can proliferate, but these rates are exceedingly low and are not sufficient for myocardial repair after injury. In the embryonic heart, the T-box transcription factor Tbx20 is required for cardiomyocyte proliferation, and Tbx20 overexpression (Tbx20OE) promotes fetal characteristics in adult cardiomyocytes when initiated before birth in mice. We hypothesize that Tbx20OE, when induced in adult cardiomyocytes, promotes proliferation and improves cardiac repair after injury. Methods and Results: Mice were generated with tamoxifen-inducible Tbx20OE specifically in differentiated cardiomyocytes driven by αMHCMerCreMer. Tbx20OE initiated in adult cardiomyocytes leads to increased numbers of mononucleated proliferating cardiomyocytes, increased expression of cyclins, and increased total numbers of cardiomyocytes. No changes in cardiac function or heart weight/body weight ratios were observed, although the average size of cardiomyocytes with Tbx20OE is smaller than controls. In addition cardiac proliferative pathways, including AKT, Yap1, and IGF1, are activated, while cell cycle inhibitors, including Meis1 and p21, are decreased. In order to determine if Tbx20 promotes cardiac repair after injury, Tbx20OE was induced 3 days post-myocardial infarction (MI). In Tbx20OE mice subjected to MI, cardiac function was significantly improved, the infarct scar size was smaller, and increased pHH3+ cardiomyocytes were observed. Likewise, capillary density and expression of VegfA and bFGF are increased in the injured myocardium with Tbx20OE. Ongoing studies will determine direct regulatory interactions of Tbx20 with genes and regulatory pathways that promote cardiomyocyte proliferation and repair in adults. Conclusions: Tbx20OE in adult CM activates cell proliferation also improves cardiac function and repair in mice when induced post-MI.