Abstract 5271: Transcription Factor Tbx3 Reprograms Adult Myocardial Cells into Nodal-like Cells
The sinus node initiates the electrical impulse required for coordinated contraction. The conduction system has a distinct phenotype and gene expression program compared to the bordering working myocardium. Transcriptional repressor Tbx3 is expressed in all developing and mature components of the central conduction system. Tbx3 is strictly required for sinus node development and gene regulation in vivo, acting as a genetic switch imposing the pacemaker gene program and phenotype on myocardium during development. We hypothesize that Tbx3 is able to convert the phenotype of adult cardiomyocytes from working myocardium into a sinus node-like phenotype and therefore could be a useful candidate for biological pacemaker formation strategies. Transgenic mice were generated that initiate Tbx3 expression in all myocardium upon administration of tamoxifen. Efficient Tbx3 activation by recombination (80–90%) was observed in the atrium and the ventricle. By quantitative PCR we found efficient down-regulation of key working myocardial genes including Cx40 and Cx43, Nav1.5 (SCN5A) and inward potassium rectifier channels (Kir) within 5 days after initial tamoxifen administration (n=12). ECG recordings revealed QRS broadening of hearts expressing Tbx3 in the working myocardium. Optical mapping demonstrated conduction slowing in both atrium and ventricle. Up-regulation of genes important for pacemaker function, such as Hcn4, was not found. Isolated Tbx3 expressing atrium preparations were not spontaneously active. We conclude that in the fully differentiated working myocardium, Tbx3 is able to suppress a large panel of working myocardial genes, including genes for high conductance gap-junctions, the fast sodium channel, and inward-rectifiers potassium channels, i.e. genes that suppress pacemaker activity and that are normally expressed at very low levels in the sinus node. Therefore, Tbx3 could be of additional value in biological pacemaker formation strategies.