Abstract P2029: The Role Of Runx1 In Cardiomyocyte Cell Cycle Activity And Its Impact On Cardiac Regeneration

Factors responsible for cardiomyocyte proliferation may serve as a potential therapeutic to stimulate endogenous myocardial regeneration following insult, such as ischemic injury. A previously published forward genetics approach assessing the frequency of a rare and presumed proliferation-competent subpopulation of cardiomyocytes, mononuclear diploid cardiomyocytes (MNDCMs), led us to the transcription factor RUNX1. It is established that RUNX1 induction in cardiomyocytes increases after injury. Here, we examine the effect of RUNX1 on cardiomyocyte cell cycle and establishment of the MNDCM population during postnatal development and cardiac regeneration using both cardiomyocyte-specific gain-and loss of function mouse models. We hypothesize that RUNX1 overexpression (OE) increases cardiomyocyte cell cycle activity with expansion of the MNDCM population, thereby extending the neonatal regenerative window and positively impacting adult cardiac remodeling post injury. During postnatal development, RUNX1 KO decreased postnatal cardiomyocyte cell cycle activity, while RUNX1 OE extended the period of cell cycle activation. This extension observed in RUNX1 OE mice is complete with cytokinesis resulting in an expansion of the MNDCM population and total cardiomyocyte endowment. To determine whether RUNX1 could similarly regulate cardiomyocyte cell cycle in a regenerative and non-regenerative model, we induce P6 and 8-week MIs to measure cell cycle activity and cardiac function post injury. RUNX1 OE neonatal mice with a P6 MI displayed no difference in cardiomyocyte cell cycle activity 7 post injury compared to control littermates. However, RUNX1 OE in adult mice with an 8-week MI showed increased cardiomyocyte cell cycle activity with completion of cytokinesis 2 weeks post injury and limited improvement in cardiac function 28 days post injury. RUNX1 influences cardiomyocyte cell cycle activation in the context of normal postnatal development and adult MI. Conversely, this phenomenon does not appear to translate to the neonatal injury context. We are examining this possible discrepancy with further experiments to fully understand .