Abstract 348: Epigenetic Regulation in Heart Regeneration

Abstract

Existing treatments for myocardial infarction (MI) include Medication, intervention, and surgical bypass. These strategies are mainly used to prevent disease progression, but do not address the fundamental problem of cardiomyocyte loss. Therefore, developing new effective therapeutic strategies to preserve the pumping function after MI is highly desired. Acute injuries, such as MI, are companied with quick and massive loss of histone acetylation in injured cells, which lead to severe organ damage. Therefore, maintaining proper histone acetylation in a swift manner will likely protect the affected cell and organ function. In this study, we showed that valproic acid (VPA), a pan HDAC inhibitor and a FDA approved drug for epilepsy and bipolar disorders, reduced ~50% of the infarct size and preserves the pumping function of heart after MI in rats. Moreover, 60 min after infarction, VPA administration still significantly decreased infarct size in MI rats. Mechanistically, we identified that that VPA treatment triggered a Foxm1 pathway, which in turn activated genes essential for cell survival and proliferation and inflammation suppression. Importantly, overexpression of Foxm1 provided similar heart protective effect after MI as VPA treatment. In contrast, inhibition of Foxm1 activity abolished the cardiac protective effect of VPA. In parallel, we have applied novel biodegradable nanofibrous microspheres as cell carriers for cell transplantation. These microspheres dramatically improve engraftment of exogenously delivered cells and functional recovery of the infarcted hearts. Intriguingly, the efficacy of cell engraftment appears to correlate with the cell carrier’s ability to maintain the acetylation status of the cells. We expect that the combined HDAC inhibitor treatment with cell carrier-mediated CM transplantation will work synergistically to regenerate infarcted heart functioning and lead to effective clinical applications in heart regeneration therapy.