Abstract P1011: Pharmacological Targeting Of Tip60 For Heart Regeneration And Repair

Abstract

In recent decades, many cardiovascular diseases have been ascribed to acetylation-dependent regulatory mechanisms, as revealed by the beneficial effects of targeting de-acetylase proteins. By contrast, we are targeting the acetyltransferase Tip60 (Tat-interactive protein 60 kD), a pleiotropic tumor suppressor encoded by the Kat5 gene. Using a murine genetic model, we recently reported that cardiomyocyte (CM)-specific disruption of Kat5 markedly protected against the damaging effects of myocardial infarction (MI). To establish therapeutic relevance, we have begun to evaluate the potential cardioprotective effects of TH1834, a small MW drug designed to specifically target the acetyltransferase domain of Tip60. Daily systemic administration of TH1834 on days 3-16 post-MI efficiently preserved cardiac function for up to 28 days post-MI, which was accompanied by reduced scar formation, diminished CM apoptosis, and activation of CM cell-cycle in the absence of CM hypertrophy. Subsequent gene ontology enrichment analysis of transcriptome sequencing data revealed that, among a total of 2,051 differentially expressed genes, 154 cell-cycle regulators and 96 apoptotic markers were altered by TH1834 treatment at day 10 post-MI; significant transcriptional changes in genes involved in cardiac muscle contraction, CM differentiation processes, and responses to ischemia/hypoxia were also identified. These data demonstrate that TH1834 administration promotes retention of post-MI function via enhanced remuscularization and by inhibiting cell death, supporting the translational potential of targeting Tip60 as a novel treatment for ischemic heart disease.