Abstract 152: Tip60 Depletion Promotes Cardiomyocyte Proliferation and Attenuates Ischemic Injury in the Adult Heart

Abstract

The pathogenesis of myocardial infarction (MI) is largely attributed to the loss of cardiomyocytes (CMs) and their insufficient regeneration. Inducing the proliferation of pre-existing CMs has emerged as a potential therapeutic strategy for cardiac repair. Results in our laboratory indicate that Tip60 (Tat-interactive protein 60 kD), a pan-acetylase protein encoded by the Kat5 gene, inhibits CM proliferation consequent to its induction of the DNA damage response (DDR) at neonatal stages, which has recently been shown to cause CM replicative senescence. To determine whether Tip60 depletion permits re-entry of adult CMs into the cell-cycle and confers protection from MI, we are employing a line of Kat5 flox/flox mice wherein Tip60 is conditionally and specifically depleted in CMs via tamoxifen-induced activation of a Myh6 -driven merCremer transgene. In uninjured hearts, Tip60 depletion results in transient thickening of the left ventricular walls, accompanied by markedly increased expression of G 2 /M-phase cell cycle regulators (cyclins A2 & B1, Cdk1) and de-differentiation markers (Myh7, Osm, OsmR, Runx1), diminished CM size, decreased expression of cell-cycle inhibitors (p27, Meis1), and remarkable increases in Ki67 and pH3-positive CMs as well as non-CMs. In hearts infarcted by permanent ligation, tamoxifen administration increases fractional shortening, ejection fraction, and anterior wall thickening within 7 days, conditions that are sustained for at least 18 additional days, when reduced scarring is indicated by trichrome staining. Taken together, these results indicate that Tip60 depletion in adult heart may preserve cardiac performance after MI by inducing CM regeneration. These findings should help advance our understanding of the molecular mechanisms that keep CMs in replicative senescence, establishing a possible therapeutic target for maintaining and restoring cardiac muscle after MI.