Tip60 Depletion In Adult Cardiomyocytes Promotes Proliferation And Preserves Cardiac Function After Myocardial Infarction

Cardiac disease and injury are accompanied by significant cardiomyocyte (CM) loss. CMs are essentially non-regenerable, preventing re-muscularization and resulting in permanent dysfunction during the healing process. The identification of factors from multiple layers of inhibitors that induce and maintain CM’s pronounced state of proliferative senescence provides potential therapeutic targets. Tip60 ( T at- i nteractive p rotein, 60 kD), a pan-acetylase tumor suppressor encoded by the Kat5 gene, activates multiple anti-proliferative pathways in other cell types. Tip60 is known to acetylate Atm and p53, which respectively activate the DNA damage response and apoptosis. And, Tip60 regulates intracellular levels of p21 and Tert polymerase in a fashion designed to maintain proliferative senescence. Although these functions promote CM proliferative senescence and Tip60 is strongly expressed in the myocardium, whether Tip60 regulates these activities in CMs remains unknown. This study tests the hypothesis that Tip60 inhibits CM cell-cycle activation, promotes apoptosis in the myocardium, and prevents regeneration after cardiac injury. In adult mice containing LoxP -flanked Kat5 alleles and a tamoxifen-inducible Cre-recombinase transgene driven by Myh6 (Kat5 flox/flox;Myh6-merCremer ) , Tip60 depletion three days after myocardial infarction (MI) preserved cardiac function as assessed by echocardiography at 10, 21, and 28 days post-MI. Histologic evaluation revealed that depletion of Tip60 in CMs significantly diminished scarring and increased CM cell-cycle activation, as indicated by increased numbers of Ki67-, BrdU- and pH3-positive CMs at 28 days post-MI. This was accompanied by the presence of CMs in the infarct border zone expressing smooth muscle α-actin, indicative of CM de-differentiation, and by reduced apoptosis in the remote zone as assessed by TUNEL and cleaved caspase-3 staining, suggesting reduced cardiac remodeling. These findings suggest that genetic depletion of Tip60 protects CMs from ischemia-induced cell death while promoting CM proliferation, implicating Tip60 as a novel candidate for cardiac therapeutics.