Department of Pharmacology and Toxicology and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.
Department of Cell Biology, Neurobiology and Anatomy and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.
J Mol Cell Cardiol. 2021 Jun;155:88-98. doi: 10.1016/j.yjmcc.2021.02.005. Epub 2021 Feb 18.
Tip60, a pan-acetyltransferase encoded by the Kat5 gene, is enriched in the myocardium; however, its function in the heart is unknown. In cancer cells, Tip60 acetylates Atm (Ataxia-telangiectasia mutated), enabling its auto-phosphorylation (pAtm), which activates the DNA damage response (DDR). It was recently reported that activation of pAtm at the time of birth induces the DDR in cardiomyocytes (CMs), resulting in proliferative senescence. We therefore hypothesized that Tip60 initiates this process, and that depletion of Tip60 accordingly diminishes the DDR while extending the duration of CM cell-cycle activation. To test this hypothesis, an experimental model was used wherein a Myh6-driven Cre-recombinase transgene was activated on postnatal day 0 (P0) to recombine floxed Kat5 alleles and induce Tip60 depletion in neonatal CMs, without causing pathogenesis. Depletion of Tip60 resulted in reduced numbers of pAtm-positive CMs during the neonatal period, which correlated with reduced numbers of pH2A.X-positive CMs and decreased expression of genes encoding markers of the DDR as well as inflammation. This was accompanied by decreased expression of the cell-cycle inhibitors Meis1 and p27, activation of the cell-cycle in CMs, reduced CM size, and increased numbers of mononuclear/diploid CMs. Increased expression of fetal markers suggested that Tip60 depletion promotes a fetal-like proliferative state. Finally, infarction of Tip60-depleted hearts at P7 revealed improved cardiac function at P39 accompanied by reduced fibrosis, increased CM cell-cycle activation, and reduced apoptosis in the remote zone. These findings indicate that, among its pleiotropic functions, Tip60 induces the DDR in CMs, contributing to proliferative senescence.
Tip60 是由 Kat5 基因编码的一种泛乙酰转移酶，在心肌中富集；然而，其在心脏中的功能尚不清楚。在癌细胞中，Tip60 乙酰化 Atm（共济失调毛细血管扩张突变），使其自身磷酸化（pAtm），从而激活 DNA 损伤反应（DDR）。最近有报道称，出生时激活 pAtm 会诱导心肌细胞（CMs）中的 DDR，导致增殖性衰老。因此，我们假设 Tip60 启动了这一过程，相应地耗尽 Tip60 会减少 DDR，同时延长 CM 细胞周期激活的持续时间。为了验证这一假设，我们使用了一种实验模型，其中 Myh6 驱动的 Cre 重组酶转基因在出生后第 0 天（P0）被激活，以重组 floxed Kat5 等位基因，并在新生儿 CMs 中诱导 Tip60 耗竭，而不会导致发病。Tip60 的耗竭导致新生儿期 pAtm 阳性 CMs 的数量减少，这与 pH2A.X 阳性 CMs 的数量减少以及 DDR 和炎症相关基因的表达减少有关。这伴随着细胞周期抑制剂 Meis1 和 p27 的表达减少、CM 中的细胞周期激活、CM 大小减小以及单核/二倍体 CMs 的数量增加。胎儿标志物表达增加表明 Tip60 耗竭促进了类似于胎儿的增殖状态。最后，P7 时 Tip60 耗竭的心脏梗死显示 P39 时心脏功能改善，同时纤维化减少、CM 细胞周期激活增加以及远程区凋亡减少。这些发现表明，在其多种功能中，Tip60 在 CMs 中诱导 DDR，导致增殖性衰老。
