Depletion of Tip60 from In Vivo Cardiomyocytes Increases Myocyte Density, Followed by Cardiac Dysfunction, Myocyte Fallout and Lethality.
Depletion of Tip60 from In Vivo Cardiomyocytes Increases Myocyte Density, Followed by Cardiac Dysfunction, Myocyte Fallout and Lethality.
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DOI：
10.1371/journal.pone.0164855
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Lough J
中科院分区：
文献类型：
--
作者：
Fisher JB;Horst A;Wan T;Kim MS;Auchampach J;Lough J
Tat 相互作用蛋白 60 (Tip60) 由 Kat5 基因编码，是乙酰转移酶 MYST 家族的成员。癌症生物学研究表明，Tip60 可诱导 DNA 损伤反应、细胞凋亡和细胞周期抑制。尽管 Tip60 在心肌中表达，但其在心肌细胞 (CM) 中的作用尚不清楚。早期研究表明，对全球靶向 Kat5+/- 单倍剂量不足的小鼠施加心脏应激会导致细胞凋亡的抑制和 CM 细胞周期的激活，尽管 Tip60 蛋白水平仅适度降低。因此，有兴趣的是在没有压力的情况下使用 Kat5LoxP/-;Myh6-Cre 小鼠确定从 CM 中特异性和显着地消耗 Tip60 的效果。我们报告了使用该模型的初步发现，其中从新生儿早期开始，在 2-12 周龄的小鼠中评估了从心室 CM 中特异性消耗 Tip60 蛋白的效果。尽管 5'-溴脱氧尿苷免疫染色表明 CM 增殖在任何这些阶段都没有改变，但 2 周龄心室中 CM 密度增加，当 TUNEL 染色显示细胞凋亡受到抑制时，这种情况在 4 周龄心脏中持续存在。到第 4 周，连接蛋白 43 的水平耗尽，其模式发生畸形，同时心脏肥大标志物表达和间质纤维化增加。随后在 8 周时出现收缩功能障碍，随后发生广泛的细胞凋亡和 CM 衰退，随后在小鼠接近 12 周龄时出现死亡。总之，从新生儿心脏发育的早期阶段开始，心室肌中 Tip60 的慢性消耗会导致 8 周后 CM 死亡；因此，Tip60 蛋白在心脏中具有至关重要的功能。
Tat-interactive protein 60 (Tip60), encoded by the Kat5 gene, is a member of the MYST family of acetyltransferases. Cancer biology studies have shown that Tip60 induces the DNA damage response, apoptosis, and cell-cycle inhibition. Although Tip60 is expressed in the myocardium, its role in cardiomyocytes (CMs) is unclear. Earlier studies here showed that application of cardiac stress to globally targeted Kat5+/—haploinsufficient mice resulted in inhibition of apoptosis and activation of the CM cell-cycle, despite only modest reduction of Tip60 protein levels. It was therefore of interest to ascertain the effects of specifically and substantially depleting Tip60 from CMs using Kat5LoxP/-;Myh6-Cre mice in the absence of stress. We report initial findings using this model, in which the effects of specifically depleting Tip60 protein from ventricular CMs, beginning at early neonatal stages, were assessed in 2–12 week-old mice. Although 5’-bromodeoxyuridine immunostaining indicated that CM proliferation was not altered at any of these stages, CM density was increased in 2 week-old ventricles, which persisted in 4 week-old hearts when TUNEL staining revealed inhibition of apoptosis. By week 4, levels of connexin-43 were depleted, and its patterning was dysmorphic, concomitant with an increase in cardiac hypertrophy marker expression and interstitial fibrosis. This was followed by systolic dysfunction at 8 weeks, after which extensive apoptosis and CM fallout occurred, followed by lethality as mice approached 12 weeks of age. In summary, chronic depletion of Tip60 from the ventricular myocardium beginning at early stages of neonatal heart development causes CM death after 8 weeks; hence, Tip60 protein has a crucial function in the heart.
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影响因子：
20.1
作者：
Pinto AR;Ilinykh A;Ivey MJ;Kuwabara JT;D'Antoni ML;Debuque R;Chandran A;Wang L;Arora K;Rosenthal NA;Tallquist MD
通讯作者：
Tallquist MD
影响因子：
4.6
作者：
Heallen, Todd;Morikawa, Yuka;Martin, James F.
通讯作者：
Martin, James F.
DOI：
10.1083/jcb.201012049
发表时间：
2011-08-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sdek P;Zhao P;Wang Y;Huang CJ;Ko CY;Butler PC;Weiss JN;Maclellan WR
通讯作者：
Maclellan WR
影响因子：
21.3
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
通讯作者：
Tzahor, Eldad
影响因子：
4.6
作者：
Huang, CQ;Sheikh, F;Chen, J
通讯作者：
Chen, J