The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice
The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice
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DOI：
10.1016/j.bbrc.2014.04.112
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发表时间：
2014-06-13
影响因子：
3.1
通讯作者：
Fan, Juexin
中科院分区：
文献类型：
--
作者：
Qiao, Weiwei;Zhang, Weili;Fan, Juexin
组蛋白乙酰化/去乙酰化的失衡参与了肥大胎儿基因的表达和心肌肥大的发生。虽然组蛋白去乙酰化酶在肥大中发挥双重作用，但目前的证据表明，组蛋白乙酰转移酶如p300和PCAF可作为促肥大因子。然而，它仍然是难以捉摸的，是否一些组蛋白乙酰转移酶可以防止肥大的发展。M0 F是属于MYST（MOZ、Ybf 2/Sas 3、Sas 2和TIP 60）家族的组蛋白乙酰转移酶。在这项研究中，我们报告了MOF表达下调，在失败的人心脏和肥大的小鼠心脏在蛋白质和mRNA水平。为了评估MOF在心肌肥大中的作用，我们产生了心脏特异性MOF转基因小鼠。在基线时，MOF转基因小鼠与其野生型同窝小鼠没有显示出任何差异。然而，心脏特异性MOF过表达保护小鼠免受横向主动脉缩窄（TAC）诱导的心脏肥大，降低心脏重量（HW）/体重（BW），肺重量/BW和HW/胫骨长度的比值，降低左心室壁厚度和增加缩短分数。我们还观察到与野生型小鼠相比，TAC攻击的MOF转基因小鼠中肥大胎儿基因的表达较低。机械上，MOF过表达增加过氧化氢酶和MnSOD的表达，其阻断TAC诱导的ROS和ROS下游促进肥大的c-Raf-MEK-ERK通路。总之，我们的研究结果确定了一种新的抗肥大作用的MOF，和MOF是第一个报告的抗肥大组蛋白乙酰转移酶。(c)2014爱思唯尔公司All rights reserved.
Imbalance between histone acetylation/deacetylation critically participates in the expression of hypertrophic fetal genes and development of cardiac hypertrophy. While histone deacetylases play dual roles in hypertrophy, current evidence reveals that histone acetyltransferase such as p300 and PCAF act as prohypertrophic factors. However, it remains elusive whether some histone acetyltransferases can prevent the development of hypertrophy. Males absent on the first (MOF) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. Here in this study, we reported that MOF expression was down-regulated in failing human hearts and hypertrophic murine hearts at protein and mRNA levels. To evaluate the roles of MOF in cardiac hypertrophy, we generated cardiac-specific MOF transgenic mice. MOF transgenic mice did not show any differences from their wide-type littermates at baseline. However, cardiac-specific MOF overexpression protected mice from transverse aortic constriction (TAC)-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observed lower expression of hypertrophic fetal genes in TAC-challenged MOF transgenic mice compared with that of wide-type mice. Mechanically, MOF overexpression increased the expression of Catalase and MnSOD, which blocked TAC-induced ROS and ROS downstream c-Raf-MEK-ERK pathway that promotes hypertrophy. Taken together, our findings identify a novel anti-hypertrophic role of MOF, and MOF is the first reported anti-hypertrophic histone acetyltransferase. (c) 2014 Elsevier Inc. All rights reserved.