Epigenetic silencing of TIMP4 in heart failure.
Epigenetic silencing of TIMP4 in heart failure.
复制标题
DOI：
10.1111/jcmm.12901
复制
发表时间：
2016-11
影响因子：
5.3
通讯作者：
Tyagi SC
中科院分区：
文献类型：
--
作者：
Chaturvedi P;Tyagi SC
基质金属蛋白酶组织抑制剂4（TIMP 4）是基质金属蛋白酶9（MMP 9）的内源性关键调节剂之一，我们先前报道了心脏特异性TIMP 4引发收缩并有助于心脏祖细胞的分化。尽管研究表明心力衰竭时TIMP 4的表达下降，但其机制尚不清楚。本研究旨在确定TIMP 4在主动脉-腔静脉（AV）瘘引起的心力衰竭进展中沉默的机制。我们假设在心力衰竭中存在TIMP 4的表观遗传沉默。为了验证这一假设，我们通过在C57 BL/6小鼠中创建AV瘘来创建心力衰竭模型，并研究了启动子甲基化（甲基化特异性PCR、高分辨率解链、甲基化敏感性限制性酶和亚硫酸钠处理，然后测序）、组蛋白修饰（ChIP测定）和调节TIMP 4（mir 122 a）和MMP 9（mir 29 b和mir 455 - 5 p）的microRNA。通过超声心动图评估动静脉瘘术后的心功能生理参数。我们观察到TIMP 4启动子中有7个CpG岛，在心力衰竭的进展过程中甲基化，导致其表观遗传沉默。此外，mir 122 a的上调水平部分有助于TIMP 4的调节。因此，MMP 9上调并导致心脏重塑。这是一个新的报告，以解释心脏衰竭中TIMP 4的表观遗传沉默。
Tissue inhibitor of matrix metalloprotease 4 (TIMP4) is endogenously one of the key modulators of matrix metalloprotease 9 (MMP9) and we have reported earlier that cardiac specific TIMP4 instigates contractility and helps in differentiation of cardiac progenitor cells. Although studies show that the expression of TIMP4 goes down in heart failure but the mechanism is unknown. This study aims to determine the mechanism of silencing of TIMP4 in heart failure progression created by aorta‐vena cava (AV) fistula. We hypothesize that there is epigenetic silencing of TIMP4 in heart failure. To validate this hypothesis, we created heart failure model by creating AV fistula in C57BL/6 mice and looked into the promoter methylation (methylation specific PCR, high resolution melting, methylation sensitive restriction enzyme and Na bisulphite treatment followed by sequencing), histone modification (ChIP assay) and microRNAs that regulate TIMP4 (mir122a) and MMP9 (mir29b and mir455‐5p). The physiological parameters in terms of cardiac function after AV fistula were assessed by echocardiography. We observed that there are 7 CpG islands in the TIMP4 promoter which get methylated during the progression of heart failure which leads to its epigenetic silencing. In addition, the up‐regulated levels of mir122a in part, contribute to regulation of TIMP4. Consequently, MMP9 gets up‐regulated and leads to cardiac remodeling. This is a novel report to explain the epigenetic silencing of TIMP4 in heart failure.
登录
查看更多内容
影响因子：
4.8
作者：
Koskivirta, Ilpo;Kassiri, Zamaneh;Khokha, Rama
通讯作者：
Khokha, Rama
DOI：
10.1016/j.bbrc.2014.04.112
发表时间：
2014-06-13
影响因子：
3.1
作者：
Qiao, Weiwei;Zhang, Weili;Fan, Juexin
通讯作者：
Fan, Juexin
影响因子：
1.9
作者：
Azhikina, Tatyana;Kozlova, Alena;Sverdlov, Eugene
通讯作者：
Sverdlov, Eugene
影响因子：
4.6
作者：
Chaturvedi, Pankaj;Kalani, Anuradha;Tyagi, Suresh C.
通讯作者：
Tyagi, Suresh C.
影响因子：
4.3
作者：
Tyagi, SC;Campbell, SE;Voelker, DJ
通讯作者：
Voelker, DJ