Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction.
Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction.
复制标题
维尔纳综合征基因突变导致心脏衰老，导致左心室功能障碍从舒张期向收缩期转变。
DOI：
10.1093/eurheartj/ehy566.p6548
复制
发表时间：
2018
影响因子：
39.3
通讯作者：
Murohara T
中科院分区：
文献类型：
--
作者：
Kamihara T;Bando YK;Nishimura K;Murohara T
背景/简介：沃纳综合征是一种由 DNA 解旋酶调节蛋白 (WRN) 功能障碍引起的过早衰老疾病。然而，关于早衰是否与心脏衰老有关的信息很少。据报道，WRN 577位氨基酸（AA）取代（WRN-K577M）会消除ATP酶和解旋酶活性，其突变小鼠表现出加速皮肤老化。目的：我们旨在阐明WRN-K577M是否与小鼠心脏老化有关。方法：对携带WRN-K577M的基于C57/BL6的突变小鼠进行研究 在18周龄和84周龄时进行评估。结果：18周龄（18w-WRN-K577M）时，WRN-K577M的外观正常。然而，18w-WRN-K577M 中心脏衰老标志物（p53 和 γH2AX）和 TUNEL 检测到的细胞凋亡有所增强（WRN-KD 中的 p53 与 CON 相比增加了 1.20 倍，WRN-KD 中的 γH2AX 与 CON 中相比增加了 1.78 倍，P < 0.05）。 18w-WRN-K577M的体重与年龄匹配的对照小鼠相似，然而，18w-WRN-K577M表现出心脏肥大（以mg为单位；18w-WRN-K577M为130±7，野生为113±5）。 18w-WRN-K577M 表现出左心室舒张功能障碍，而左心室收缩功能得以保留，并伴有心脏纤维化和肥厚。一致地，肥大相关信号传导升高（WRN-KD 中的 mTOR 与 CON 相比；1.4 倍，AKT；1.4 倍，ERK；1.4 倍）。 18w-WRN-K577M 心脏的 DNA 微阵列分析表明，与野生型相比，253 个基因上调。其中，16个基因比野生型增加了>4倍（图A）。 KEGG本体显示这些基因的特征如下：肥大（Myh7、Klkb11）、纤维化（Fgf21、Ctgf）和炎症分子（Ap1s3、Pla2g2e、Has1、MMP9）。值得注意的是，18w-WRN-K577M 表现出正常血糖。相比之下，在 84 周龄时，WRN-K577M 表现出明显的脱发、运动行为迟缓（图 B）、左心室收缩功能障碍（LVFS；26.2±2%）和左心室壁厚度下降，同时心肌细胞大小持续减小，心脏纤维化和细胞凋亡增加。
Background/Introduction: Werner syndrome is a premature aging disorder caused by dysfunction of the DNA-helicase-regulatory protein (WRN). However, there is little information whether progeria may link to cardiac aging. Amino acid (AA) substitution of WRN at position 577 (WRN-K577M) has been reported to abolish the ATPase and helicase activities and its mutant mice exhibits accelerated skin aging.Purpose: We aimed to elucidate whether WRN-K577M is responsible for cardiac aging in mice.Methods: C57/BL6-based mutant mice harboring WRN-K577M were evaluated at 18 week-old and 84 week-old.Results: At 18-week-old (18w-WRN-K577M), appearance of WRN-K577M was normal. However, cardiac aging markers (p53 and γH2AX) and apoptosis detected by TUNEL were augmented in 18w-WRN-K577M (p53 in WRN-KD versus CON; 1.20 fold increase, γH2AX in WRN-KD versus CON; 1.78 fold increase, P< 0.05). Body weight of 18w-WRN-K577M was similar to the age-matched control mice, however, 18w-WRN-K577M exhibited cardiomegaly (in mg; 130±7 for 18w-WRN-K577M and 113±5 for wild). 18w-WRN-K577M exhibited diastolic left-ventricular (LV) dysfunction, whereas their systolic LV function was preserved, with concomitant cardiac fibrosis and hypertrophy. Consistently, hypertrophy-associated signaling was elevated (mTOR in WRN-KD versus CON; 1.4 fold, AKT; 1.4 fold, ERK; 1.4 fold). DNA microarray analysis of 18w-WRN-K577M heart revealed that the 253 genes was upregulated compared to wild-type. Among them, 16 genes were increased> 4 fold higher than wild (Figure A). KEGG ontology revealed that characteristics of these genes were as follows: hypertrophy (Myh7, Klkb11), fibrosis (Fgf21, Ctgf), and inflammatory molecules (Ap1s3, Pla2g2e, Has1, MMP9). Notably, 18w-WRN-K577M exhibited normoglycemia. In contrast, at 84-week-old, WRN-K577M exhibited significant hair loss, retarded locomotive behavior (Figure B), systolic LV dysfunction (LVFS; 26.2±2%) and decline in LV wall thickness with consistent decrease in cardiomyocyte size and increase in cardiac fibrosis and apoptosis.Topic: