长非编码 RNA AK144717 通过调节 HMGB1 的细胞分布和随后的 DNA 损伤反应,加剧病理性心肌肥厚。

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tianyu Wu, Yao Lu, Yue Yu, Yan Hua, Gaoyuan Ge, Wei Zhao, Kaiyan Chen, Zhuen Zhong, Fengxiang Zhang
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引用次数: 0

摘要

心脏肥大过程中氧化应激诱导的DNA损伤会激活共济失调毛细血管扩张症突变体(ATM)介导的DNA损伤应答(DDR)信号转导,进而加剧病理性心肌细胞的生长。本研究旨在确定长非编码 RNA(lncRNA)与心脏肥大和 DDR 的功能关联。通过芯片分析确定了假小鼠和横主动脉缩窄(TAC)组小鼠心室lncRNA的改变,并发现一种新型lncRNA AK144717在TAC手术或血管紧张素II(Ang II)刺激诱导的病理性心肌肥厚发展过程中逐渐上调。沉默AK144717与ATM抑制剂KU55933具有相似的抗肥厚作用,也能抑制肥厚刺激诱导的ATM-DDR信号激活。AK144717参与DDR和心肌肥厚与它与HMGB1的相互作用密切相关,因为沉默HMGB1会取消AK144717敲除的效果。AK144717与HMGB1的结合阻止了HMGB1与SIRT1之间的相互作用,从而导致HMGB1乙酰化增加,进而发生细胞转运。总之,我们的研究强调了 AK144717 通过与 HMGB1 相互作用并调控 DDR 在肥厚反应中的作用,暗示 AK144717 是治疗病理性心脏增生的一个很有前景的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Long noncoding RNA AK144717 exacerbates pathological cardiac hypertrophy through modulating the cellular distribution of HMGB1 and subsequent DNA damage response.

DNA damage induced by oxidative stress during cardiac hypertrophy activates the ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR) signaling, in turn aggravating the pathological cardiomyocyte growth. This study aims to identify the functional associations of long noncoding RNA (lncRNAs) with cardiac hypertrophy and DDR. The altered ventricular lncRNAs in the mice between sham and transverse aortic constriction (TAC) group were identified by microarray analysis, and a novel lncRNA AK144717 was found to gradually upregulate during the development of pathological cardiac hypertrophy induced by TAC surgery or angiotensin II (Ang II) stimulation. Silencing AK144717 had a similar anti-hypertrophic effect to that of ATM inhibitor KU55933 and also suppressed the activated ATM-DDR signaling induced by hypertrophic stimuli. The involvement of AK144717 in DDR and cardiac hypertrophy was closely related to its interaction with HMGB1, as silencing HMGB1 abolished the effects of AK144717 knockdown. The binding of AK144717 to HMGB1 prevented the interaction between HMGB1 and SIRT1, contributing to the increased acetylation and then cytosolic translocation of HMGB1. Overall, our study highlights the role of AK144717 in the hypertrophic response by interacting with HMGB1 and regulating DDR, hinting that AK144717 is a promising therapeutic target for pathological cardiac growth.

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来源期刊
Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences 生物-生化与分子生物学
CiteScore
13.20
自引率
1.20%
发文量
546
审稿时长
1.0 months
期刊介绍: Journal Name: Cellular and Molecular Life Sciences (CMLS) Location: Basel, Switzerland Focus: Multidisciplinary journal Publishes research articles, reviews, multi-author reviews, and visions & reflections articles Coverage: Latest aspects of biological and biomedical research Areas include: Biochemistry and molecular biology Cell biology Molecular and cellular aspects of biomedicine Neuroscience Pharmacology Immunology Additional Features: Welcomes comments on any article published in CMLS Accepts suggestions for topics to be covered
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