NUAK1 Inhibition Alleviates Ischemia-Reperfusion Injury via SYNE1-YAP1.

IF 18 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation research Pub Date : 2026-06-22 DOI:10.1161/circresaha.126.328256

Yangjinming Bai,Tingting Zhao,Qian Wang,Rui Zhang,Zhixing Wei,Yudong Fei,Xingxing Cai,Zhengyang Wu,Ji Yan,Yichao Zhang,Kaiyan Chen,Yuepeng Wang,Yi-Gang Li

{"title":"NUAK1 Inhibition Alleviates Ischemia-Reperfusion Injury via SYNE1-YAP1.","authors":"Yangjinming Bai,Tingting Zhao,Qian Wang,Rui Zhang,Zhixing Wei,Yudong Fei,Xingxing Cai,Zhengyang Wu,Ji Yan,Yichao Zhang,Kaiyan Chen,Yuepeng Wang,Yi-Gang Li","doi":"10.1161/circresaha.126.328256","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nMechanosensitive nuclear signaling contributes to myocardial ischemia-reperfusion injury, but the substrates and mechanisms of NUAK1 (AMPK-related kinase 5) remain unclear. We investigated whether NUAK1 regulates SYNE1 (Nesprin-1)/linker of nucleoskeleton and cytoskeleton-dependent nuclear gating of YAP1 (Yes-associated protein 1) during hypoxia/reoxygenation and ischemia-reperfusion injury.\r\n\r\nMETHODS AND RESULTS\r\nQuantitative phosphoproteomics identified a conserved NUAK1-dependent phosphorylation site in striated muscle-enriched Nesprin1-α2/SYNE1 (S434; S8284 in nesprin-1 giant). Coimmunoprecipitation and in vitro kinase assays supported direct SYNE1 phosphorylation by NUAK1. In neonatal mouse ventricular myocytes, genetic or pharmacological inhibition of NUAK1 decreased apoptotic signaling, reduced SYNE1 stability, enhanced YAP1 nuclear localization, and altered nuclear YAP1 dynamics. SYNE1 phosphosite mutants and nuclear/cytoplasmic fractionation supported a NUAK1-SYNE1 axis that restrains YAP1 nuclear accumulation under stress. Atomic force microscopy linked this pathway to nuclear mechanical remodeling. In a mouse model of ischemia-reperfusion injury, NUAK1 inhibition reduced acute myocardial damage and improved remodeling indices.\r\n\r\nCONCLUSIONS\r\nNUAK1-dependent SYNE1 phosphorylation shapes nuclear mechanosignaling during ischemic stress. NUAK1 downregulation promotes cardiomyocyte YAP1 nuclear activity and attenuates injury responses.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"13 1","pages":""},"PeriodicalIF":18.0000,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/circresaha.126.328256","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

BACKGROUND Mechanosensitive nuclear signaling contributes to myocardial ischemia-reperfusion injury, but the substrates and mechanisms of NUAK1 (AMPK-related kinase 5) remain unclear. We investigated whether NUAK1 regulates SYNE1 (Nesprin-1)/linker of nucleoskeleton and cytoskeleton-dependent nuclear gating of YAP1 (Yes-associated protein 1) during hypoxia/reoxygenation and ischemia-reperfusion injury. METHODS AND RESULTS Quantitative phosphoproteomics identified a conserved NUAK1-dependent phosphorylation site in striated muscle-enriched Nesprin1-α2/SYNE1 (S434; S8284 in nesprin-1 giant). Coimmunoprecipitation and in vitro kinase assays supported direct SYNE1 phosphorylation by NUAK1. In neonatal mouse ventricular myocytes, genetic or pharmacological inhibition of NUAK1 decreased apoptotic signaling, reduced SYNE1 stability, enhanced YAP1 nuclear localization, and altered nuclear YAP1 dynamics. SYNE1 phosphosite mutants and nuclear/cytoplasmic fractionation supported a NUAK1-SYNE1 axis that restrains YAP1 nuclear accumulation under stress. Atomic force microscopy linked this pathway to nuclear mechanical remodeling. In a mouse model of ischemia-reperfusion injury, NUAK1 inhibition reduced acute myocardial damage and improved remodeling indices. CONCLUSIONS NUAK1-dependent SYNE1 phosphorylation shapes nuclear mechanosignaling during ischemic stress. NUAK1 downregulation promotes cardiomyocyte YAP1 nuclear activity and attenuates injury responses.

查看原文本刊更多论文

NUAK1抑制通过SYNE1-YAP1减轻缺血再灌注损伤。

机械敏感性核信号参与心肌缺血-再灌注损伤，但NUAK1 （ampk相关激酶5）的底物和机制尚不清楚。我们研究了NUAK1是否在缺氧/再氧化和缺血再灌注损伤中调控SYNE1 (nesprin1)/核骨架连接子和YAP1 （Yes-associated protein 1）的细胞骨架依赖核门控。方法与结果定量磷酸化蛋白组学在横纹肌富集的Nesprin1-α2/SYNE1中发现了一个保守的nuak1依赖性磷酸化位点（在Nesprin1巨体中为S434；在Nesprin1巨体中为S8284）。共免疫沉淀和体外激酶实验支持NUAK1直接磷酸化SYNE1。在新生小鼠心室肌细胞中，遗传或药物抑制NUAK1可降低凋亡信号，降低SYNE1稳定性，增强YAP1核定位，改变核YAP1动力学。SYNE1磷酸化突变体和核/细胞质分离支持NUAK1-SYNE1轴，该轴在胁迫下抑制YAP1核积累。原子力显微镜将这一途径与核机械重塑联系起来。在小鼠缺血再灌注损伤模型中，NUAK1抑制可减轻急性心肌损伤，改善重构指标。结论snak1依赖性SYNE1磷酸化影响缺血应激过程中的核机械信号。NUAK1下调可促进心肌细胞YAP1核活性，减轻损伤反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.