SPATA2/CYLD Pathway-Dependent Deubiquitylation of p53 Promotes Ferroptosis in Rat Heart After Ischaemia/Reperfusion Through Suppression of SLC7A11

IF 2.2 4区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Heart, Lung and Circulation Pub Date : 2025-07-01 DOI:10.1016/j.hlc.2024.11.028

Dan-Qing Duan MS , Ming-Rui Li PhD , Li-Qun Lu PhD , Bi-Feng Yao MS , Lin-Lu Huang BS , Xiu-Ju Luo PhD , Jun Peng MD, PhD

{"title":"SPATA2/CYLD Pathway-Dependent Deubiquitylation of p53 Promotes Ferroptosis in Rat Heart After Ischaemia/Reperfusion Through Suppression of SLC7A11","authors":"Dan-Qing Duan MS , Ming-Rui Li PhD , Li-Qun Lu PhD , Bi-Feng Yao MS , Lin-Lu Huang BS , Xiu-Ju Luo PhD , Jun Peng MD, PhD","doi":"10.1016/j.hlc.2024.11.028","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aim</h3><div>Ferroptosis is an iron-dependent cell death and contributes to myocardial ischaemia/reperfusion (I/R) injury. Downregulation of glutathione peroxidase 4 (GPX4) is a key factor to accelerate ferroptosis, but the underlying mechanisms are not fully elucidated. Solute carrier family 7A member 11 (SLC7A11) plays a key role in maintaining the normal level of GPX4, and its transcription is suppressed by p53, whose level is controlled by spermatogenesis-associated protein 2 (SPATA2)/cylindromatosis (CYLD) pathway in a de-ubiquitination-dependent way. This study aims to explore whether SPATA2/CYLD pathway promotes myocardial ferroptosis in rat hearts after I/R through p53-dependent inhibition of SLC7A11.</div></div><div><h3>Methods</h3><div>The rat hearts were subjected to 1 h-ischaemia plus 3 h-reperfusion to establish a myocardial I/R injury model, and H9c2 cells were subjected to 8 h-hypoxia plus 12 h-re-oxygenation (H/R) to mimic myocardial I/R injury in vitro.</div></div><div><h3>Results</h3><div>Both the rat hearts and the cultured cardiomyocytes showed elevated levels of SPATA2 and CYLD, concomitant with the increased p53 levels and the enhanced interaction between SPATA2 and CYLD; these phenomena were reversed by knockdown of SPATA2. Mechanistically, knockdown of SPATA2 restored the ubiquitination of p53 and decreased p53 level in the H/R-treated cardiomyocytes, accompanied by increases in the levels of SLC7A11 and GPX4, and reduction of ferroptosis. Furthermore, suppression of SPATA2 by lurasidone, a predicted inhibitor of SPATA2, in the I/R-treated rat hearts also achieved similar results.</div></div><div><h3>Conclusion</h3><div>SPATA2/CYLD pathway-dependent de-ubiquitylation of p53 promotes ferroptosis in rat heart after I/R through a mechanism involving suppression of SLC7A11.</div></div>","PeriodicalId":13000,"journal":{"name":"Heart, Lung and Circulation","volume":"34 7","pages":"Pages 719-729"},"PeriodicalIF":2.2000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Heart, Lung and Circulation","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1443950624019310","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Background & Aim

Ferroptosis is an iron-dependent cell death and contributes to myocardial ischaemia/reperfusion (I/R) injury. Downregulation of glutathione peroxidase 4 (GPX4) is a key factor to accelerate ferroptosis, but the underlying mechanisms are not fully elucidated. Solute carrier family 7A member 11 (SLC7A11) plays a key role in maintaining the normal level of GPX4, and its transcription is suppressed by p53, whose level is controlled by spermatogenesis-associated protein 2 (SPATA2)/cylindromatosis (CYLD) pathway in a de-ubiquitination-dependent way. This study aims to explore whether SPATA2/CYLD pathway promotes myocardial ferroptosis in rat hearts after I/R through p53-dependent inhibition of SLC7A11.

Methods

The rat hearts were subjected to 1 h-ischaemia plus 3 h-reperfusion to establish a myocardial I/R injury model, and H9c2 cells were subjected to 8 h-hypoxia plus 12 h-re-oxygenation (H/R) to mimic myocardial I/R injury in vitro.

Results

Both the rat hearts and the cultured cardiomyocytes showed elevated levels of SPATA2 and CYLD, concomitant with the increased p53 levels and the enhanced interaction between SPATA2 and CYLD; these phenomena were reversed by knockdown of SPATA2. Mechanistically, knockdown of SPATA2 restored the ubiquitination of p53 and decreased p53 level in the H/R-treated cardiomyocytes, accompanied by increases in the levels of SLC7A11 and GPX4, and reduction of ferroptosis. Furthermore, suppression of SPATA2 by lurasidone, a predicted inhibitor of SPATA2, in the I/R-treated rat hearts also achieved similar results.

Conclusion

SPATA2/CYLD pathway-dependent de-ubiquitylation of p53 promotes ferroptosis in rat heart after I/R through a mechanism involving suppression of SLC7A11.

查看原文本刊更多论文

SPATA2/CYLD通路依赖的p53去泛素化通过抑制SLC7A11促进缺血/再灌注后大鼠心脏铁凋亡。

背景与目的：铁下垂是一种铁依赖性细胞死亡，有助于心肌缺血/再灌注（I/R）损伤。谷胱甘肽过氧化物酶4（谷胱甘肽过氧化物酶4）的下调是加速铁下垂的关键因素，但其机制尚未完全阐明。溶质载体家族7A成员11 （SLC7A11）在维持GPX4正常水平中起关键作用，其转录受p53抑制，其水平受精子发生相关蛋白2 (SPATA2)/圆柱体病（CYLD）通路以去泛素化依赖的方式控制。本研究旨在探讨SPATA2/CYLD通路是否通过p53依赖性抑制SLC7A11促进I/R后大鼠心肌铁下垂。方法：大鼠心脏缺血1 H +再灌注3 H建立心肌I/R损伤模型，H9c2细胞缺氧8 H +再氧合12 H模拟体外心肌I/R损伤。结果：大鼠心脏及培养心肌细胞SPATA2、CYLD水平升高，p53水平升高，SPATA2与CYLD相互作用增强；这些现象通过敲低SPATA2而被逆转。在机制上，SPATA2的下调恢复了H/ r处理心肌细胞中p53的泛素化，降低了p53水平，同时伴随着SLC7A11和GPX4水平的升高，以及铁下沉的减少。此外，在I/ r处理的大鼠心脏中，鲁拉西酮（一种预测的SPATA2抑制剂）抑制SPATA2也取得了类似的结果。结论：SPATA2/CYLD通路依赖的p53去泛素化通过抑制SLC7A11的机制促进I/R后大鼠心脏铁凋亡。

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

Heart, Lung and Circulation CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

4.50

自引率

3.80%

发文量

912

审稿时长

11.9 weeks

期刊介绍： Heart, Lung and Circulation publishes articles integrating clinical and research activities in the fields of basic cardiovascular science, clinical cardiology and cardiac surgery, with a focus on emerging issues in cardiovascular disease. The journal promotes multidisciplinary dialogue between cardiologists, cardiothoracic surgeons, cardio-pulmonary physicians and cardiovascular scientists.