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http://purl.uniprot.org/citations/35843476http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35843476http://www.w3.org/2000/01/rdf-schema#comment"

Introduction

Ferroptosis, a newly identified type of programmed cell death type, has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury. However, little is known about ferroptosis regulation in I/R injury.

Objectives

We identified activating transcription factor 3 (ATF3) as a vital regulator of I/R induced ferroptosis and investigated the effects and potential mechanism of ATF3 in cardiac ferroptosis.

Methods

In this study, the dynamic RNA-sequencing (RNA-seq) analysis were performed on mouse hearts exposed to different I/R schedules to identify that ATF3 represents an important modulatory molecule in myocardial I/R injury. Then knockout, rescue and overexpression methods were used in mice and neonatal mouse cells (NMCs) to illustrate the effect of ATF3 on myocardial I/R injury. Loss/gain of function techniques were used both in vivo and in vitro to explore the effects of ATF3 on ferroptosis in I/R injury. Furthermore, chromatin immunoprecipitation sequence (ChIP-seq) analysis was performed in the AC16 human cardiomyocyte cell line to investigate potential genes regulated by ATF3.

Results

ATF3 expression reached highest level at early stage of reperfusion, knockout of ATF3 significantly aggravated I/R injury, which could be rescued by ATF3 re-expression. Knockout and the re-expression of ATF3 changed the transcription levels of multiple ferroptosis genes. In addition, results showed that overexpression of ATF3 inhibits cardiomyocyte ferroptosis triggered by erastin and RSL3. Lastly, ChIP-seq and dual luciferase activity analysis revealed ATF3 could bind to the transcription start site of Fanconi anaemia complementation group D2 (FANCD2) and increased the FANCD2 promoter activity. Furthermore, we first demonstrated that overexpression of FANCD2 exerts significant anti-ferroptosis and cardioprotective effect on AC16 cell H/R injury.

Conclusion

ATF3 inhibits cardiomyocyte ferroptotic death in I/R injury, which might be related with regulating FANCD2. Our study provides new insight into the molecular target for the therapy of myocardial I/R injury."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.org/dc/terms/identifier"doi:10.1016/j.freeradbiomed.2022.07.006"xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Chen A."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Chen G."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Liu H."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Lu W."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Lin Y."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Song X."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Wang X."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Yang C."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Wen D."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Yan J."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Mo H."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Mei X."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Luo T."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Xiao H."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Ling Y."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/author"Yan J.'"xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/date"2022"xsd:gYear
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/name"Free Radic Biol Med"xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/pages"122-135"xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/title"A novel function of ATF3 in suppression of ferroptosis in mouse heart suffered ischemia/reperfusion."xsd:string
http://purl.uniprot.org/citations/35843476http://purl.uniprot.org/core/volume"189"xsd:string
http://purl.uniprot.org/citations/35843476http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/35843476
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