Dataset Information

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

ABSTRACT:

Background

Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function.

Methods

We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA.

Results

Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis.

Conclusions

Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

SUBMITTER: Ju J

PROVIDER: S-EPMC10304620 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

Ju Jie J Li Xin-Min XM Zhao Xue-Mei XM Li Fu-Hai FH Wang Shao-Cong SC Wang Kai K Li Rui-Feng RF Zhou Lu-Yu LY Liang Lin L Wang Yin Y Zhang Yu-Hui YH Wang Kun K

Journal of biomedical science 20230627 1

<h4>Background</h4>Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function.<h4>Methods</h4>We perform ...[more]

PMID: 37370086

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Project description:IntroductionMyocardial ischemia-reperfusion injury (MIRI) is a prevalent complication in patients with myocardial infarction. The pathological mechanism of MIRI remains elusive. Ferroptosis plays a critical role in MIRI. This study aimed to investigate the role of spermidine/spermine N1-acetyltransferase 1 (Sat1) in MIRI by regulation of ferroptosis.MethodsRats and H9C2 cells were used to perform MIRI model. The extent of myocardial damage and associated pathological changes were evaluated. Protein expression was detected by western blot. Then we observed the mitochondrial morphology and measured cell viability and damage. The levels of lipid peroxide and glutathione were measured, and lipid reactive oxygen species (ROS) was quantified. Differentially expressed genes (DEGs) in MIRI were analyzed. Moreover, to explore the role of Sat1 in MIRI, this study utilized adeno-associated virus 9 and lentiviral transduction to modulate Sat1 expression in rats and H9C2 cells, respectively. The transcription factor that regulates Sat1 expression was predicated. Luciferase reporter gene experiment was conducted to reveal the potential sites of Sox2 binding to Sat1.ResultsThis study revealed that ferroptosis was involved in MIRI. Through bioinformatic analysis, Sat1 was identified as a significant gene in MIRI, which has been reported as an inducer of ferroptosis. Our results showed that Sat1 expression was significantly increased in MIRI. Next, the study showed that inhibition of Sat1 alleviated MIRI by suppressing ferroptosis in vivo and in vitro, and over-expression of Sat1 promoted MIRI via activation of ferroptosis. Furthermore, Sat1 and its interacting genes were enriched in several signaling pathways, including ferroptosis and the MAPK signaling pathway. The results showed that Sat1 regulated MIRI through ferroptosis via MAPK/ERK pathway. Moreover, it is found that Sox2 can suppress Sat1 expression at the transcriptional level. The potential binding site was TAACAAAGGAA.ConclusionIn sum, this study demonstrated Sat1 expression was increased in MIRI, inhibition of Sat1 can alleviate MIRI by regulating ferroptosis via MAPK/ERK pathway, and Sat1 was negatively regulated by Sox2. These findings suggested that Sat1 may serve as a potential therapeutic target for the treatment of MIRI.

Project description:ObjectiveIschemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia-reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia.MethodsA middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h post-operation, rats were intraperitoneally injected with 45 mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72 h after reperfusion. Additionally, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe2+ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis.ResultsIn the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline.ConclusionFerroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI.

Dataset Information

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

Background

Methods

Results

Conclusions

Publications

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

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