Author:
Ju Jie,Li Xin-Min,Zhao Xue-Mei,Li Fu-Hai,Wang Shao-Cong,Wang Kai,Li Rui-Feng,Zhou Lu-Yu,Liang Lin,Wang Yin,Zhang Yu-Hui,Wang Kun
Abstract
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.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Biochemistry (medical),Cell Biology,Clinical Biochemistry,Molecular Biology,General Medicine,Endocrinology, Diabetes and Metabolism
Reference47 articles.
1. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254–743.
2. Ying L, Benjanuwattra J, Chattipakorn SC, et al. The role of RIPK3-regulated cell death pathways and necroptosis in the pathogenesis of cardiac ischaemia-reperfusion injury. Acta Physiol. 2021;231(2): e13541.
3. Ju J, Song YN, Wang K. mechanism of ferroptosis: a potential target for cardiovascular diseases treatment. Aging Dis. 2021;12(1):261–76.
4. Shen S, Wang Z, Sun H, et al. Role of NLRP3 inflammasome in myocardial ischemia-reperfusion injury and ventricular remodeling. Med Sci Monit. 2022;28: e934255.
5. Sole C, Lawrie CH. Circular RNAs and cancer: opportunities and challenges. Adv Clin Chem. 2020;99:87–146.
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