CircSnx12 Is Involved in Ferroptosis During Heart Failure by Targeting miR-224-5p.

Haoyuan Zheng,Yunen Liu,Lin Shi,Mingxiao Hou,Changci Tong

doi:10.3389/fcvm.2021.656093

Abstract

Circular RNA (circRNA) is a subclass of non-coding RNAs that enables the circular transcripts resistant to the exonuclease digestion. Iron homeostasis is essential for the body to maintain normal physiological functions. At present, the relationship among circRNA, iron metabolism and heart failure remains largely unknown. This study aimed to explore the regulatory mechanism of circRNA and iron metabolism in heart failure. We obtained circRNA, miRNA and mRNA data from public databases and built a ceRNA network. The prediction results were verified in the myocardial tissues of pressure overload-induced heart failure mice through the use of histopathological staining methods, iron and malondialdehyde (MDA) measurement tests, quantitative real-time PCR (qRT-PCR), Western blot analysis and luciferase reporter assay. A total of 4 genes related to iron metabolism and oxidative stress were identified, and a ceRNA network involving 7 circRNAs, 7 miRNAs, and 4 mRNAs was constructed using bioinformatics tools. The results of qRT-PCR and Western blot analyses indicated that the expression level of FTH1 was similar with that predicted by bioinformatics analysis. Echocardiographic measurement showed that heart failure mice have lower fractional shortening and ejection fraction. Moreover, the myocardium of heart failure mice displayed obvious fibrosis as well as increased levels of iron and MDA compared to control mice. Besides, circSnx12 could act as an endogenous sponge to bind with miR-224-5p, and the 3'UTR region of FTH1 also had miRNA binding sites. A circRNA-miRNA-mRNA regulatory network was successfully constructed by identifying differentially expressed genes related to iron metabolism. This new approach reveals potential circRNA targets for the treatment of heart failure.

Highlights

Heart failure (HF) has become a major healthcare burden worldwide, as it is one of the leading causes of morbidity and mortality globally
We found that FTH1 was down-regulated, as consistent with the target prediction results (Figure 5A). miR-3082-5p was down-regulate in the transverse aortic constriction (TAC) group (Figure 6A), but miR-1306-5p and miR-2245p was up-regulate (Figures 6B,E)
We found that the expression levels of FTH1 and ATP6V1A were lower in TAC group than in SHAM group (Figures 5C–F), which were consistent with the qRTPCR data

Summary

Introduction

Heart failure (HF) has become a major healthcare burden worldwide, as it is one of the leading causes of morbidity and mortality globally. Prior research has made great progress in understanding the pathophysiological mechanisms of HF, but little is known about its gene-level alterations. In-depth exploration of the molecular mechanisms underlying HF pathogenesis can provide new ideas for optimal HF therapy and gain new insights into HF biomarkers and drug development [1]. In this study, the expression profiling datasets of TACinduced HF animal model were used for subsequent analysis. This model is the same as the modeling method in the datasets

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Conclusion