Inhibition of DNMT-1 alleviates ferroptosis through NCOA4 mediated ferritinophagy during diabetes myocardial ischemia/reperfusion injury

Wenyuan Li,Zhongyuan Xia,Yan Leng,Yao Wang,Wei Li

doi:10.1038/s41420-021-00656-0

Wenyuan Li, Zhongyuan Xia + Show 3 more

Open Access

https://doi.org/10.1038/s41420-021-00656-0

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Abstract

The purpose of this study was to investigate whether inhibition of DNA (cytosine-5)-methyltransferase 1 (DNMT-1) alleviated ferroptosis through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy during diabetes myocardial (DM) ischemia/reperfusion (I/R) injury (IRI). Rat DM + sham (DS), I/R, and DM + I/R (DIR), H9c2 cell high glucose (HG), hypoxia reoxygenation (H/R), and high-glucose hypoxia reoxygenation (HH/R) models were established. DNMT-1 inhibitor 5-Aza-2’-deoxycytidine (5-aza-CdR) was administered to rat and cell models. The protein level of DNMT-1, NCOA4, FTH, GPX4, Beclin-1, and P62 was detected by western blotting. Compared with normal sham (NS) group, myocardial tissue was injured in DS and I/R models. The level of DNMT-1, NCOA4, and ferroptosis was increased. Moreover, the cell injury was more serious in rat DIR or HH/R model. 5-Aza-CdR could reduce NCOA4-mediated ferritinophagy and myocardial injury in DIR and HH/R models. Moreover, the siRNA for NCOA4 could also reduce the level of ferritinophagy and cell injury in HH/R model. 5-Aza-CdR enhanced the protective effect for NCOA4-siRNA in the process of cell injury. Inhibition of DNMT-1 could reduce ferroptosis during DIR, which the NCOA4-mediated ferritinophagy might be regulated.

Highlights

Diabetes is closely related to cardiovascular disease and is an independent risk factor for cardiovascular complications and mortality after myocardial infarction [1]
Ferritinophagy was first proposed by Mancias et al [8] and the researchers identified nuclear receptor coactivator 4 (NCOA4) as a selective autophagy by quantitative proteomics
The researchers identified NCOA4 as a receptor for selective autophagy through quantitative proteomics, which mediates the degradation of ferritin in autophagosomes

Summary

Introduction

Diabetes is closely related to cardiovascular disease and is an independent risk factor for cardiovascular complications and mortality after myocardial infarction [1]. Diabetes increases the risk of cardiovascular disease, which is the main reason for the increased incidence of coronary artery disease and stroke, and increased risk of heart failure. Ischemic heart disease is the leading cause of heart failure and death in patients with heart disease worldwide. Rapid restoration of blood supply to ischemic tissue is the standard clinical treatment for myocardial infarction. This may lead to oxidative damage to cells and additional cell death, called “ischemia-reperfusion (I/R) injury (IRI)” ([2]). At present, reducing reperfusion injury after myocardial infarction is a hotspot in clinical research for the treatment of myocardial IRI

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