Abstract
Background This study was aimed at exploring the biological function and molecular mechanism of ferroptosis of LRP6 modulation in cardiomyocytes of myocardial infarction (MI). Method We established the ferroptosis model of MI in vivo and in vitro and constructed the modulation network of circRNA-miRNA-LRP6 by bioinformatics analysis; then, we focused on exploring the regulatory relationship of LRP6 and its upstream genes circRNA1615 and miR-152-3p in the RIP experiments and the double luciferase reporter gene assay. Also, we tested the LRP6-mediated autophagy-related ferroptosis in MI. Results Ferroptosis was found in cardiomyocytes of MI, and ferroptosis inhibitor Ferrostatin-1 (Fer-1) could improve the pathological process of MI. LRP6 was involved in the process of ferroptosis in cardiomyocytes, and LRP6 deletion regulated ferroptosis in cardiomyocytes through autophagy. Screening and identification of the upstream gene circRNA1615 would target LRP6. circRNA1615 inhibited ferroptosis in cardiomyocytes, and circRNA1615 could regulate the expression of LRP6 through sponge adsorption of miR-152-3p, prevent LRP6-mediated autophagy-related ferroptosis in cardiomyocytes, and finally control the pathological process of MI. Conclusions circRNA1615 inhibits ferroptosis via modulation of autophagy by the miRNA152-3p/LRP6 molecular axis in cardiomyocytes of myocardial infarction.
Highlights
Myocardial infarction (MI) is the main cause of high incidence and sudden cardiac death; as the reperfusion follows, the ischemic myocardium aggravates its structural injuries, increases cardiomyocyte deaths, and expands the infarcted sizes, which further impairs cardiac function [1]
The cardiomyocytes were closely arranged, and their morphology was natural in the sham group; in the myocardial infarction (MI) group, the injured myocardial cells presented with coagulative necrosis, disappearing cardiomyocytes with new granulation tissue and gradual fibrosis, inflammatory cell infiltration, and bleeding (Figure 1(c))
Based on the analysis of the lipoprotein receptor-related protein 6 (LRP6) regulatory network, it was found that mmu-miR-466c-5p, mmu-miR-466o-5p, and mmu-miR-679-5p miRNA had strong binding abilities, while the GEO database data (GSE90123) showed that the expression of miR-152-3p was enriched in exosomes derived from H9c2 cells under hypoxic conditions in 4 hours [15], and we found that it significantly rose at 7 days in the hypoxia-treated cardiomyocytes (Figures 4(b) and 4(c))
Summary
Myocardial infarction (MI) is the main cause of high incidence and sudden cardiac death; as the reperfusion follows, the ischemic myocardium aggravates its structural injuries, increases cardiomyocyte deaths, and expands the infarcted sizes, which further impairs cardiac function [1]. In the I/R injuries of mouse heart, the iron chelators and glutaminolysis inhibitors significantly mitigated cardiomyocyte cell death and damage of heart tissue and function [5]. This study was aimed at exploring the biological function and molecular mechanism of ferroptosis of LRP6 modulation in cardiomyocytes of myocardial infarction (MI). We established the ferroptosis model of MI in vivo and in vitro and constructed the modulation network of circRNA-miRNA-LRP6 by bioinformatics analysis; we focused on exploring the regulatory relationship of LRP6 and its upstream genes circRNA1615 and miR-152-3p in the RIP experiments and the double luciferase reporter gene assay. CircRNA1615 inhibited ferroptosis in cardiomyocytes, and circRNA1615 could regulate the expression of LRP6 through sponge adsorption of miR-152-3p, prevent LRP6-mediated autophagy-related ferroptosis in cardiomyocytes, and control the pathological process of MI. CircRNA1615 inhibits ferroptosis via modulation of autophagy by the miRNA1523p/LRP6 molecular axis in cardiomyocytes of myocardial infarction Conclusions. circRNA1615 inhibits ferroptosis via modulation of autophagy by the miRNA1523p/LRP6 molecular axis in cardiomyocytes of myocardial infarction
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