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.

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Identification of effective cardiac biomarkers and therapeutic targets for myocardial infarction (MI) will play an important role in early diagnosis and improving prognosis. Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage, cancer and neurological diseases. Its modulators were involved in transferrin receptor, iron chelator, clock protein ARNTL, etc. Its mechanisms included the inhibition of system X C − , diminished GPX4 activity, change of mitochondrial voltage-dependent anion channels and rising intracellular reactive oxygen species level. Further, the inhibitors of apoptosis, pyroptosis and autophagy did not prevent the occurrence of ferroptosis, but iron chelating agents and antioxidants could inhibit it. Noticeably, ferroptosis is an important pattern of cardiomyocyte death in the infarcted area, which may play a vital role in support of the myocardial pathological process of heart disease. However, the molecular mechanism of ferroptosis in the pathogenesis and the development of MI is not clear. Therefore, a greater depth of exploration of the mechanism of ferroptosis and its inhibitors will undoubtedly improve the pathological process of MI, which may be expected to identify ferroptosis as novel diagnostic and therapeutic targets of MI.

CircRNA (circular RNA) is a kind of closed circular structure of noncoding RNA molecules without 5′ hat structure and 3′ polyA, mainly located in the cytoplasm or stored in exosomes. It is not affected by RNA exonuclease, so it's stable and hard to be degraded. Proved to be widespread in a variety of eukaryotes, most circRNAs are cyclized by exons, some are lasso structures formed by intron cyclization. Recently, circRNAs have been demonstrated to play crucial roles in cardiomyocyte hypertrophy, fibrosis, autophagy and apoptosis, participating in the development of heart failure. There is increasing evidence that circRNAs may be a novel target for the treatment of heart failure.

Background In contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity. Methods and results CLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure. Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest. Conclusion In patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes. ClinicalTrials identifier ISRCTN43070564