Abstract
Increased neutrophil recruitment represents a hallmark event in myocardial ischemia/reperfusion (I/R) injury due to the ensuing inflammatory response. Circular RNAs (circRNAs) are important regulatory molecules involved in cell physiology and pathology. Herein, we analyzed the role of a novel circRNA circ_SMG6 in the regulation of neutrophil recruitment following I/R injury, which may associate with the miR-138-5p/EGR1/TLR4/TRIF axis. Myocardial I/R injury was modeled in vivo by ligation of the left anterior descending (LAD) artery followed by reperfusion in mice and in vitro by exposing a cardiomyocyte cell line (HL-1) to hypoxia/reoxygenation (H/R). Gain- and loss-of-function experiments were performed to evaluate the effect of the circ_SMG6/miR-138-5p/EGR1/TLR4/TRIF axis on cardiac functions, myocardial infarction, myocardial enzyme levels, cardiomyocyte activities, and neutrophil recruitment. We found that the EGR1 expression was increased in myocardial tissues of I/R mice. Knockdown of EGR1 was found to attenuate I/R-induced cardiac dysfunction and infarction area, pathological damage, and cardiomyocyte apoptosis. Mechanistic investigations showed that circ_SMG6 competitively bound to miR-138-5p and consequently led to upregulation of EGR1, thus facilitating myocardial I/R injury in mice and H/R-induced cell injury. Additionally, ectopic EGR1 expression augmented neutrophil recruitment and exacerbated the ensuing I/R injury, which was related to the activated TLR4/TRIF signaling pathway. Overall, our findings suggest that circ_SMG6 may deteriorate myocardial I/R injury by promoting neutrophil recruitment via the miR-138-5p/EGR1/TLR4/TRIF signaling. This pathway may represent a potential therapeutic target in the management of myocardial I/R injury.
Highlights
When acute myocardial infarction occurs, blood flow exhibits immediate restoration to the ischemic myocardium, resulting in cardiomyocyte death, known as myocardial ischemia/reperfusion (I/R) injury [1]
Sh-Early growth response 1 (EGR1) itself only downregulated the EGR1 expression without obvious effects on circ_SMG6 and miR-138-5p expression (Figure 3(j)). These results collectively indicated that circ_SMG6 negatively mediated miR-138-5p and promoted EGR1 expression, through which the circ_SMG6/miR-138-5p/ EGR1 axis confers a role in I/R injury
Myocardial I/R injury can greatly contribute to tissue injury, which eventually leads to morbidity and mortality in a variety of pathologies, such as myocardial infarction, acute kidney injury. and ischemic stroke [21]
Summary
When acute myocardial infarction occurs, blood flow exhibits immediate restoration to the ischemic myocardium, resulting in cardiomyocyte death, known as myocardial ischemia/reperfusion (I/R) injury [1]. Circular RNAs (circRNAs), endogenous transcripts expressed across species, developmental stages, and pathologies, have been implicated in multiple cardiovascular diseases, including I/R injury and myocardial infarction, rendering them the potential as therapeutic targets in these diseases [5]. Such a circRNA, circ_HIPK3 has been reported to induce apoptosis of cardiomyocytes and aggravates myocardial I/R injury [6]. This study is aimed at identifying the potential role of a novel circRNA circ_SMG6 in myocardial I/R injury. The RNA22 database predicted the presence of binding sites between circ_SMG6 and microRNA (miR)-
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