miR-125 family regulates XIRP1 and FIH in response to myocardial infarction

Abstract

MicroRNAs (miRNAs) are powerful regulators of protein expression. Many play important roles in cardiac development and disease. While several miRNAs and targets have been well-characterized, the abundance of miRNAs and the numerous potential targets for each suggests that the vast majority of these interactions have yet to be described. The goal of this study was to characterize miRNA expression in the mouse heart after coronary artery ligation (LIG) and identify novel mRNA targets altered during the initial response to ischemic stress. We performed small RNA-sequencing of ischemic heart tissue 1 day and 3 days after ligation and identified 182 differentially expressed miRNAs. We then selected relevant mRNA targets from all potential targets by correlating miRNA and mRNA expression from a corresponding RNA-seq dataset. From this analysis we chose to focus, as proof of principle, on two miRNAs from the miR-125 family, miR-125a and miR-351, and two of their potential mRNA targets, Xin actin-binding repeat-containing protein 1 (XIRP1) and factor inhibiting HIF (FIH). We found miR-125a to be less abundant and XIRP1 more abundant after ligation. In contrast, the related murine miRNA miR-351 was substantially upregulated in response to ischemic injury and FIH expression correspondingly decreased. Luciferase reporter assays confirmed direct interactions between these miRNAs and targets. In summary, we utilized a correlative analysis strategy combining miRNA and mRNA expression data to identify functional miRNA-mRNA relationships in the heart after ligation. These findings provide insight into the response to ischemic injury and suggest future therapeutic targets.

The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor

“…The miR-125 family (178), miR-135a-5p (82,189), miR-214 (172) and miR-355 (180) negatively regulate FIH mRNA in the murine and rat heart and/or in cardiomyocytes. miRNAmediated reduction of FIH mRNA was protective against cardiac injury (82,172,180).…”

“…Studies analysing miRNA-dependent FIH regulation support that a decrease in FIH levels is protective against cardiac tissue injury in mice and rats (172,178,180). Overall, these results suggest that inhibition of FIH may be cardioprotective.…”