Septic-Induced microRNA Expression Modulations Are Linked to Angiogenesis, Vasomotion, and Hypoxia-Induced Processes

Abstract

Sepsis is an exaggerated immune reaction to an infection, which leads to organ dysfunction especially circulatory failure. This is based on cellular processes, which are regulated by post-transcriptional gene expression modulations including microRNAs (miRNAs). In order to elucidate the role miRNAs play in septic processes, monocytes and endothelial cells were grown in an inflammatory milieu. In addition, aortas from septic mice were investigated. Expression of miRNAs was analysed by both next generation sequencing (NGS) and NanoString technology, and miRNA targets were identified by in silico analysis. Clear alterations in miRNA expression profiles were found in monocytes, endothelial cells, and aortas exposed to septic conditions compared to the respective control. In silico analysis revealed several of the differentially expressed miRNAs to be involved in cellular response to hypoxia. In endothelial cells, for instance, miR-21-5p and miR-106b-5p emerged, which are known to interact with hypoxia inducible factor 1 alpha (HIF-1α), a major player in the process of angiogenesis. In line with this, in aortas expression changes were observed for miR-144-3p, which targets HIF-1α as well. Further validated target genes of differentially expressed miRNAs encompass the vascular endothelial growth factor receptor 1 (VEGFR1) and the vascular endothelial growth factor A (VEGFA), which represent essential mediators of angiogenesis. Moreover, several miRNAs impacting on genes encoding mediators of vasomotion were identified to be altered in their expression profiles in context of an inflammatory milieu. Altogether, the data indicate that miRNAs are an interesting starting point for functional and mechanistic sepsis research.