Abstract
BackgroundEndothelial dysfunction plays a critical role in the development of sepsis-related organ failure; however, the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways. We hypothesized that miRNA may play an etiologic role in the endothelial dysfunction of sepsis and that their extracellular expression levels would be altered in those with shock.MethodsThirteen miRNAs were identified by literature search and analysis of the contents of human EPC-derived exosomes using real-time PCR. Plasma samples were obtained from patients within 24 hours of their admission to ICUs with severe sepsis (n = 62) and from healthy controls (n = 32) and real-time PCR was used to measure the expression of the candidate miRNAs. The Wilcoxon rank sum test was used to compare expression levels of the 13 candidate miRNAs in septic patients with (n = 29) and without (n = 33) shock while logistic regression was used to determine the area under the curve for associations between miRNA expression and shock. Bioinformatic analyses using miRNA databases were performed to identify pathways and gene targets of differentially expressed miRNA with potential relevance to sepsis-related shock.ResultsMiRNA-34a expression was significantly increased in the group who developed shock (p = 0.03) while miR-15a and miR-27a expressions were significantly decreased in this group (p = 0.006 and 0.03, respectively). The combined expression of these three miRNAs predicted shock with an area under the curve of 0.78 (95 % CI 0.66–0.90). In silico analyses predict that these three miRNAs regulate genes involved in endothelial cell cycle, apoptosis, VEGF signaling, LPS-stimulated MAPK signaling, and nuclear factor kappa B signaling.ConclusionsThe plasma levels of miRNA are altered in patients with severe sepsis complicated by shock and may offer prognostic value as well as insights into the mechanisms of endothelial dysfunction in sepsis.
Highlights
Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; the mechanisms that govern its development are not fully understood
Subjects who experienced shock had no significant differences in their rates of mechanical ventilation, acute respiratory distress syndrome (ARDS), or acute kidney injury as well as intensive care unit (ICU) or hospital lengths of stay; they did have a nonsignificant trend toward higher acute physiology and chronic health evaluation (APACHE) II scores at enrollment and a significantly higher mortality rate
Altered plasma expression levels of miR-15a, -27a, and -34a are associated with the development of shock in patients with severe sepsis
Summary
Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways. Our previous work demonstrated that treatment of murine sepsis with human endothelial progenitor cells (EPCs) improves survival while attenuating vascular leak and its resultant organ failure [14]. Endothelial progenitor cells release exosomes that contain miRNAs known to promote the homeostasis and barrier integrity of endothelial cells [14,15,16,17] and may be a mechanism by which EPCs modulate sepsis-induced vascular leak. A deeper understanding of the role that endothelial-relevant miRNAs may play in the pathogenesis of endothelial dysfunction and shock is warranted
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