Abstract
BackgroundExosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock.MethodsBlood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array.ResultsAs compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold).ConclusionsExosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.
Highlights
Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress
Using TaqMan® Array Microfluidic Cards technology (Applied Biosystems/Thermo Fisher Scientific, Foster City, CA, USA) and qRT-PCR, we simultaneously evaluated 754 mature miRNAs (TaqMan MicroRNA Array v3.0; Life Technologies/Thermo Fisher Scientific, Grand Island, NY, USA) and 90 genes related to immune response (TaqMan Low Density Array Immune Profiling; Life Technologies/Thermo Fisher Scientific)
Differential miRNA expression in patients with sepsis according to outcomes To identify circulating miRNAs that could be related to clinical outcome, we further investigated the samples collected from patients with sepsis at Intensive care unit (ICU) admission and analyzed their miRNA expression according to hospital outcomes
Summary
Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Previous studies demonstrated that a special type of EV, named exosomes and mostly originated from platelets, induce superoxide production and apoptosis in vascular cells during sepsis by inflammatory and redox mechanisms [10, 11]. Our group established a correlation between exosomes and organ dysfunction by demonstrating exosome-induced myocardial depression in isolated heart and papillary muscle preparations. This dysfunction was mediated by a mechanism associated with myocardial nitric oxide production [12]
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