Unknown,Transcriptomics,Genomics,Proteomics

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Differential Expression of microRNAs following activated protein C treatment in a rat model of septic shock

ABSTRACT: Sepsis induces systemic stress by augmenting inflammatory and pro-coagulant responses resulting in microvascular dysfunction and end organ failure, events modulated by the Protein C pathway. MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional regulation of gene transcription yet their role in sepsis remains poorly defined. We hypothesized that aPC selectively alters the expression of specific miRNAs implicated in protection of hepatic function during septic shock. Male Sprague-Dawley rats underwent sham surgery or cecal ligation and puncture (CLP). Twenty-four later, animals were randomized and treated with aPC (1mg/kg) or vehicle (0.9% (w/v) saline) via an indwelling venous catheter at 12 hour intervals for 24 hours. Gene array was performed on hepatic RNA to determine miRNA expression, and predicted mRNA targets determined using a bioinformatics approach. Of 351 rat miRNAs examined by microarray hybridization, 17 were highly expressed during sepsis and restored to basal levels after aPC treatment. In silico analysis identified 9 miRNAs significantly regulating target genes of the focal adhesion pathway. These data suggest aPC treatment coordinates beneficial cytoprotective effects during sepsis by modulating miRNA expression. While translational effects remain to be fully elucidated in a clinical setting, we demonstrate herein the potential experimental and computational benefits for use of microRNA analysis in sepsis. 12 samples were analyzed. Microarray experiments were performed, in which liver tissue was harvested from variuous groups (Sham+Vehicle, Sham+aPC, CLP+Vehicle, CLP+aPC; n=3/group) and pooled.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Cathy Moore

PROVIDER: E-GEOD-34790 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.

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Differential Expression of microRNAs following activated protein C treatment in a rat model of septic shock

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