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Front Physiol. 2019 Oct 31;10:1370. doi: 10.3389/fphys.2019.01370. eCollection 2019.

A Dynamic Transcriptional Analysis Reveals IL-6 Axis as a Prominent Mediator of Surgical Acute Response in Non-ischemic Mouse Heart.

Author information

1
INSERM 1060, INRA 1397, INSA Lyon, CarMeN Laboratory, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
2
IHU OPeRa, Groupement Hospitalier EST, Bron, France.
3
Laboratory of Experimental and Clinical Pharmacology, Department of Chemistry and Biochemistry, Doctoral School of Sciences and Technology, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
4
ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, University of Lyon, Lyon, France.
5
Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.

Abstract

Background:

Ischemic heart diseases are a major cause of death worldwide. Different animal models, including cardiac surgery, have been developed over time. Unfortunately, the surgery models have been reported to trigger an important inflammatory response that might be an effect modifier, where involved molecular processes have not been fully elucidated yet.

Objective:

We sought to perform a thorough characterization of the sham effect in the myocardium and identify the interfering inflammatory reaction in order to avoid misinterpretation of the data via systems biology approaches.

Methods and Results:

We combined a comprehensive analytical pipeline of mRNAseq dataset and systems biology analysis to characterize the acute phase response of mouse myocardium at 0 min, 45 min, and 24 h after surgery to better characterize the molecular processes inadvertently induced in sham animals. Our analysis showed that the surgical intervention induced 1209 differentially expressed transcripts (DETs). The clustering of positively co-regulated transcript modules at 45 min fingerprinted the activation of signalization pathways, while positively co-regulated genes at 24 h identified the recruitment of neutrophils and the differentiation of macrophages. In addition, we combined the prediction of transcription factors (TF) regulating DETs with protein-protein interaction networks built from these TFs to predict the molecular network which have induced the DETs. By mean of this retro-analysis of processes upstream gene transcription, we revealed a major role of the Il-6 pathway and further confirmed a significant increase in circulating IL-6 at 45 min after surgery.

Conclusion:

This study suggests that a strong induction of the IL-6 axis occurs in sham animals over the first 24 h and leads to the induction of inflammation and tissues' homeostasis processes.

KEYWORDS:

heart damage; inflammation; interleukin 6; kinetical analysis; transcriptomics

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