Integrative analysis of differentially expressed genes and miRNAs predicts complex T3-mediated protective circuits in a rat model of cardiac ischemia reperfusion

Francesca Forini,Stefano Doccini,Giuseppina Nicolini,Romina D’Aurizio,Claudia Kusmic,Milena Rizzo,Marco Groth,Mario Baumgart,Letizia Pitto,Giorgio Iervasi

doi:10.1038/s41598-018-32237-0

Abstract

Thyroid hormone (T3) dyshomeostasis in the cardiac ischemia-reperfusion (IR) setting negatively impacts on mitochondria function and extracellular matrix remodeling. The modulation of cardiac miRNAs may represent the underlying molecular mechanisms, but a systems biology perspective investigating this critical issue in depth is still lacking. A rat model of myocardial IR, with or without an early short-term T3-replacement, was used to predict putative T3-dependent miRNA-gene interactions targeted to mitochondria quality control and wound healing repair. As evidenced by mRNA and miRNA expression profiling, the T3 supplementation reverted the expression of 87 genes and 11 miRNAs that were dysregulated in the untreated group. In silico crossing and functional analysis of the T3-associated differentially expressed transcripts, identified a signature of interconnected miRNA-gene regulatory circuits that confer resistance to noxious cascades of acute stress. In this network the T3-down-regulated Tp53, Jun and Sp1 transcription factors emerge as critical nodes linking intrinsic cell death and oxidative stress pathways to adverse remodeling cascades. The data presented here provide a novel insight into the molecular basis of T3 cardioprotection in the early post-IR phase and highlight the contribution of a previously unappreciated complex T3-regulatory network that may be helpful in translating T3 replacement into clinical practice.

Highlights

Heart disease following acute myocardial infarction represents a serious health problem and a major cause of death worldwide
To better mimic a physiological condition with a view to a translational perspective, we evaluated the cardioprotective effects of a new T3 dose that was sufficient to correct the post ischemic low T3 state (lowT3S) without inducing other systemic changes, i.e. a T3 replacement dose
T3 supplementation did not result in alteration of body weight, heart rate, respiration rate or body temperature that remained comparable among groups (Table 1)

Summary

Introduction

Heart disease following acute myocardial infarction represents a serious health problem and a major cause of death worldwide. In patients with acute myocardial infarction (AMI) a condition of reduced T3 plasma level, known as low T3 state (lowT3S), represents a risk of cardiac disease progression and higher mortality[6,7] Along this line, increasing clinical and experimental findings prompt for a cardioprotective role of lowT3S correction through T3 administration in cardiac disease[8,9]. Since one single miRNA may affect the expression of several genes, as well as several miRNAs may target the same gene, to unravel the contribution of T3 to post ischemic signaling activation the integration of high throughput data is essential To our knowledge such studies have not been conducted on pre-clinical models of cardiac IR. To this aim we applied a systems biology approach to integrate miRNA and mRNA expression profiling analysis in rats subjected to cardiac IR with or without post-IR T3 replacement

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