Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning.

Alex Gallinat,Gemma Vilahur,Lina Badimon,Teresa Padró

doi:10.3390/ijms23042087

Abstract

Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by post-conditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria.

Highlights

Despite a drop in mortality of acute myocardial infarction (AMI) in the past decades due to the application of primary percutaneous coronary intervention (PPCI) [1,2], AMI survivors are at high risk of developing heart failure (HF) [3,4], which is a cause of a high morbidity and mortality worldwide [5] and of huge global burden on healthcare and economic resources [6]
The proteomic characterization of the myocardium at risk revealed at least 26 mitochondrial proteins to be differentially regulated as a result of ischemia, revascularization, and post-conditioning in the swine heart (Supplemental Table S1)
Our systems biology analysis results collectively highlight a dual role for post-conditioning both for promoting metabolic reprogramming and a protective response potentially mediated by VDAC2 and DJ-1 in the mitochondria

Summary

Introduction

Despite a drop in mortality of acute myocardial infarction (AMI) in the past decades due to the application of primary percutaneous coronary intervention (PPCI) [1,2], AMI survivors are at high risk of developing heart failure (HF) [3,4], which is a cause of a high morbidity and mortality worldwide [5] and of huge global burden on healthcare and economic resources [6]. AMI is an ischemic event caused by the sudden interruption of coronary blood supply to the myocardium. Infarct size is the major predictor of AMI clinical outcomes [9,10]. The early and successful restoration of coronary blood flow by PPCI is the most effective strategy to limit infarct size. This process that occurs within the very first minutes of reflow paradoxically has the potential to exacerbate damage and accounts for a significant part of the final infarct size [11,12]. A better understanding of the mechanisms at play in the ischemic myocardium is needed in order to both explore novel cardioprotective strategies and to improve translation

Methods

Results

Discussion

Conclusion