Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection.

Dominika Lukovic,Denise Traxler,Andreas Spannbauer,Rita Garamvölgyi,Katrin Zlabinger,Martin Riesenhuber,Alfred Gugerell,Örs Petnehazy,Zoltán Giricz,Mariann Gyöngyösi,Noemi Pavo,Tamás Baranyai,Rainer Schulz,Johannes Winkler,Péter Ferdinandy,Dietmar Pils,Levente Tóth,Zoltán V Varga,András Jakab

doi:10.3390/ijms20020344

Abstract

Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC (n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI.

Highlights

Since the first demonstration of cardioprotection in a postconditioned cat model, decades of intensive research have been devoted to the translation of ischaemic postconditioning (IPostC) to clinical settings [1]
Analysis of circulating biochemical markers demonstrated an effect of myocardial infarction (MI) and IPostC on the enzymatic release of myoglobin, an early marker of myocardial damage, and cardiac troponin I type 3, an indicator of acute myocardial injury with typical release within hours up to a few days after MI
MI with (p = 0.0243) and without (p = 0.0016) IPostC induced a significant release of myoglobin into the plasma compared to the control group at the 3-h follow-up, and increased serum cardiac troponin I type 3 (cTnI3) concentrations at the 3-day follow-up, without any differences among groups

Summary

Introduction

Since the first demonstration of cardioprotection in a postconditioned cat model, decades of intensive research have been devoted to the translation of ischaemic postconditioning (IPostC) to clinical settings [1]. Preclinical research on rodents argues in favor of IPostC-elicited cardioprotection manifesting improved outcomes of myocardial infarction (MI) [2,3]. Large animal models of IPostC have demonstrated varying success with regards to improvement in left ventricular function and reduced infarct size [4,5]. Recent clinical studies have reported heterogeneous outcomes when applying IPostC immediately after achieving reperfusion in primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) [6,7,8]. The discrepancies between preclinical models showing beneficial effects, and clinical trials failing to show meaningful cardioprotection, have been attributed to differences in study design, the assessment of cardioprotective effects (imaging or biochemical markers vs. clinical outcome), and heterogeneous study populations in clinical trials with an impact of co-morbidities and co-medications, anaesthetics [10]

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