Proteomic footprint of myocardial ischemia/reperfusion injury: Longitudinal study of the at-risk and remote regions in the pig model

Aleksandra Binek,Jesús Vázquez,Carlos Galán-Arriola,Juan Antonio López,Inmaculada Jorge,Borja Ibanez,Jaume Agüero,Emilio Camafeita,Andres Pun,Rodrigo Fernández-Jiménez,Valentin Fuster,Navratan Bagwan

doi:10.1038/s41598-017-11985-5

Abstract

Reperfusion alters post-myocardial infarction (MI) healing; however, very few systematic studies report the early molecular changes following ischemia/reperfusion (I/R). Alterations in the remote myocardium have also been neglected, disregarding its contribution to post-MI heart failure (HF) development. This study characterizes protein dynamics and contractile abnormalities in the ischemic and remote myocardium during one week after MI. Closed-chest 40 min I/R was performed in 20 pigs sacrificed at 120 min, 24 hours, 4days, and 7days after reperfusion (n = 5 per group). Myocardial contractility was followed up by cardiac magnetic resonance (CMR) and tissue samples were analyzed by multiplexed quantitative proteomics. At early reperfusion (120 min), the ischemic area showed a coordinated upregulation of inflammatory processes, whereas interstitial proteins, angiogenesis and cardio-renal signaling processes increased at later reperfusion (day 4 and 7). Remote myocardium showed decreased contractility at 120 min- and 24 h-CMR accompanied by transient alterations in contractile and mitochondrial proteins. Subsequent recovery of regional contractility was associated with edema formation on CMR and increases in inflammation and wound healing proteins on post-MI day 7. Our results establish for the first time the altered protein signatures in the ischemic and remote myocardium early after I/R and might have implications for new therapeutic targets to improve early post-MI remodeling.

Highlights

Reperfusion alters post-myocardial infarction (MI) healing; very few systematic studies report the early molecular changes following ischemia/reperfusion (I/R)
The remote myocardium showed a significant transitory alteration in regional myocardial function, with systolic wall thickening (SWT) significantly reduced at 120 min and 24 h, and recovering to baseline values at day 7 post-reperfusion
The SWT time course in the ischemic and remote myocardium is shown in Fig. 2, together with a representative bullseye display of SWT of one pig at all time-points evaluated

Summary

Introduction

Reperfusion alters post-myocardial infarction (MI) healing; very few systematic studies report the early molecular changes following ischemia/reperfusion (I/R). Reperfusion is known to alter post-MI myocardial healing[9,10], to date there have been no systematic studies on the molecular changes occurring in the post-reperfused myocardium at early stages after I/R. The molecular alterations taking place in the remote myocardium at early post-MI stages are poorly understood. This lack of knowledge is important because the remote myocardium plays an important role in the development of maladaptive LV remodeling and subsequent HF after MI16,17. The precise molecular and cellular events taking place during these highly dynamic early post-I/R phases remain largely unknown

Methods

Results

Conclusion