Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling

Noemi Pavo, Dominika Lukovic, Katrin Zlabinger, Abelina Zimba, David Lorant, Georg Goliasch, Johannes Winkler, Dietmar Pils, Katharina Auer, Hendrik Jan Ankersmit, Zoltán Giricz, Tamas Baranyai, Márta Sárközy, András Jakab, Rita Garamvölgyi, Maximilian Y. Emmert, Simon P. Hoerstrup, Derek J. Hausenloy, Péter Ferdinandy, Gerald MaurerMariann Gyöngyösi

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Abstract

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.

Original languageEnglish
Article number43958
JournalScientific reports
Volume7
DOIs
Publication statusPublished - Mar 7 2017

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Pavo, N., Lukovic, D., Zlabinger, K., Zimba, A., Lorant, D., Goliasch, G., Winkler, J., Pils, D., Auer, K., Jan Ankersmit, H., Giricz, Z., Baranyai, T., Sárközy, M., Jakab, A., Garamvölgyi, R., Emmert, M. Y., Hoerstrup, S. P., Hausenloy, D. J., Ferdinandy, P., ... Gyöngyösi, M. (2017). Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling. Scientific reports, 7, [43958]. https://doi.org/10.1038/srep43958