1. Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling
- Author
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Zoltán Giricz, Derek J. Hausenloy, Abelina Zimba, David Lorant, Simon P. Hoerstrup, Andras Jakab, Rita Garamvölgyi, Márta Sárközy, Katharina Auer, Georg Goliasch, Gerald Maurer, Tamás Baranyai, Dominika Lukovic, Noemi Pavo, Maximilian Y. Emmert, Péter Ferdinandy, Dietmar Pils, Hendrik Jan Ankersmit, Johannes Winkler, Katrin Zlabinger, Mariann Gyöngyösi, University of Zurich, and Pavo, Noemi
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,Sus scrofa ,Ischemia ,610 Medicine & health ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Physical Conditioning, Animal ,Internal medicine ,medicine ,Animals ,Gene Regulatory Networks ,Myocardial infarction ,Ventricular remodeling ,STAT3 ,Neprilysin ,Cardioprotection ,1000 Multidisciplinary ,Multidisciplinary ,Ventricular Remodeling ,Clusterin ,biology ,business.industry ,Gene Expression Profiling ,Computational Biology ,High-Throughput Nucleotide Sequencing ,11359 Institute for Regenerative Medicine (IREM) ,medicine.disease ,10020 Clinic for Cardiac Surgery ,Disease Models, Animal ,STAT1 Transcription Factor ,030104 developmental biology ,10036 Medical Clinic ,Cardiology ,biology.protein ,business ,Signal Transduction - 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.
- Published
- 2017