title: Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling.
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.
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Noemi
authors.initials: N
authors.lastname: Pavo
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dominika
authors.initials: D
authors.lastname: Lukovic
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Zlabinger
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Abelina
authors.initials: A
authors.lastname: Zimba
authors.affiliation: Department of Anaesthesiology, Medical University of Vienna, Vienna, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Lorant
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Goliasch
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna, Austria.|CeMSIIS - Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pils
authors.affiliation: Department of Obstretrics and Gynecology - Molecular Oncology Group, Medical University of Vienna, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Auer
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Jan Ankersmit
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Baranyai
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Sárközy
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
authors.forename: András
authors.initials: A
authors.lastname: Jakab
authors.affiliation: Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Kaposvar, Hungary.
authors.forename: Rita
authors.initials: R
authors.lastname: Garamvölgyi
authors.affiliation: Swiss Centre for Regenerative Medicine, University of Zurich, Zurich, Switzerland.|Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland.|Clinic for Cardiovascular Surgery, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Maximilian Y
authors.initials: MY
authors.lastname: Emmert
authors.affiliation: Swiss Centre for Regenerative Medicine, University of Zurich, Zurich, Switzerland.|Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland.|Clinic for Cardiovascular Surgery, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.|Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.|Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.|Pharmahungary Group, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Maurer
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Mariann
authors.initials: M
authors.lastname: Gyöngyösi
mesh_terms: D000818:Animals; D019295:Computational Biology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D007511:Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D015260:Neprilysin / Q000096:biosynthesis; D010805:Physical Conditioning, Animal / Q000379:methods*; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D034421:Sus scrofa; D020257:Ventricular Remodeling
chemical_list: D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015260:Neprilysin