Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion

// Noemi Pavo 1 , Dominika Lukovic 1 , Katrin Zlabinger 1 , David Lorant 2 , Georg Goliasch 1 , Johannes Winkler 1 , Dietmar Pils 3, 4 , Katharina Auer 5 , Hendrik Jan Ankersmit 4 , Zoltan Giricz 6 , Marta Sarkozy 7 , Andras Jakab 8, 9 , Rita Garamvolgyi 10 , Maximilian Y. Emmert 11, 12, 13 , Simon P. Hoerstrup 11, 12, 13 , Derek J. Hausenloy 14, 15, 16, 17, 18, 19 , Peter Ferdinandy 6, 20 , Gerald Maurer 1 and Mariann Gyongyosi 1 1 Department of Cardiology, Medical University of Vienna, Vienna, Austria 2 Department of Anaesthesiology, Medical University of Vienna, Vienna, Austria 3 Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria 4 Department of Surgery, Medical University of Vienna, Vienna, Austria 5 Molecular Oncology Group, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria 6 Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary 7 Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary 8 Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria 9 Center for MR-Research, University Children’s Hospital Zurich, Zurich, Switzerland 10 Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Kaposvar, Hungary 11 Swiss Centre for Regenerative Medicine, University of Zurich, Zurich, Switzerland 12 Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland 13 Clinic for Cardiovascular Surgery, University Hospital of Zurich, Zurich, Switzerland 14 The Hatter Cardiovascular Institute, University College London, London, UK 15 Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore 16 National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore 17 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 18 The National Institute of Health Research, University College London Hospitals Biomedical Research Centre, London, UK 19 Barts Heart Centre, St Bartholomew’s Hospital, London, UK 20 Pharmahungary Group, Szeged, Hungary Correspondence to: Mariann Gyongyosi, email: mariann.gyongyosi@meduniwien.ac.at Keywords: cardioprotection, gene expression, NOGA mapping, ischemia/reperfusion, LV remodelling Received: March 17, 2017     Accepted: May 10, 2017     Published: June 12, 2017 ABSTRACT We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium.