Research Papers:

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

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

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Oncotarget. 2017; 8:67227-67240. https://doi.org/10.18632/oncotarget.18438

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Noemi Pavo1, Dominika Lukovic1, Katrin Zlabinger1, David Lorant2, Georg Goliasch1, Johannes Winkler1, Dietmar Pils3,4, Katharina Auer5, Hendrik Jan Ankersmit4, Zoltán Giricz6, Márta Sárközy7, András Jakab8,9, Rita Garamvölgyi10, Maximilian Y. Emmert11,12,13, Simon P. Hoerstrup11,12,13, Derek J. Hausenloy14,15,16,17,18,19, Péter Ferdinandy6,20, Gerald Maurer1 and Mariann Gyöngyösi1

1Department of Cardiology, Medical University of Vienna, Vienna, Austria

2Department of Anaesthesiology, Medical University of Vienna, Vienna, Austria

3Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria

4Department of Surgery, Medical University of Vienna, Vienna, Austria

5Molecular Oncology Group, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

6Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary

7Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary

8Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria

9Center for MR-Research, University Children’s Hospital Zurich, Zurich, Switzerland

10Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Kaposvar, Hungary

11Swiss Centre for Regenerative Medicine, University of Zurich, Zurich, Switzerland

12Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland

13Clinic for Cardiovascular Surgery, University Hospital of Zurich, Zurich, Switzerland

14The Hatter Cardiovascular Institute, University College London, London, UK

15Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore

16National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore

17Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

18The National Institute of Health Research, University College London Hospitals Biomedical Research Centre, London, UK

19Barts Heart Centre, St Bartholomew’s Hospital, London, UK

20Pharmahungary Group, Szeged, Hungary

Correspondence to:

Mariann Gyöngyösi, email: [email protected]

Keywords: cardioprotection, gene expression, NOGA mapping, ischemia/reperfusion, LV remodelling

Received: March 17, 2017    Accepted: May 10, 2017    Published: June 12, 2017


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.

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