Thromb Haemost 2020; 120(01): 168-180
DOI: 10.1055/s-0039-3400299
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3

Alexander Akhmedov*
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Fabrizio Montecucco*
4  First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
5  IRCCS Ospedale Policlinico San Martino Genoa–Italian Cardiovascular Network, Genoa, Italy
,
Sarah Costantino
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Daria Vdovenko
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Ariane Schaub Clerigué
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Daniel S. Gaul
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Fabienne Burger
6  Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Aline Roth
6  Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Federico Carbone
4  First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
,
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Mohammad Amrollahi-Sharifabadi
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
,
Valerio Gaetano Vellone
7  Division of Pathology, Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Genoa, Italy
8  Pathology Academic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
,
Urs Eriksson
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
9  GZO Regional Health Center, Wetzikon, Switzerland
,
Christian M. Matter
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Lindsey A. Crowe
10  Division of Radiology, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland
,
Jean-Paul Vallée
10  Division of Radiology, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland
,
Francesco Paneni
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Paul M. Vanhoutte
11  Department of Pharmacology, Hong Kong University, Hong Kong, Peoples Republic of China
,
Giovanni G. Camici
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
3  Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
François Mach*
6  Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Thomas F. Lüscher*
1  Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
2  Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
12  Royal Brompton and Harefield Hospitals, Imperial College London, London, United Kingdom
› Author Affiliations
Funding This research was funded by the Swiss National Science Foundation (Grant #310030–135815 to T.F.L.; Grant #310030–118245 to F.M.; Grant #32003B-134963/1 to F.M.; Grant #310030–1659 and #310030–165990 to C.M.M., and Grant #310030_175546 to G.G.C.), the Swiss Heart Foundation (to F.P.), the Holcim Stiftung (to S.C.), the Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and Oncology (to G.G.C.), and the Foundation for Cardiovascular Research – Zurich Heart House (to A.A. and G.G.C.), Zurich, Switzerland. This work was supported in part by the Centre for Biomedical Imaging (CIBM) of EPFL, University of Geneva and the University Hospitals of Geneva and Lausanne, and the Swiss National Science Foundation for its financial support for the PRISMA MRI (R'Equip grants: SNF No. 326030–150816). G.G.C. and F.P. are the recipient of a Sheikh Khalifa's Foundation Assistant Professorship at the Faculty of Medicine, University of Zurich. The study was supported by a grant from the Italian Cardiovascular Network of the Italian ministry of Health to F.M.
Further Information

Publication History

02 July 2019

18 September 2019

Publication Date:
13 December 2019 (online)

Abstract

Ischemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac JunD messenger ribonucleic acid expression was reduced while JunB increased. Cardiac-specific JunD overexpressing mice (JunDTg/0 ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.

* These authors contributed equally to this work.


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