Author + information
- Received November 4, 2018
- Revision received March 12, 2019
- Accepted March 19, 2019
- Published online June 10, 2019.
- Bartolo Ferraro, PhDa,b,∗,
- Giovanna Leoni, PhDa,b,∗,
- Rabea Hinkel, DVMb,c,d,
- Steffen Ormanns, MDe,
- Nicole Paulin, DVMa,b,
- Almudena Ortega-Gomez, PhDa,b,
- Joana R. Viola, PhDa,b,
- Renske de Jong, PhDa,
- Dario Bongiovanni, MDb,c,
- Tarik Bozoglu, PhDc,
- Sanne L. Maas, MSca,b,
- Michele D’Amico, PhDf,
- Thorsten Kessler, MDb,g,
- Tanja Zeller, PhDh,i,
- Michael Hristov, MDa,
- Chris Reutelingsperger, PhDj,
- Hendrik B. Sager, MDb,g,
- Yvonne Döring, PhDa,b,
- Matthias Nahrendorf, MDk,
- Christian Kupatt, MDb,c and
- Oliver Soehnlein, MD, PhDa,b,l,∗ (, )@LMU_Muenchen
- aInstitute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität Munich, Munich, Germany
- bDeutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany
- cMedizinische Klinik I, TU Munich, Germany
- dDeutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Department of Laboratory Animal Science, Göttingen, Germany
- eInstitute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
- fDepartment of Experimental Medicine, University of Campania, Campania, Italy
- gDepartment of Cardiology, German Heart Center Munich, Munich, Germany
- hDZHK, Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany
- iClinic for Cardiology, University Heart Center, Hamburg, Germany
- jDepartment of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands
- kCenter for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- lDepartment of Physiology and Pharmacology (FyFa) and Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- ↵∗Address for correspondence
: Dr. Oliver Soehnlein, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstr. 9, 80336 Munich, Germany.
Background Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration.
Objectives This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.
Methods AnxA1 knockout (AnxA1−/−) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.
Results AnxA1−/− mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1−/− mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)–A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx3cr1creERT2Vegfflox/flox or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.
Conclusions AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.
↵∗ Drs. Ferraro and Leoni contributed equally to this work.
The authors’ research is supported by the Deutsche Forschungsgemeinschaft (SFB914 TP B08, SFB1123 TP A06 and B05, SO876/6-1, SO876/11-1, SA 1668/5-1), the German Centre for Cardiovascular Research, the Fritz Thyssen foundation, the Vetenskapsrådet (2017-01762), Deutsche Herzstiftung (F/28/17), the Else-Kröner-Fresenius Stiftung, European Research Council (STRATO 759272), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 675111, and the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7/2007-2013) under REA grant agreement n° 608765. Dr. Nahrendorf has served as a consultant for Verseau, IFM Therapeutics, and Sigilon; and has received research support from Behring, Medtronic, Novartis, and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received November 4, 2018.
- Revision received March 12, 2019.
- Accepted March 19, 2019.
- 2019 The Authors