Bartolo Ferraro1, Giovanna Leoni1, Rabea Hinkel2, Steffen Ormanns3, Nicole Paulin1, Almudena Ortega-Gomez1, Joana R Viola1, Renske de Jong4, Dario Bongiovanni5, Tarik Bozoglu6, Sanne L Maas1, Michele D'Amico7, Thorsten Kessler8, Tanja Zeller9, Michael Hristov4, Chris Reutelingsperger10, Hendrik B Sager8, Yvonne Döring1, Matthias Nahrendorf11, Christian Kupatt5, Oliver Soehnlein12. 1. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany. 2. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany; Medizinische Klinik I, TU Munich, Germany; Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Department of Laboratory Animal Science, Göttingen, Germany. 3. Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. 4. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität Munich, Munich, Germany. 5. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany; Medizinische Klinik I, TU Munich, Germany. 6. Medizinische Klinik I, TU Munich, Germany. 7. Department of Experimental Medicine, University of Campania, Campania, Italy. 8. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany; Department of Cardiology, German Heart Center Munich, Munich, Germany. 9. DZHK, Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany; Clinic for Cardiology, University Heart Center, Hamburg, Germany. 10. Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands. 11. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 12. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany; Department of Physiology and Pharmacology (FyFa) and Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: oliver.soehnlein@gmail.com.
Abstract
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.
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.
Authors: Kyle I Mentkowski; Asma Mursleen; Jonathan D Snitzer; Lindsey M Euscher; Jennifer K Lang Journal: Am J Physiol Heart Circ Physiol Date: 2020-04-24 Impact factor: 4.733