TY - JOUR
T1 - Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair
AU - Ferraro, Bartolo
AU - Leoni, Giovanna
AU - Hinkel, Rabea
AU - Ormanns, Steffen
AU - Paulin, Nicole
AU - Ortega-Gomez, Almudena
AU - Viola, Joana R.
AU - de Jong, Renske
AU - Bongiovanni, Dario
AU - Bozoglu, Tarik
AU - Maas, Sanne L.
AU - D'Amico, Michele
AU - Kessler, Thorsten
AU - Zeller, Tanja
AU - Hristov, Michael
AU - Reutelingsperger, Chris
AU - Sager, Hendrik B.
AU - Döring, Yvonne
AU - Nahrendorf, Matthias
AU - Kupatt, Christian
AU - Soehnlein, Oliver
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/6/18
Y1 - 2019/6/18
N2 - 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.
AB - 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.
KW - annexin A1
KW - cardiac repair
KW - inflammation
KW - myocardial infarct
KW - neovascularization
UR - http://www.scopus.com/inward/record.url?scp=85066267336&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2019.03.503
DO - 10.1016/j.jacc.2019.03.503
M3 - Article
C2 - 31196457
AN - SCOPUS:85066267336
SN - 0735-1097
VL - 73
SP - 2990
EP - 3002
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 23
ER -