Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair

Bartolo Ferraro; Giovanna Leoni; Rabea Hinkel; Steffen Ormanns; Nicole Paulin; Almudena Ortega-Gomez; Joana R. Viola; Renske de Jong; Dario Bongiovanni; Tarik Bozoglu; Sanne L. Maas; Michele D'Amico; Thorsten Kessler; Tanja Zeller; Michael Hristov; Chris Reutelingsperger; Hendrik B. Sager; Yvonne Doering; Matthias Nahrendorf; Christian Kupatt; Oliver Soehnlein

doi:10.1016/j.jacc.2019.03.503

Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair

Bartolo Ferraro, Giovanna Leoni, Rabea Hinkel, Steffen Ormanns, Nicole Paulin, Almudena Ortega-Gomez, Joana R. Viola, Renske de Jong, Dario Bongiovanni, Tarik Bozoglu, Sanne L. Maas, Michele D'Amico, Thorsten Kessler, Tanja Zeller, Michael Hristov, Chris Reutelingsperger, Hendrik B. Sager, Yvonne Doering, Matthias Nahrendorf, Christian KupattOliver Soehnlein^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 Cx(3)cr1cre(ERT2)Vegf(flox/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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Original language	English
Pages (from-to)	2990-3002
Number of pages	13
Journal	Journal of the American College of Cardiology
Volume	73
Issue number	23
DOIs	https://doi.org/10.1016/j.jacc.2019.03.503
Publication status	Published - 18 Jun 2019

Keywords

annexin A1
cardiac repair
inflammation
myocardial infarct
neovascularization
ANNEXIN A1
HEART
INFARCTION
PEPTIDE
INJURY
REPERFUSION
BALANCE

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Ferraro, B., Leoni, G., Hinkel, R., Ormanns, S., Paulin, N., Ortega-Gomez, A., Viola, J. R., de Jong, R., Bongiovanni, D., Bozoglu, T., Maas, S. L., D'Amico, M., Kessler, T., Zeller, T., Hristov, M., Reutelingsperger, C., Sager, H. B., Doering, Y., Nahrendorf, M., ... Soehnlein, O. (2019). Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair. Journal of the American College of Cardiology, 73(23), 2990-3002. https://doi.org/10.1016/j.jacc.2019.03.503

@article{0120532d00424a968f7a6a30a42300e2,

title = "Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair",

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 Cx(3)cr1cre(ERT2)Vegf(flox/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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.",

keywords = "annexin A1, cardiac repair, inflammation, myocardial infarct, neovascularization, ANNEXIN A1, HEART, INFARCTION, PEPTIDE, INJURY, REPERFUSION, BALANCE",

author = "Bartolo Ferraro and Giovanna Leoni and Rabea Hinkel and Steffen Ormanns and Nicole Paulin and Almudena Ortega-Gomez and Viola, {Joana R.} and {de Jong}, Renske and Dario Bongiovanni and Tarik Bozoglu and Maas, {Sanne L.} and Michele D'Amico and Thorsten Kessler and Tanja Zeller and Michael Hristov and Chris Reutelingsperger and Sager, {Hendrik B.} and Yvonne Doering and Matthias Nahrendorf and Christian Kupatt and Oliver Soehnlein",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jun,

day = "18",

doi = "10.1016/j.jacc.2019.03.503",

language = "English",

volume = "73",

pages = "2990--3002",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Science",

number = "23",

}

Ferraro, B, Leoni, G, Hinkel, R, Ormanns, S, Paulin, N, Ortega-Gomez, A, Viola, JR, de Jong, R, Bongiovanni, D, Bozoglu, T, Maas, SL, D'Amico, M, Kessler, T, Zeller, T, Hristov, M, Reutelingsperger, C, Sager, HB, Doering, Y, Nahrendorf, M, Kupatt, C & Soehnlein, O 2019, 'Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair', Journal of the American College of Cardiology, vol. 73, no. 23, pp. 2990-3002. https://doi.org/10.1016/j.jacc.2019.03.503

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 - Doering, Yvonne

AU - Nahrendorf, Matthias

AU - Kupatt, Christian

AU - Soehnlein, Oliver

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 Cx(3)cr1cre(ERT2)Vegf(flox/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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

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 Cx(3)cr1cre(ERT2)Vegf(flox/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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

KW - annexin A1

KW - cardiac repair

KW - inflammation

KW - myocardial infarct

KW - neovascularization

KW - ANNEXIN A1

KW - HEART

KW - INFARCTION

KW - PEPTIDE

KW - INJURY

KW - REPERFUSION

KW - BALANCE

U2 - 10.1016/j.jacc.2019.03.503

DO - 10.1016/j.jacc.2019.03.503

M3 - Article

C2 - 31196457

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 -