TY - JOUR
T1 - Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs
AU - Baehr, Andrea
AU - Umansky, Kfir Baruch
AU - Bassat, Elad
AU - Jurisch, Victoria
AU - Klett, Katharina
AU - Bozoglu, Tarik
AU - Hornaschewitz, Nadja
AU - Solyanik, Olga
AU - Kain, David
AU - Ferraro, Bartolo
AU - Cohen-Rabi, Renee
AU - Krane, Markus
AU - Cyran, Clemens
AU - Soehnlein, Oliver
AU - Laugwitz, Karl Ludwig
AU - Hinkel, Rabea
AU - Kupatt, Christian
AU - Tzahor, Eldad
N1 - The authors thank laboratory members E.T. and C.K.; O. Goresh and B. Siani for animal husbandry; and R. Levine, S. Goldsmith, C. Raanan, and M. Osin for histology. Dr Baehr, Dr Hinkel, Dr Klett, Dr Hornaschewitz, Dr Krane, and Dr Umansky performed the pig experiments under the guidance of Dr Kupatt and Dr Laugwitz. V. Jurisch, Dr Hornaschewitz, Dr Klett, Dr Ferraro, Dr Solyanik, and Dr Bozoglu performed the histologic analysis of the pig experiments. Dr Solyanik performed the magnetic resonance imaging analysis under the guidance of Dr Cyran. Dr Bassat, Dr Umansky, R. Cohen-Rabi, and Dr Kain performed the mouse in vivo experiments under the guidance of Dr Tzahor, who also conceived this project. Dr Tzahor, Dr Kupatt, and Dr Umansky wrote the article. This work was supported by grants to Dr Tzahor from the European Research Council (ERC StG 281289, CM turnover, by the European Union’s Horizon 2020 research and innovation program, and ERC AdG 788194, CardHeal), the Britain-Israel Research and Academic Exchange, Foundation LeDucq Transatlantic Network of Excellence, the Israel Science Foundation, and the Israel Ministry of Science & Technology. Dr Kupatt received funds from the Federal Ministry of Education and Research (Deutsches Zentrum für Herz-Kreislauf-Forschung EV large animal platform), the Deutsche Forschungsgemeinschaft (Transregional Program SFB 267), and the Else-Kröner-Fresenius Foundation.
PY - 2020/9
Y1 - 2020/9
N2 - Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia-reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin's mechanisms of action. Conclusions: A single dose of agrin is capable of reducing ischemia-reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.
AB - Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia-reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin's mechanisms of action. Conclusions: A single dose of agrin is capable of reducing ischemia-reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.
U2 - https://doi.org/10.1161/CIRCULATIONAHA.119.045116
DO - https://doi.org/10.1161/CIRCULATIONAHA.119.045116
M3 - مقالة
C2 - 32508131
SN - 0009-7322
VL - 142
SP - 868
EP - 881
JO - Circulation
JF - Circulation
IS - 9
ER -