Andrea Baehr1, Kfir Baruch Umansky2, Elad Bassat2, Victoria Jurisch1, Katharina Klett1, Tarik Bozoglu1, Nadja Hornaschewitz1, Olga Solyanik3, David Kain2, Bartolo Ferraro4, Renee Cohen-Rabbi2, Markus Krane5, Clemens Cyran3, Oliver Soehnlein4, Karl Ludwig Laugwitz1, Rabea Hinkel6, Christian Kupatt1, Eldad Tzahor2. 1. I. Medizinische Klinik & Poliklinik, University Clinic Rechts der Isar, Technical University Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance Munich, Germany. 2. The Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. 3. Department of Radiology, Klinikum Großhadern, LMU Munich, Germany. 4. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance Munich, Germany; Institute for Cardiovascular Prevention (IPEK), LMU Munich, Germany. 5. Department of Surgery, German Heart Center Munich, Germany. 6. I. Medizinische Klinik & Poliklinik, University Clinic Rechts der Isar, Technical University Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance Munich, Germany; Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Department of Laboratory Animal Science, Göttingen, Germany.
Abstract
Background: Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We previously reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Methods: To test the therapeutic potential of Agrin in a preclinical porcine model we performed ischemia reperfusion (I/R) injuries using balloon occlusion for 60 minutes followed by either 3, 7 or 28 days reperfusion period. Results: We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of recombinant human Agrin improved heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin's mechanisms of action. Conclusions: We show that 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.
Background: Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We previously reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Methods: To test the therapeutic potential of Agrin in a preclinical porcine model we performed ischemia reperfusion (I/R) injuries using balloon occlusion for 60 minutes followed by either 3, 7 or 28 days reperfusion period. Results: We first demonstrate that local (antegrade) delivery of recombinant humanAgrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of recombinant humanAgrin improved heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin's mechanisms of action. Conclusions: We show that 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.
Authors: Andreas Spannbauer; Julia Mester-Tonczar; Denise Traxler; Nina Kastner; Katrin Zlabinger; Ena Hašimbegović; Martin Riesenhuber; Noemi Pavo; Georg Goliasch; Mariann Gyöngyösi Journal: Biomolecules Date: 2020-09-29