Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs

Author:

Baehr Andrea12,Umansky Kfir Baruch3,Bassat Elad3,Jurisch Victoria12,Klett Katharina12,Bozoglu Tarik12ORCID,Hornaschewitz Nadja12,Solyanik Olga4,Kain David3,Ferraro Bartolo5,Cohen-Rabi Renee3,Krane Markus6,Cyran Clemens4,Soehnlein Oliver25,Laugwitz Karl Ludwig12,Hinkel Rabea127,Kupatt Christian12,Tzahor Eldad3ORCID

Affiliation:

1. I Medizinische Klinik & Poliklinik, University Clinic Rechts der Isar, Technical University Munich, Germany (A.B., V.J., K.K., T.B., N.H., K.L.L., R.H., C.K.).

2. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (A.B., V.J., K.K., T.B., N.H., B.F., O.S., K.L.L., R.H., C.K.).

3. The Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel (K.B.U., E.B., D.K., R.C.-R., E.T.).

4. Department of Radiology, Klinikum Großhadern (O.S., C.C.), LMU Munich, Germany.

5. Institute for Cardiovascular Prevention (B.F., O.S.), LMU Munich, Germany.

6. Department of Surgery, German Heart Center Munich, Germany (M.K.).

7. Department of Laboratory Animal Science, Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Göttingen, Germany (R.H.).

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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