期刊
CIRCULATION
卷 142, 期 9, 页码 868-881出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.119.045116
关键词
agrin; heart failure; myocardial infarction
资金
- European Research Council (ERC StG) [281289]
- European Union
- ERC [AdG 788194]
- Britain-Israel Research and Academic Exchange, Foundation LeDucq Transatlantic Network of Excellence
- Israel Science Foundation
- Israel Ministry of Science Technology
- Federal Ministry of Education and Research (Deutsches Zentrum fur Herz-Kreislauf-Forschung EV large animal platform)
- Deutsche Forschungsgemeinschaft [SFB 267]
- Else-Kroner-Fresenius Foundation
- European Research Council (ERC) [281289] Funding Source: European Research Council (ERC)
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.
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