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Open Access 01-03-2015 | Original Contribution

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Authors: Emma Robinson, Roslyn S. Cassidy, Mitchel Tate, Youyou Zhao, Samuel Lockhart, Danielle Calderwood, Rachel Church, Mary K. McGahon, Derek P. Brazil, Barbara J. McDermott, Brian D. Green, David J. Grieve

Published in: Basic Research in Cardiology | Issue 2/2015

Abstract

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β₃) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.

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Title: Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
Authors: Emma Robinson
Roslyn S. Cassidy
Mitchel Tate
Youyou Zhao
Samuel Lockhart
Danielle Calderwood
Rachel Church
Mary K. McGahon
Derek P. Brazil
Barbara J. McDermott
Brian D. Green
David J. Grieve
Publication date: 01-03-2015
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 2/2015
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-015-0476-7

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Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

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