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

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-myocar...

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Autores principales: Robinson, Emma, Cassidy, Roslyn S., Tate, Mitchel, Zhao, Youyou, Lockhart, Samuel, Calderwood, Danielle, Church, Rachel, McGahon, Mary K., Brazil, Derek P., McDermott, Barbara J., Green, Brian D., Grieve, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344953/
https://www.ncbi.nlm.nih.gov/pubmed/25725809
http://dx.doi.org/10.1007/s00395-015-0476-7
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author Robinson, Emma
Cassidy, Roslyn S.
Tate, Mitchel
Zhao, Youyou
Lockhart, Samuel
Calderwood, Danielle
Church, Rachel
McGahon, Mary K.
Brazil, Derek P.
McDermott, Barbara J.
Green, Brian D.
Grieve, David J.
author_facet Robinson, Emma
Cassidy, Roslyn S.
Tate, Mitchel
Zhao, Youyou
Lockhart, Samuel
Calderwood, Danielle
Church, Rachel
McGahon, Mary K.
Brazil, Derek P.
McDermott, Barbara J.
Green, Brian D.
Grieve, David J.
author_sort Robinson, Emma
collection PubMed
description 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-β(3)) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-015-0476-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-43449532015-03-04 Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix Robinson, Emma Cassidy, Roslyn S. Tate, Mitchel Zhao, Youyou Lockhart, Samuel Calderwood, Danielle Church, Rachel McGahon, Mary K. Brazil, Derek P. McDermott, Barbara J. Green, Brian D. Grieve, David J. Basic Res Cardiol Original Contribution 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-β(3)) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-015-0476-7) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-03-01 2015 /pmc/articles/PMC4344953/ /pubmed/25725809 http://dx.doi.org/10.1007/s00395-015-0476-7 Text en © The Author(s) 2015 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Contribution
Robinson, Emma
Cassidy, Roslyn S.
Tate, Mitchel
Zhao, Youyou
Lockhart, Samuel
Calderwood, Danielle
Church, Rachel
McGahon, Mary K.
Brazil, Derek P.
McDermott, Barbara J.
Green, Brian D.
Grieve, David J.
Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title_full Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title_fullStr Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title_full_unstemmed Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title_short Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
title_sort exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix
topic Original Contribution
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344953/
https://www.ncbi.nlm.nih.gov/pubmed/25725809
http://dx.doi.org/10.1007/s00395-015-0476-7
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