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Published in: Basic Research in Cardiology 1/2016

Open Access 01-01-2016 | Original Contribution

Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages

Authors: Mitchel Tate, Emma Robinson, Brian D. Green, Barbara J. McDermott, David J. Grieve

Published in: Basic Research in Cardiology | Issue 1/2016

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Abstract

In addition to its' established metabolic and cardioprotective effects, glucagon-like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP-1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4–12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80++ macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4-treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting.
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Metadata
Title
Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages
Authors
Mitchel Tate
Emma Robinson
Brian D. Green
Barbara J. McDermott
David J. Grieve
Publication date
01-01-2016
Publisher
Springer Berlin Heidelberg
Published in
Basic Research in Cardiology / Issue 1/2016
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-015-0518-1

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