title: Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages.
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.
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Mitchel
authors.initials: M
authors.lastname: Tate
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Robinson
authors.affiliation: Institute for Global Food Security, School of Biological Sciences, Belfast, BT9 5HN, UK.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McDermott
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK. d.grieve@qub.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Grieve
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D000077270:Exenatide; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: Cardiac remodelling; Experimental diabetes; Extracellular matrix; Glucagon-like peptide-1; Inflammation