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

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• 作者：Mitchel Tate ; Emma Robinson ; Brian D. Green…
• 关键词：Glucagon ; like peptide ; 1 ; Experimental diabetes ; Cardiac remodelling ; Extracellular matrix ; Inflammation
• 刊名：Basic Research in Cardiology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：111
• 期：1
• 全文大小：6,245 KB
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• 作者单位：Mitchel Tate (1)
  Emma Robinson (1)
  Brian D. Green (2)
  Barbara J. McDermott (1)
  David J. Grieve (1)
  
  1. Wellcome-Wolfson Institute for Experimental Medicine, Queen鈥檚 University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
  2. Institute for Global Food Security, School of Biological Sciences, Belfast, BT9 5HN, UK
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1435-1803

文摘

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鈥?2 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. Keywords Glucagon-like peptide-1 Experimental diabetes Cardiac remodelling Extracellular matrix Inflammation