title: Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9-36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression.
  
  
  METHODS
  Adult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9-36)amide or vehicle control for 4 weeks.
  
  
  RESULTS
  Infarct size was similar between groups with no effect of GLP-1(9-36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9-36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9-36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9-36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9-36)amide versus exendin-4.
  
  
  CONCLUSIONS
  These data suggest that GLP-1(9-36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.
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: 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: Samuel
authors.initials: S
authors.lastname: Lockhart
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: McPeake
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Karla M
authors.initials: KM
authors.lastname: O'Neill
authors.affiliation: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Edgar
authors.affiliation: School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, BT9 5HN, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Calderwood
authors.affiliation: School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, 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; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000627:therapeutic use*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014688:Venoms / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D019716:Tissue Inhibitor of Metalloproteinase-2; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Cardiac remodelling; GLP-1(9–36)amide; Glucagon-like peptide-1 (GLP-1); Myocardial infarction