title: Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe⁻/⁻ mice.
abstract: BACKGROUND
  [corrected] Glucagon-like peptide-1 (GLP-1) based therapies are new treatment options for patients with type 2 diabetes. Recent reports suggest vasoprotective actions of GLP-1. Similar beneficial effects might be reached by GLP-1(9-37) and the c-terminal GLP-1 split product (28-37) although both peptides do not activate the GLP-1 receptor. We therefore investigated the actions of GLP-1(7-37), GLP-1(9-37) as well as GLP-1(28-37) on vascular lesion formation in a mouse model of atherosclerosis.
  
  
  RESULTS
  GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) and LacZ (control) were overexpressed for a period of 12 weeks in apoe(-/-) mice on high-fat diet (n = 10/group) using an adeno-associated viral vector system. Neither of the constructs changed overall lesion size. However, GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) significantly reduced plaque macrophage infiltration (GLP-1(7-37): 40.6%, GLP-1(9-37): 47.0%, GLP-1(28-37): 40.1% decrease, p < 0.05) and plaque MMP-9 expression (GLP-1(7-37): 41.6%, GLP-1(9-37): 50.2%, GLP-1(28-37): 44.0% decrease, p < 0.05) compared to LacZ in the aortic arch. Moreover, all GLP-1 constructs increased plaque collagen content (GLP-1(7-37): 49.3%, GLP-1(9-37): 86.0%, GLP-1(28-37): 81.9% increase, p < 0.05) and increased fibrous cap thickness (GLP-1(7-37): 188.0%, GLP-1(9-37): 179.9% GLP-1(28-37): 111.0% increase, p < 0.05). These effects of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) on plaque macrophage infiltration, MMP-9 expression and plaque collagen content were confirmed in the aortic root.
  
  
  CONCLUSIONS
  GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) reduce plaque inflammation and increase phenotypic characteristics of plaque stability in a murine model of atherosclerosis. Future studies are needed to determine whether these effects translate into improved plaque stability and less cardiovascular events in high-risk patients with type 2 diabetes.
authors.affiliation: Department of Internal Medicine I, University Hospital of the RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Burgmaier
authors.forename: Ana
authors.initials: A
authors.lastname: Liberman
authors.forename: Julia
authors.initials: J
authors.lastname: Möllmann
authors.forename: Florian
authors.initials: F
authors.lastname: Kahles
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reith
authors.forename: Corinna
authors.initials: C
authors.lastname: Lebherz
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.forename: Michael
authors.initials: M
authors.lastname: Lehrke
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D054795:Incretins / Q000378:metabolism; D007249:Inflammation; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000235:genetics; D019076:Transgenes
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D054795:Incretins; D008055:Lipids; D010446:Peptide Fragments; D052216:Glucagon-Like Peptide 1; D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Atherosclerosis; GLP-1; Incretins; Plaque stability; Type 2 diabetes