title: Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice.
abstract: OBJECTIVE
  Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice.
  
  
  METHODS
  Apoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined.
  
  
  RESULTS
  Administration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation.
  
  
  CONCLUSIONS
  Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nagashima
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Terasaki
authors.forename: M
authors.initials: M
authors.lastname: Tomoyasu
authors.forename: K
authors.initials: K
authors.lastname: Nohtomi
authors.forename: J
authors.initials: J
authors.lastname: Kim-Kaneyama
authors.forename: A
authors.initials: A
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D054795:Incretins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D054795:Incretins; D010446:Peptide Fragments; D010455:Peptides; C101760:gastric inhibitory polypeptide (1-42); C515715:gastric inhibitory polypeptide (3-42); C114437:glucagon-like peptide-1 (9-36)-amide; C055453:glucagon-like peptide 1 (7-36)amide; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase