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Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice

Aims/hypothesis 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 developme... Full description

Journal Title: Diabetologia 2011-07-24, Vol.54 (10), p.2649-2659
Main Author: Nagashima, M
Other Authors: Watanabe, T , Terasaki, M , Tomoyasu, M , Nohtomi, K , Kim-Kaneyama, J , Miyazaki, A , Hirano, T
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer-Verlag
ID: ISSN: 0012-186X
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recordid: cdi_gale_infotracacademiconefile_A266466446
title: Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
format: Article
creator:
  • Nagashima, M
  • Watanabe, T
  • Terasaki, M
  • Tomoyasu, M
  • Nohtomi, K
  • Kim-Kaneyama, J
  • Miyazaki, A
  • Hirano, T
subjects:
  • Acetyl-CoA C-Acetyltransferase - metabolism
  • Animals
  • Apolipoproteins
  • Apolipoproteins E - genetics
  • Apolipoproteins E - metabolism
  • Article
  • Atherosclerosis
  • Atherosclerosis (general aspects, experimental research)
  • Atherosclerosis - drug therapy
  • Atherosclerosis - metabolism
  • Atherosclerosis - pathology
  • Biological and medical sciences
  • Blood and lymphatic vessels
  • Blotting, Western
  • Cardiology. Vascular system
  • CD36 Antigens - metabolism
  • Cell Line
  • Cells, Cultured
  • Cholesterol
  • dependent insulinotropic polypeptide
  • Diabetes
  • Diabetes. Impaired glucose tolerance
  • Dipeptidyl peptidase
  • Dipeptidyl peptidase-4
  • Endocrine pancreas. Apud cells (diseases)
  • endocrine system
  • Endocrinology
  • Endocrinopathies
  • Etiopathogenesis. Screening. Investigations. Target tissue resistance
  • Foam Cells - cytology
  • Foam Cells - drug effects
  • Gastric Inhibitory Polypeptide - pharmacology
  • Gene expression
  • Glucagon
  • Glucagon-Like Peptide 1 - analogs & derivatives
  • Glucagon-Like Peptide 1 - pharmacology
  • Glucagon-like peptide-1
  • Glucose
  • Glucose-dependent insulinotropic polypeptide
  • hormone antagonists
  • hormone substitutes
  • hormones
  • Human Physiology
  • Humans
  • Incretin
  • Incretins - pharmacology
  • Internal Medicine
  • like peptide
  • Macrophages
  • Male
  • Medical sciences
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Mouse model
  • Peptide Fragments - pharmacology
  • Peptides
  • Peptides - pharmacology
  • Prevention
  • Real-Time Polymerase Chain Reaction
  • Type 2 diabetes
ispartof: Diabetologia, 2011-07-24, Vol.54 (10), p.2649-2659
description: Aims/hypothesis 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/interpretation 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.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleNative incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
creatorNagashima, M ; Watanabe, T ; Terasaki, M ; Tomoyasu, M ; Nohtomi, K ; Kim-Kaneyama, J ; Miyazaki, A ; Hirano, T
creatorcontribNagashima, M ; Watanabe, T ; Terasaki, M ; Tomoyasu, M ; Nohtomi, K ; Kim-Kaneyama, J ; Miyazaki, A ; Hirano, T
descriptionAims/hypothesis 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/interpretation 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.
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1EISSN: 1432-0428
2DOI: 10.1007/s00125-011-2241-2
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languageeng
publisherBerlin/Heidelberg: Springer-Verlag
subjectAcetyl-CoA C-Acetyltransferase - metabolism ; Animals ; Apolipoproteins ; Apolipoproteins E - genetics ; Apolipoproteins E - metabolism ; Article ; Atherosclerosis ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - drug therapy ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Biological and medical sciences ; Blood and lymphatic vessels ; Blotting, Western ; Cardiology. Vascular system ; CD36 Antigens - metabolism ; Cell Line ; Cells, Cultured ; Cholesterol ; dependent insulinotropic polypeptide ; Diabetes ; Diabetes. Impaired glucose tolerance ; Dipeptidyl peptidase ; Dipeptidyl peptidase-4 ; Endocrine pancreas. Apud cells (diseases) ; endocrine system ; Endocrinology ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Foam Cells - cytology ; Foam Cells - drug effects ; Gastric Inhibitory Polypeptide - pharmacology ; Gene expression ; Glucagon ; Glucagon-Like Peptide 1 - analogs & derivatives ; Glucagon-Like Peptide 1 - pharmacology ; Glucagon-like peptide-1 ; Glucose ; Glucose-dependent insulinotropic polypeptide ; hormone antagonists ; hormone substitutes ; hormones ; Human Physiology ; Humans ; Incretin ; Incretins - pharmacology ; Internal Medicine ; like peptide ; Macrophages ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolism ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Mouse model ; Peptide Fragments - pharmacology ; Peptides ; Peptides - pharmacology ; Prevention ; Real-Time Polymerase Chain Reaction ; Type 2 diabetes
ispartofDiabetologia, 2011-07-24, Vol.54 (10), p.2649-2659
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2Terasaki, M
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6Miyazaki, A
7Hirano, T
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0Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
1Diabetologia
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descriptionAims/hypothesis 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/interpretation 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.
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3Apolipoproteins E - genetics
4Apolipoproteins E - metabolism
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6Atherosclerosis
7Atherosclerosis (general aspects, experimental research)
8Atherosclerosis - drug therapy
9Atherosclerosis - metabolism
10Atherosclerosis - pathology
11Biological and medical sciences
12Blood and lymphatic vessels
13Blotting, Western
14Cardiology. Vascular system
15CD36 Antigens - metabolism
16Cell Line
17Cells, Cultured
18Cholesterol
19dependent insulinotropic polypeptide
20Diabetes
21Diabetes. Impaired glucose tolerance
22Dipeptidyl peptidase
23Dipeptidyl peptidase-4
24Endocrine pancreas. Apud cells (diseases)
25endocrine system
26Endocrinology
27Endocrinopathies
28Etiopathogenesis. Screening. Investigations. Target tissue resistance
29Foam Cells - cytology
30Foam Cells - drug effects
31Gastric Inhibitory Polypeptide - pharmacology
32Gene expression
33Glucagon
34Glucagon-Like Peptide 1 - analogs & derivatives
35Glucagon-Like Peptide 1 - pharmacology
36Glucagon-like peptide-1
37Glucose
38Glucose-dependent insulinotropic polypeptide
39hormone antagonists
40hormone substitutes
41hormones
42Human Physiology
43Humans
44Incretin
45Incretins - pharmacology
46Internal Medicine
47like peptide
48Macrophages
49Male
50Medical sciences
51Medicine
52Medicine & Public Health
53Metabolic Diseases
54Metabolism
55Mice
56Mice, Knockout
57Microscopy, Confocal
58Mouse model
59Peptide Fragments - pharmacology
60Peptides
61Peptides - pharmacology
62Prevention
63Real-Time Polymerase Chain Reaction
64Type 2 diabetes
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titleNative incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
authorNagashima, M ; Watanabe, T ; Terasaki, M ; Tomoyasu, M ; Nohtomi, K ; Kim-Kaneyama, J ; Miyazaki, A ; Hirano, T
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62Prevention
63Real-Time Polymerase Chain Reaction
64Type 2 diabetes
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abstractAims/hypothesis 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/interpretation 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.
copBerlin/Heidelberg
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pmid21786155
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