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

Abstract

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.

• Authors: M Nagashima, T Watanabe, M Terasaki, M Tomoyasu, K Nohtomi, J Kim-Kaneyama, A Miyazaki, T Hirano
• Journal: Diabetologia (Diabetologia) Vol. 54 Issue 10 Pg. 2649-59 (Oct 2011) ISSN: 1432-0428 [Electronic] Germany
• PMID: 21786155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• CD36 Antigens
• Incretins
• Peptide Fragments
• Peptides
• gastric inhibitory polypeptide (1-42)
• gastric inhibitory polypeptide (3-42)
• glucagon-like peptide-1 (9-36)-amide
• glucagon-like peptide 1 (7-36)amide
• exendin (9-39)
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• Acat1 protein, mouse
• Acetyl-CoA C-Acetyltransferase

Topics

• Acetyl-CoA C-Acetyltransferase (metabolism)
• Animals
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (drug therapy, metabolism, pathology)
• Blotting, Western
• CD36 Antigens (metabolism)
• Cell Line
• Cells, Cultured
• Foam Cells (cytology, drug effects)
• Gastric Inhibitory Polypeptide (pharmacology)
• Glucagon-Like Peptide 1 (analogs & derivatives, pharmacology)
• Humans
• Incretins (pharmacology)
• Male
• Mice
• Mice, Knockout
• Microscopy, Confocal
• Peptide Fragments (pharmacology)
• Peptides (pharmacology)
• Real-Time Polymerase Chain Reaction