Published in:
Open Access 01-10-2011 | Article
Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
Published in: Diabetologia | Issue 10/2011
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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 Pro3(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 (Pro3)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.