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

Cardiology

Journal of Clinical & Experimental Cardiology

Author(s): Nagashima M, Watanabe T, Terasaki M, Tomoyasu M, Nohtomi K,

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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.
This article was published in Diabetologia and referenced in Journal of Clinical & Experimental Cardiology

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