Abstract 10278: Incretin-Based Treatments Prevent the Development of Atherosclerotic Lesions in Apolipoprotein E-Null Mice
Background: Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes.
Objectives: 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: The 17-week-old ApoE-/- mice (N=159) were administered GLP-1 (2.2 nmol/kg/day), GIP (25 nmol/kg/day), or liraglutide (107 nmol/kg/day), a long-acting GIP analogue, by osmotic mini-pumps, or vildagliptin analogue (PKF275-055 100 μmol/kg/day), a dipeptidyl peptidase-4 (DPP-4) inhibitor, as drinking water, over a period of 4 weeks. Aortic atherosclerosis, oxidized LDL-induced cholesterol ester accumulation (foam cell formation), and related gene expression in exudate peritoneal macrophages were determined.
Results: Administration of GLP-1, GIP, liraglutide, or PKF275-055 significantly reduced the surface areas of atherosclerotic lesions and suppressed atheromatous plaque size and macrophage accumulation in the aortic root, compared with vehicle controls. The suppressive effects of these agents on atherosclerosis were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) in exudate peritoneal macrophages. Both GLP-1 and GIP receptors were detected in the exudate peritoneal macrophages obtained from non-treated ApoE-/- mice. Incubation with active GLP-1 or GIP for 48 hours significantly suppressed foam cell formation in these macrophages. This effect was wholly abolished in macrophages pretreated with the receptor antagonists, and it did not appear in macrophages incubated with the inactive forms of GLP-1 and GIP.
Conclusions: Our study provides the first evidence that both GLP-1 and GIP exert actions, via their own receptors, to suppress the development of atherosclerotic lesions associated with the downregulation of molecules essential for foam cell formation (CD36 and ACAT-1). These findings attest to the beyond-glycemic benefits of incretin-based therapies and thus open up a new therapeutic window for the treatment of atherosclerosis and its related diseases in type 2 diabetes.
- © 2010 by American Heart Association, Inc.