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Updated: May 30, 2026
Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice
M Nagashima1, T Watanabe, M Terasaki
1Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
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.
Insights
Active forms of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) reduce atherosclerosis in mice. These incretins suppress foam cell formation in macrophages by downregulating CD36 and ACAT-1.
Area of Science:
- Cardiovascular Research
- Diabetes Mellitus
- Endocrinology
Background:
- Incretin-based therapies are suggested to protect against cardiovascular disease in type 2 diabetes.
- The specific roles of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in preventing atherosclerosis require further investigation.
Purpose of the Study:
- To investigate the potential of GLP-1 and GIP to prevent atherosclerosis development in apolipoprotein E-deficient (Apoe-/-) mice.
- To elucidate the mechanisms by which GLP-1 and GIP might exert anti-atherogenic effects.
Main Methods:
- Apoe-/- mice were treated with active GLP-1(7-36)amide or GIP(1-42), or their inactive counterparts, for 4 weeks.
- Aortic atherosclerosis, oxidized LDL-induced foam cell formation in macrophages, and related gene expression were assessed.
- Specific receptor antagonists and signaling pathway modulators were used to investigate the mechanisms of action.
Main Results:
- GLP-1(7-36)amide and GIP(1-42) significantly reduced atherosclerotic lesions and macrophage infiltration in the aorta.
- These anti-atherosclerotic effects were associated with decreased foam cell formation and downregulation of CD36 and ACAT-1 in macrophages.
- GLP-1 and GIP receptors were detected on macrophages, and direct incubation with these incretins suppressed foam cell formation.
Conclusions:
- Active forms of GLP-1 and GIP demonstrate anti-atherogenic properties by suppressing macrophage foam cell formation.
- These effects are mediated through GLP-1 and GIP receptors, involving cAMP activation and downregulation of CD36 and ACAT-1.
- The findings support a potential therapeutic role for GLP-1 and GIP in mitigating atherosclerosis in diabetic patients.
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