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

Abstract

Aims/hypothesisSeveral 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.MethodsApoe−/− 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.ResultsAdministration 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/interpretationOur 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2241-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

“…Similar to results reported previously 13 , apoE / mice infused with saline vehicle in the present study exhibited marked atherosclerotic lesions in the proximal portion of the aorta at 21 weeks of age, whereas 4-week infusion of GLP-1 significantly suppressed the size of the atherosclerotic lesions with infiltrating monocytes / macrophages in the aortic root. Staining of cross-sections of the aortic root with anti-SM2 antibody or anti-SMemb antibody Fig.…”

“…After the 4-week infusion period, the 21-week-old apoE / mice were anesthetized with diethyl ether, drained of blood via the descending vena cava, and subjected to whole-body perfusion with PBS via a left ventricular cannula 13,[16][17][18][19] . The whole aorta was fixed by perfusion with PBS containing 4 paraformaldehyde, excised from the root to the abdominal area, and carefully stripped of connective and adipose tissues.…”

“…Liraglutide stimulates nitric oxide production 10 and attenuates tumor necrosis factor--induced oxidative stress and inflammation, as well as the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells 11,12 . Chronic infusion of GLP-1 suppresses monocyte / macrophage infiltration into the aortic wall and the development of atherosclerotic lesions in apolipoprotein E-deficient apoE / mice, an animal model of spontaneous atherosclerosis 13 . GLP-1 works via GLP-1R to suppress oxidized low-density lipoprotein oxLDL -induced foam cell formation in exudate peritoneal macrophages, and this suppressive effect is followed by activation of cAMP 13 .…”

“…Chronic infusion of GLP-1 suppresses monocyte / macrophage infiltration into the aortic wall and the development of atherosclerotic lesions in apolipoprotein E-deficient apoE / mice, an animal model of spontaneous atherosclerosis 13 . GLP-1 works via GLP-1R to suppress oxidized low-density lipoprotein oxLDL -induced foam cell formation in exudate peritoneal macrophages, and this suppressive effect is followed by activation of cAMP 13 .…”

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…Although AAA development is driven by complicated interactions of various mechanisms, there are a number of similarities in the pathophysiology of AAA saline or Ang (2000 ng/kg/min, Wako, Osaka, Japan) and one for saline, GLP-1 [2.16 nmol/kg/day; human GLP-1 amide, AnaSpec, CA, USA], or GIP (25 nmol/kg/day; human GIP, AnaSpec) 8) . MK0626 was delivered with food at an approximate dose of 6 mg/kg/day 14,15) .…”