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Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice.

ABSTRACT: OBJECTIVE:Core2 1-6-N-glucosaminyltransferase-I (C2GlcNAcT-I) modification of adhesion molecules is required for optimal binding to target ligands. The objective of this study was to determine the role of C2GlcNAcT-I in the recruitment of Ly-6C(hi) monocytes to atherosclerotic lesions and in lesion formation in mice. METHODS AND RESULTS:In a whole-blood binding assay, Ly-6C(hi) monocytes and certain lymphocytes and natural killer cells from wild-type mice bound to P- and E-selectin. C2GlcNAcT-I deficiency abrogated leukocyte binding to P- and E-selectin in this assay as well as in an in vitro flow chamber assay. Moreover, C2GlcNAcT-I deficiency decreased Ly-6C(hi) monocyte interactions with atherosclerotic arteries under physiological flow conditions and also inhibited monocyte recruitment to the peritoneal cavity in mice challenged with thioglycollate. In apolipoprotein E-deficient (apoE(-/-)) mice, lack of C2GlcNAcT-I resulted in fewer and smaller atherosclerotic lesions in mouse aortas. Atherosclerosis was also suppressed in C2GlcNAcT-I(-/-)/apoE(-/-) chimeric mice transplanted with C2GlcNAcT-I(+/+) bone marrow cells. CONCLUSIONS:C2GlcNAcT-I in both leukocytes and blood vessel wall cells contributes to leukocyte recruitment to the arterial wall. C2GlcNAcT-I deficiency leads to the formation of small, macrophage-poor, and collagen-rich atherosclerotic lesions.

SUBMITTER: Wang H

PROVIDER: S-EPMC2666734 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice.

Wang Huan H Tang Rong R Zhang Weiyu W Amirikian Karine K Geng Zhen Z Geng Jianguo J Hebbel Robert P RP Xia Lijun L Marth Jamey D JD Fukuda Minoru M Katoh Shigeki S Huo Yuqing Y

Arteriosclerosis, thrombosis, and vascular biology 20081204 2

<h4>Objective</h4>Core2 1-6-N-glucosaminyltransferase-I (C2GlcNAcT-I) modification of adhesion molecules is required for optimal binding to target ligands. The objective of this study was to determine the role of C2GlcNAcT-I in the recruitment of Ly-6C(hi) monocytes to atherosclerotic lesions and in lesion formation in mice.<h4>Methods and results</h4>In a whole-blood binding assay, Ly-6C(hi) monocytes and certain lymphocytes and natural killer cells from wild-type mice bound to P- and E-selecti ...[more]

PMID: 19057022

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Project description: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 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/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.

Dataset Information

Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice.

Publications

Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice.

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