AIMS/HYPOTHESIS: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release. RESULTS: Treatment of Apoe (-/-) mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p < 0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p < 0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p < 0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p=NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. CONCLUSIONS/ INTERPRETATION: Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.
AIMS/HYPOTHESIS: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe (-/-) mice. METHODS:Apoe (-/-) mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release. RESULTS: Treatment of Apoe (-/-) mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p < 0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p < 0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p < 0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p=NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. CONCLUSIONS/ INTERPRETATION:Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.
Authors: Si Hyoung Kim; Jun Goo Kang; Chul Sik Kim; Sung-Hee Ihm; Moon Gi Choi; Hyung Joon Yoo; Seong Jin Lee Journal: Endocrine Date: 2017-12-28 Impact factor: 3.633
Authors: Julia Collin; Mario Gössl; Yoshiki Matsuo; Rebecca R Cilluffo; Andreas J Flammer; Darrell Loeffler; Ryan J Lennon; Robert D Simari; Daniel B Spoon; Raimund Erbel; Lilach O Lerman; Sundeep Khosla; Amir Lerman Journal: Int J Cardiol Date: 2014-11-26 Impact factor: 4.164