Abstract 9436: Sitagliptin Reduces Plaque Macrophage Content and Stabilizes Arteriosclerotic Lesions in Apoe-Deficient Mice
Objective: Glucagon-like peptide-1(7-36) (GLP-1) based therapies are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes are at a high risk to develop a severe atherosclerosis, we investigated the effect of GLP-1 on chemokine-induced migration of human monocytes and macrophage MMP-9 expression, both crucial steps in atherogenesis and plaque destabilisation. Furthermore, we explored the translation of these effects to plaque inflammation and plaque stability in ApoE-/- mice treated with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1.
Methods and Results: In the modified Boyden-chamber, pretreatment with GLP-1 reduced the MCP-1 induced migration of isolated human monocytes in a concentration dependent manner from a 3.3±0.8 to a 1.4±0.5 fold induction at 10 nM GLP-1 (n = 8, p < 0.05), which was associated with a decreased MLC-phosphorylation in these cells. Similar effects were seen when RANTES was used as a chemokine to induce cell migration. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages as determined by zymography. In vivo, treatment of ApoE-/- mice with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1, resulted in a 75% reduction of macrophage infiltration, a 75% reduction in plaque MMP-9 expression and a more than 3-fold increase in plaque collagen content compared to controls as shown by MAC3, Picrosirus Red and immunohistologic staining, respectively (n=6-8, p < 0.05).
Conclusion: Thus, GLP-1 reduces plaque inflammation and increases plaque stability potentially by inhibiting chemokine-induced migration of monocytes and by inhibition of macrophage MMP-9 expression. The effects observed may provide a potential mechanism of how GLP-1 based therapies may modulate vascular disease in high-risk patients with type 2 diabetes mellitus.
- © 2011 by American Heart Association, Inc.