Abstract 13248: DPP-4 Inhibition Reduces Atherosclerosis by Priming Monocytes into Alternative M2 Macrophages

Abstract

Introduction: Major parts of the population in the western world are suffering from atherosclerotic diseases like coronary and peripheral artery disease or stroke. Interventional and pharmacological therapies at present focus on the treatment of vascular stenoses, secondary prophylaxis or reduction of cardiovascular risk factors. Hypothesis: In this project, we want to establish the pharmacological inhibition of DPP4 as a new therapeutic concept focussing on macrophage polarization during development of atherosclerosis. Methods: Non-diabetic ApoE-/- mice were treated with normal diet or high fat diet for three months to induce arterial atherosclerotic lesion formation. The descending aorta was stained using Oil-Red-O to quantify atherosclerotic lesions. In parallel mice were treated with Sitagliptin or placebo. Macrophage subtype content (M1, M2) in the aortic wall was quantified using FACS. Results: Mice on high fat diet treated with Sitagliptin showed a dramatic reduction in atherosclerotic lesion formation in contrast to placebo treated animals. Regarding total macrophage content in the vascular wall we could not detect a difference between the treatment groups. However, the number of protective M2 macrophages was more than tripled in the gliptin-treated animals. Moreover, the number of mural M2 macrophages inversely correlated with the aortic plaque burden. In further analyses we could demonstrate that Sitagliptin favoured macrophage polarization to alternatively activated M2 macrophages via the CXCR4-signaling pathway. Conclusions: We demonstrated that long-term Sitagliptin treatment in ApoE-/- animals on high fat diet can successfully inhibit atherosclerotic lesion formation via induction of macrophage polarization to the protective M2 phenotype. Due to the promising results of this study we are currently planning to transfer the underlying therapeutical concept into a randomized clinical trial.