Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

Abstract

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; p0NS). 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.

The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE−/− mouse model

“…8 The capacity of incretin-modulating agents to influence plaque stability is not unprecedented with recent observations of increased plaque stability in the absence of a reduction in atherosclerotic disease burden being identified in DPP-4 inhibitor-treated ApoE −/− mice. 27 Interestingly, this study utilised a dietary protocol similar to protocol 2 used in our studies and suggests that plaque stabilisation can be initiated in early stage disease and continues with the establishment of high-burden atherosclerotic disease even in the absence of obvious treatment-mediated reduction in disease burden.…”

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

“…Alogliptin treatment, in ApoE 2 /2 diabetic mice, induced a significant reduction of atherosclerotic lesions and a concomitant reduction of IL-6 and IL-1b (69). Vittone et al (70) showed that in ApoE 2/2 mice, sitagliptin reduced plaque inflammation and increased plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage matrix metalloproteinase 9 release. Interestingly, it was shown that linagliptin administered in a rat model of sepsis ameliorated lipopolysaccharideinduced endothelial dysfunction in addition to reduced aortic infiltration with inflammatory cells (71).…”

Sirtuin 6 Expression and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Incretin Treatment

“…Thus, this study was designed to identify differences in SIRT6 expression, as well as in inflammatory infiltration, between carotid plaques of asymptomatic diabetic and nondiabetic patients. Experimental studies suggest that in obese mice, GLP-1-based therapies may reduce inflammation (11)(12)(13) and enhance the protein expression of SIRT1 (14). Moreover, human studies showed that sitagliptin (15) and exenatide (16), even at a single dose, exert a potent anti-inflammatory effect, and that many of these effects were persistent over a period of 12 weeks, thus suggesting that the anti-inflammatory effects of GLP-1-based therapies could help to reduce atherogenesis.…”