Preventive Effect of Dipeptidyl Peptidase-4 Inhibitor on Atherosclerosis Is Mainly Attributable to Incretin's Actions in Nondiabetic and Diabetic Apolipoprotein E-Null Mice

Abstract

AimSeveral recent reports have revealed that dipeptidyl peptidase (DPP)-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe −/−) mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).MethodsNontreated Apoe −/− mice, streptozotocin-induced diabetic Apoe −/− mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9–39), the GIP receptor blocker, (Pro3)GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined.ResultsVildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe −/− mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe −/− mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9–39) or (Pro3)GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9–39)+(Pro3)GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation.ConclusionsVildagliptin confers a substantial anti-atherosclerotic effect in both nondiabetic and diabetic mice, mainly via the action of the two incretins. However, the partial attenuation of atherosclerotic lesions by the dual incretin receptor antagonists in diabetic mice implies that vildagliptin confers a partial anti-atherogenic effect beyond that from the incretins.

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…Although in our previous studies, DPP-4I and incretins reduced atherosclerotic plaque development in Apoe / mice [8][9][10] , these effects were not observed in Ang -infused Apoe / mice. In this study, DPP- …”

“…Chronic inflammation triggers a cascade of events, such as inflammatory cell invasion, increased cytokine, and chemokine release, and abnormal regulation of extracellular matrix (ECM), ultimately resulting in vascular smooth muscle cell (VSMC) apoptosis and disruption of the elastic lamina 7) . We previously reported that administration of native glucagon-like peptide (GLP)-1, native glucose-dependent insulinotropic polypeptide (GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4I) significantly suppressed atherosclerotic lesions in the aortic wall of apolipoprotein E-null (Apoe / ) mice, a representative animal model of atherosclerosis [8][9][10] . Furthermore, incretin-related agents exert antiinflammatory effects in vascular endothelial cells, VSMCs, and monocytes/macrophages 9) .…”

“…We previously reported that administration of native glucagon-like peptide (GLP)-1, native glucose-dependent insulinotropic polypeptide (GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4I) significantly suppressed atherosclerotic lesions in the aortic wall of apolipoprotein E-null (Apoe / ) mice, a representative animal model of atherosclerosis [8][9][10] . Furthermore, incretin-related agents exert antiinflammatory effects in vascular endothelial cells, VSMCs, and monocytes/macrophages 9) . These findings suggest that incretins and DPP-4I are potentially effective against AAA as well as atherosclerosis.…”

DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages

“…Thus, they have been demonstrated to effectively prevent the progression of atherosclerosis in diabetic animal models. However, also in non-diabetic conditions, such as ApoE−/− mice, DPP-4 inhibitors can reduce the formation of atherosclerotic lesions [2,3]. Gliptins have been described to protect certain incretins like GLP-1 and GIP from cleavage, thus resulting in increased effective blood and tissue concentrations.…”

The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Reduces Aortic Damage from Hypercholesterolaemia in Apolipoprotein E-Deficient Mice

“…Compared with ApoE -/- HD + Tene mice, proinflammatory gene (TNF-α and IL-6) expression was also reduced in ApoE -/- HD+ Tene mice. It was previously reported that DPP-4 inhibitors significantly suppressed atherosclerotic lesions in the aortic wall of ApoE -/- mice, a representative animal model of atherosclerosis [33,34]. …”