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.
Highlights
Incretin-based therapies have been reported to suppress the development of atherosclerosis and its related diseases by ameliorating hyperglycemia, decreasing blood pressure and atherogenic lipoproteins, and improving vascular inflammation and endothelial dysfunction [1,2,3]
These diabetic mice exhibited the classical features of STZ-induced diabetes: i.e.; severe hyperglycemia, hyperphagia, low body weight gain, and low insulin concentration. They had elevated levels of total and non-high-density lipoprotein (HDL) cholesterols and nonesterified fatty acids (NEFA) as well as glucose compared with nondiabetic counterparts
peritoneal macrophages. Exendin(9–39) or (Pro3), Ex-9, and both had no effects on total glucagon-like peptide-1 (GLP-1) levels, and Ex-9 had no effect on total glucose-dependent insulinotropic polypeptide (GIP) levels
Summary
Incretin-based therapies have been reported to suppress the development of atherosclerosis and its related diseases by ameliorating hyperglycemia, decreasing blood pressure and atherogenic lipoproteins, and improving vascular inflammation and endothelial dysfunction [1,2,3]. If GLP-1 and GIP both have anti-atherogenic properties, the increases of both active GLP1 and active GIP by dipeptidyl peptidase (DPP)-4 inhibitor treatment are likely to suppress the development of atherosclerotic lesions in an additive fashion. Several recent reports, including our own, have shown that DPP-4 inhibitors significantly suppress the development of atherosclerotic lesions in animal models [5,6,7,8,9]. It remains unknown, whether this antiatherogenic property of DPP-4 inhibitor can be credited to higher endogenous levels of the active incretins GLP-1 and GIP. If the anti-atherosclerotic effect of DPP-4 inhibitor is derived from DPP-4 inactivation itself, DPP-4 inhibitor can elicit anti-atherogenic effects even when no increases in the active incretins take place
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