title: 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: OBJECTIVE
  Several 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).
  
  
  METHODS
  Nontreated 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, (Pro(3))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.
  
  
  RESULTS
  Vildagliptin 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 (Pro(3))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)+(Pro(3))GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation.
  
  
  CONCLUSIONS
  Vildagliptin 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.
authors: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.
authors: Michishige
authors: M
authors: Terasaki
authors: Masaharu
authors: M
authors: Nagashima
authors: Kyoko
authors: K
authors: Nohtomi
authors: Kyoko
authors: K
authors: Kohashi
authors: Masako
authors: M
authors: Tomoyasu
authors: Kyoko
authors: K
authors: Sinmura
authors: Yukinori
authors: Y
authors: Nogi
authors: Yuki
authors: Y
authors: Katayama
authors: Kengo
authors: K
authors: Sato
authors: Fumiko
authors: F
authors: Itoh
authors: Takuya
authors: T
authors: Watanabe
authors: Tsutomu
authors: T
authors: Hirano
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D017398:Alternative Splicing; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023061:Gene Order; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D054795:Incretins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077597:Vildagliptin
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D009570:Nitriles; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane
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