Effects of PKF275-055, a dipeptidyl peptidase-4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E-null mice.
We recently discovered that glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide can both prevent the development of atherosclerosis in apolipoprotein E-null (Apoe(-/-)) mice. In the present study, we attempted to extend these findings to orally administered dipeptidyl peptidase (DPP)-4 inhibitor. Seventeen-week-old Apoe(-/-) mice fed an atherogenic diet were administered a DPP-4 inhibitor, vildagliptin analogue (PKF275-055 [PKF], 100 µm/[kg d]), in drinking water over a period of 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation were determined. Orally administered PKF increased plasma levels of active glucagon-like peptide-1 by 3.5-fold, increased total glucose-dependent insulinotropic polypeptide levels by 2-fold, reduced body weight by 13%, and reduced plasma cholesterol levels by 30%. Compared with drinking water controls, PKF significantly suppressed total aortic atherosclerotic lesions, atheromatous plaque in the aortic root, and macrophage accumulation in the aortic wall by 30% to 40% (P < .001). None of these changes were associated with the PKF-induced reductions in body weight and plasma cholesterol levels. Foam cell formation was suppressed by 40% in the exudate peritoneal macrophages obtained from the PKF-treated mice. The DPP-4 inhibitor prevents the development of atherosclerotic lesions by suppressing macrophage foam cell formation.
Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, Japan.
Michishige
M
Terasaki
Masaharu
M
Nagashima
Takuya
T
Watanabe
Kyoko
K
Nohtomi
Yusaku
Y
Mori
Akira
A
Miyazaki
Tsutomu
T
Hirano
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D009570:Nitriles / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects
C569631:1-((2-adamantyl)amino)acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride; D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; D008077:Lipoproteins, LDL; D009570:Nitriles; D011759:Pyrrolidines; C099252:oxidized low density lipoprotein; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D002784:Cholesterol; D000218:Adamantane