Effects of PKF275-055, a dipeptidyl peptidase–4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E–null mice

• Published in: Metabolism, clinical and experimental clinical and experimental, 2012-07, Vol.61 (7), p.974-977
• Main Authors: Terasaki, Michishige, Nagashima, Masaharu, Watanabe, Takuya, Nohtomi, Kyoko, Mori, Yusaku, Miyazaki, Akira, Hirano, Tsutomu
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - therapeutic use; Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis (general aspects, experimental research); Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol - blood; Diet, Atherogenic; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Endocrinology & Metabolism; Feeding. Feeding behavior; Foam Cells - drug effects; Foam Cells - metabolism; Foam Cells - pathology; Fundamental and applied biological sciences. Psychology; Gastric Inhibitory Polypeptide - blood; Glucagon-Like Peptide 1 - blood; Lipoproteins, LDL - metabolism; Male; Medical sciences; Mice; Nitriles - therapeutic use; Plaque, Atherosclerotic - drug therapy; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Pyrrolidines - therapeutic use; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Weight Loss - drug effects
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2011.11.011

Abstract 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 µ m/[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.