title: Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice.
abstract: Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.
authors: Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Nasib
authors: N
authors: Ervinna
authors: Tomoya
authors: T
authors: Mita
authors: Eisuke
authors: E
authors: Yasunari
authors: Kosuke
authors: K
authors: Azuma
authors: Rica
authors: R
authors: Tanaka
authors: Satoshi
authors: S
authors: Fujimura
authors: Dewi
authors: D
authors: Sukmawati
authors: Takashi
authors: T
authors: Nomiyama
authors: Akio
authors: A
authors: Kanazawa
authors: Ryuzo
authors: R
authors: Kawamori
authors: Yoshio
authors: Y
authors: Fujitani
authors: Hirotaka
authors: H
authors: Watada
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; D014409:Tumor Necrosis Factor-alpha; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse