title: Dipeptidyl-peptidase-4 inhibitor, alogliptin, attenuates arterial inflammation and neointimal formation after injury in low-density lipoprotein (LDL) receptor-deficient mice.
abstract: BACKGROUND
  The results of recent studies suggest that dipeptidyl-peptidase-4 inhibitors have antiatherogenic effects. However, whether or not dipeptidyl-peptidase-4 inhibitors could suppress arterial inflammation and intimal hyperplasia after injury remains undetermined. The present study aims to clarify the anti-inflammatory effects of the dipeptidyl-peptidase-4 inhibitor, alogliptin (AGP), on the arteries of atherogenic low-density lipoprotein receptor-deficient (LKO) mice.
  
  
  RESULTS
  We compared intimal hyperplasia in LKO mice 2 weeks after femoral artery injury using an external vascular cuff model. All mice received oral injection of AGP (20 mg/kg per day) or normal saline (control) once daily for 14 days. Fasting blood sugar levels, serum cholesterol levels, or blood pressure did not significantly differ between the 2 groups. Plasma levels of active glucagon-like peptide-1 were higher in the AGP than in the control LKO mice (22.2±1.9 versus 15.6±0.9 pg/mL; P<0.05). Compared with saline, AGP significantly reduced intimal hyperplasia (1087±127 versus 1896±140 μm(2); P<0.001) as well as the intima/media ratio (0.08±0.01 versus 0.16±0.02; P<0.001). Immunostaining showed that AGP reduced proliferating cells (proliferating cell nuclear antigen-positive nuclei; P<0.001), percent smooth-muscle cell area (α-SMA-positive cells; P<0.001), inflammatory cells infiltration (lymphocyte antigen 6 complex-positive cells; P<0.05), tumor necrosis factor-α expression (P<0.05), and percent phospho-NF-κB-positive cell compared with saline. Levels of tumor necrosis factor -α (0.5-fold P<0.05), monocyte chemoattractant protein 1 (0.3-fold P<0.01), and interleukin-1β (0.2-fold P<0.05) mRNA were lower in the injured arteries of the AGP than in the control group.
  
  
  CONCLUSIONS
  AGP appeared to suppress neointimal formation by inhibiting inflammation, independently of its effects on glucose or cholesterol metabolism in atherogenic LKO mice.
authors.affiliation: Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.).
authors.forename: Koji
authors.initials: K
authors.lastname: Akita
authors.affiliation: Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.) Division of Cardiovascular Medicine, Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan (K.I.).
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.affiliation: Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.).
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001167:Arteritis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D058426:Neointima; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054873:Dipeptidyl-Peptidase IV Inhibitors; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D010880:Piperidines; D018809:Proliferating Cell Nuclear Antigen; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D002784:Cholesterol; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C520853:alogliptin
keywords: cytokine; dipeptidyl‐peptidase‐4 inhibitor; inflammation; intimal hyperplasia; smooth muscle cell