title: Teneligliptin, a dipeptidyl peptidase-4 inhibitor, attenuated pro-inflammatory phenotype of perivascular adipose tissue and inhibited atherogenesis in normoglycemic apolipoprotein-E-deficient mice.
abstract: Dipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether teneligliptin alters the pro-inflammatory phenotype of perivascular adipose tissue (PVAT) and inhibits atherogenesis.
  
  
  
  Teneligliptin (60mg/kg/day) was administered orally to apolipoprotein-E-deficient (ApoE-/-) mice for 20weeks. Teneligliptin significantly inhibited the development of atherosclerosis in the aortic arch compared with vehicle (P<0.05), without alteration of blood glucose level or blood pressure. Histological analyses demonstrated that teneligliptin decreased lipid deposition and MCP-1 expression (P<0.05, respectively), and tended to decrease macrophage accumulation in atherosclerotic plaques. The results of quantitative RT-PCR analysis demonstrated that teneligliptin reduced the expression of inflammatory molecules such as TNF-α and MCP-1 in the abdominal aorta. Furthermore, teneligliptin reduced the expression of a macrophage marker and Nox-4, a major NADPH oxidase subunit in adipocytes, in PVAT around the aortic arch. Administration of teneligliptin for 8weeks ameliorated endothelium-dependent vasodilation and reduced oxidative stress as determined by urinary 8-OHdG excretion (P<0.05) compared with vehicle. In vitro experiments demonstrated that exendin-4 (Ex-4), a GLP-1 analog, decreased the expression of inflammatory molecules in RAW264.7 cells. Also, Ex-4 decreased Nox4 expression in 3T3-L1 adipocytes.
  
  
  
  Teneligliptin inhibited atherogenesis with attenuation of the inflammatory phenotype in PVAT. A GLP-1 analog suppressed pro-inflammatory activation of macrophages and adipocytes. Suppression of the pro-inflammatory phenotype of PVAT might contribute, at least partially, to the cardioprotective effects of teneligliptin.
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Hotimah Masdan
authors.initials: HM
authors.lastname: Salim
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: daiju.fukuda@tokushima-u.ac.jp.
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Higashikuni
authors.affiliation: Division for Health Service Promotion, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Soeki
authors.affiliation: Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077270:Exenatide; D005260:Female; D020022:Genetic Predisposition to Disease; D054795:Incretins / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011720:Pyrazoles / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D018836:Inflammation Mediators; D010455:Peptides; D011720:Pyrazoles; D053778:Thiazolidines; D014688:Venoms; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
keywords: Atherosclerosis; DPP-4 inhibitors; Endothelial function; Inflammation; Perivascular adipose tissue