title: Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits.
abstract: Several studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits.
  
  
  
  Japanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks.
  
  
  
  Dietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment.
  
  
  
  We demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo, Japan. Electronic address: hirano@med.showa-u.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., LTD., Nagoya, Aichi, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., LTD., Nagoya, Aichi, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., LTD., Nagoya, Aichi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., LTD., Nagoya, Aichi, Japan.
authors.forename: Moritaka
authors.initials: M
authors.lastname: Goto
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008079:Lipoproteins, VLDL / Q000097:blood; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008079:Lipoproteins, VLDL; D011743:Pyrimidines; D002784:Cholesterol; C583175:anagliptin
keywords: Atherosclerosis; Cholesterol; Dipeptidyl peptidase-4; Macrophage; Rabbits