title: The synergistic effect of valsartan and LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] on vascular oxidative stress and inflammation in type 2 diabetic mice.
abstract: OBJECTIVE
  To investigate the combination effects and mechanisms of valsartan (angiotensin II type 1 receptor blocker) and LAF237 (DPP-IV inhibitor) on prevention against oxidative stress and inflammation injury in db/db mice aorta.
  
  
  METHODS
  Db/db mice (n = 40) were randomized to receive valsartan, LAF237, valsartan plus LAF237, or saline. Oxidative stress and inflammatory reaction in diabetic mice aorta were examined.
  
  
  RESULTS
  Valsartan or LAF237 pretreatment significantly increased plasma GLP-1 expression, reduced apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NAD(P)H oxidase subunits also significantly decreased resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5 ± 0.7, P < 0.05; LAF237: 10.2 ± 1.7, P < 0.05), VCAM-1 (fold change: valsartan : 5.2 ± 1.2, P < 0.05; LAF237: 4.8 ± 0.6, P < 0.05), and MCP-1 (fold change: valsartan: 3.2 ± 0.6, LAF237: 4.7 ± 0.8; P < 0.05) expression. Moreover, the combination treatment with valsartan and LAF237 resulted in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction was also higher than monotherapy with valsartan or LAF237.
  
  
  CONCLUSIONS
  These data indicated that combination treatment with LAF237 and valsartan acts in a synergistic manner on vascular oxidative stress and inflammation in type 2 diabetic mice.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Dongdong
authors.initials: D
authors.lastname: Sun
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Shenxu
authors.initials: S
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C475520:1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine; D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000068756:Valsartan; D052216:Glucagon-Like Peptide 1; D019255:NADPH Oxidases; D014633:Valine; D000218:Adamantane