title: The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis in LDLR-deficient mice.
abstract: OBJECTIVE
  To investigate the effects of darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA2), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice.
  
  
  METHODS
  Six-week-old LDLR-deficient mice were fed an atherogenic high-fat diet for 17 weeks and then randomly divided into two groups. One group was administered darapladib (50 mg·kg(-1)·d(-1); po) for 6 weeks. The other group was administered saline as a control. Serum lipid levels were measured using the corresponding kits, and three inflammatory markers--interleukin-6 (IL-6), C reactive protein (hs-CRP), and platelet activating factor (PAF)--were determined using ELISA. Atherosclerotic plaque areas were stained with Sudan IV, and inflammatory gene expression at the lesions was evaluated using quantitative real-time PCR.
  
  
  RESULTS
  The body weight and serum lipid level between the two groups were similar at the end of the dietary period. The serum lp-PLA2 activity, hs-CRP and IL-6 levels, however, were significantly reduced in the darpladib group. The inhibition of lp-PLA2 did not alter the serum PAF level. Furthermore, the plaque area, from the aortic arch to the abdominal aorta, was significantly reduced in the darpladib group. Additionally, the expression of inflammatory genes monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was significantly reduced at the lesions in the darapladib group.
  
  
  CONCLUSIONS
  Inhibition of lp-PLA2 by darapladib decreases the inflammatory burden and atherosclerotic plaque formation in LDLR-deficient mice, which may be a new strategy for the treatment of atherosclerosis.
authors.affiliation: Department of Pharmacology І, the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Miao-miao
authors.initials: MM
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Wen-yi
authors.initials: WY
authors.lastname: Wang
authors.forename: Wen-yu
authors.initials: WY
authors.lastname: Wu
authors.forename: Yan-ling
authors.initials: YL
authors.lastname: Ma
authors.forename: Wei-hai
authors.initials: WH
authors.lastname: Chen
authors.forename: Yi-ping
authors.initials: YP
authors.lastname: Wang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001547:Benzaldehydes / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017353:Gene Deletion; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy; D011973:Receptors, LDL / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D002097:C-Reactive Protein; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D010091:Oximes; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides