title: Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice.
abstract: BACKGROUND
  Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.
  
  
  RESULTS
  ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group.
  
  
  CONCLUSIONS
  Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.
authors: Department of Pharmacology I, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Wen-yi
authors: WY
authors: Wang
authors: Jie
authors: J
authors: Zhang
authors: Wen-yu
authors: WY
authors: Wu
authors: Jie
authors: J
authors: Li
authors: Yan-ling
authors: YL
authors: Ma
authors: Wei-hai
authors: WH
authors: Chen
authors: Hong
authors: H
authors: Yan
authors: Kai
authors: K
authors: Wang
authors: Wen-wei
authors: WW
authors: Xu
authors: Jian-hua
authors: JH
authors: Shen
authors: Yi-ping
authors: YP
authors: Wang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D001547:Benzaldehydes / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D012850:Sinus of Valsalva / Q000187:drug effects / Q000473:pathology; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001057:Apolipoproteins E; D001547:Benzaldehydes; D015415:Biomarkers; D002097:C-Reactive Protein; D018836:Inflammation Mediators; D008055:Lipids; D010091:Oximes; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides