title: A-002 (Varespladib), a phospholipase A2 inhibitor, reduces atherosclerosis in guinea pigs.
abstract: BACKGROUND
  The association of elevated serum levels of secretory phospholipase A2 (sPLA2) in patients with cardiovascular disease and their presence in atherosclerotic lesions suggest the participation of sPLA2 enzymes in this disease. The presence of more advanced atherosclerotic lesions in mice that overexpress sPLA2 enzymes suggest their involvement in the atherosclerotic process. Therefore, the sPLA2 family of enzymes could provide reasonable targets for the prevention and treatment of atherosclerosis. Thus, A-002 (varespladib), an inhibitor of sPLA2enzymes, is proposed to modulate the development of atherosclerosis.
  
  
  METHODS
  Twenty-four guinea pigs were fed a high saturated fat, high cholesterol diet (0.25%) for twelve weeks. Animals were treated daily with A-002 (n = 12) or vehicle (10% aqueous acacia; n = 12) by oral gavage. After twelve weeks, animals were sacrificed and plasma, heart and aorta were collected. Plasma lipids were measured by enzymatic methods, lipoprotein particles size by nuclear magnetic resonance, aortic cytokines by a colorimetric method, and aortic sinus by histological analyses.
  
  
  RESULTS
  Plasma total cholesterol, HDL cholesterol and triglycerides were not different among groups. However, the levels of inflammatory cytokines interleukin (IL)-10, IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly reduced in the treatment group. This group also had a significant 27% reduction in cholesterol accumulation in aorta compared with placebo group. Morphological analysis of aortic sinus revealed that the group treated with A-002 reduced atherosclerotic lesions by 24%.
  
  
  CONCLUSIONS
  The use of A-002 may have a beneficial effect in preventing diet-induced atherosclerosis in guinea pigs.
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA. joseoyama@hotmail.com
authors.forename: Jose O
authors.initials: JO
authors.lastname: Leite
authors.forename: Ushma
authors.initials: U
authors.lastname: Vaishnav
authors.forename: Michael
authors.initials: M
authors.lastname: Puglisi
authors.forename: Heather
authors.initials: H
authors.lastname: Fraser
authors.forename: Joaquim
authors.initials: J
authors.lastname: Trias
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Fernandez
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D001798:Blood Proteins / Q000008:administration & dosage*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D007211:Indoles / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007651:Keto Acids; D050356:Lipid Metabolism / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D064801:Phospholipase A2 Inhibitors
chemical_list: D000085:Acetates; D001798:Blood Proteins; D007211:Indoles; D007651:Keto Acids; C400481:PLIalpha; D064801:Phospholipase A2 Inhibitors; D016753:Interleukin-10; D018664:Interleukin-12; C117948:varespladib; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002784:Cholesterol