title: Translational studies of lipoprotein-associated phospholipase A₂ in inflammation and atherosclerosis.
abstract: OBJECTIVE
  This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis.
  
  
  BACKGROUND
  Lp-PLA₂ has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA₂ are indirect and confounded by species differences; whether Lp-PLA₂ is causal in coronary heart disease remains in question.
  
  
  METHODS
  We examined inflammatory regulation of Lp-PLA₂ during experimental endotoxemia in humans, probed the source of Lp-PLA₂ in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA₂, with coronary artery calcification.
  
  
  RESULTS
  In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA₂ messenger ribonucleic acid decreased transiently, and plasma Lp-PLA₂ mass declined modestly during endotoxemia. In vitro, Lp-PLA₂ expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA₂ activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification.
  
  
  CONCLUSIONS
  Circulating Lp-PLA₂ did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA₂. Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA₂ to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA₂ as a biomarker of Lp-PLA₂ actions in the vasculature.
authors.affiliation: Cardiovascular Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA. jfer@mail.med.upenn.edu
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.forename: Christine C
authors.initials: CC
authors.lastname: Hinkle
authors.forename: Nehal N
authors.initials: NN
authors.lastname: Mehta
authors.forename: Roshanak
authors.initials: R
authors.lastname: Bagheri
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Derohannessian
authors.forename: Rhia
authors.initials: R
authors.lastname: Shah
authors.forename: Megan I
authors.initials: MI
authors.lastname: Mucksavage
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Xuexia
authors.initials: X
authors.lastname: Wang
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Master
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D003324:Coronary Artery Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase