title: Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development.
abstract: Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
authors.affiliation: Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, Pennsylvania 19104, USA. robert.wilensky@uphs.upenn.edu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wilensky
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Emile R
authors.initials: ER
authors.lastname: Mohler
authors.forename: Damir
authors.initials: D
authors.lastname: Hamamdzic
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burgert
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Postle
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fenning
authors.forename: James G
authors.initials: JG
authors.lastname: Bollinger
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Hoffman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pelchovitz
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Mirabile
authors.forename: Christine L
authors.initials: CL
authors.lastname: Webb
authors.forename: LeFeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Max C
authors.initials: MC
authors.lastname: Walker
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalewski
authors.forename: Colin H
authors.initials: CH
authors.lastname: Macphee
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology* / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000097:blood; D013552:Swine; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D010091:Oximes; D010713:Phosphatidylcholines; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides