Article abstract
Nature Medicine 14, 1059 - 1066 (2008)
Published online: 21 September 2008 | doi:10.1038/nm.1870
Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development
Robert L Wilensky1, Yi Shi2, Emile R Mohler, III1, Damir Hamamdzic1, Mark E Burgert3, Jun Li3, Anthony Postle4, Robert S Fenning1, James G Bollinger5, Bryan E Hoffman3, Daniel J Pelchovitz1, Jisheng Yang1, Rosanna C Mirabile3, Christine L Webb3, LeFeng Zhang2, Ping Zhang2, Michael H Gelb5, Max C Walker3, Andrew Zalewski2,3 & Colin H Macphee3
Abstract
Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA2 is a causative agent. Here we show that selective inhibition of Lp-PLA2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 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-PLA2 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.
- Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, Pennsylvania 19104, USA.
- Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
- GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA.
- Division of Infection, Inflammation & Repair, Mail Point 825 Level F South, Southhampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
- Departments of Chemistry and Biochemistry, Campus Box 351700, 36 Bagley Hall, University of Washington, Seattle, Washington 98195, USA.
Correspondence to: Robert L Wilensky1 e-mail: robert.wilensky@uphs.upenn.edu
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