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Article
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.
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RESEARCH
Expression and purification of lipoprotein-associated phospholipase A2, a key enzyme involved in atherosclerosisActa Pharmacologica Sinica Original Article
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