Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development |
| |
Authors: | Wilensky Robert L Shi Yi Mohler Emile R Hamamdzic Damir Burgert Mark E Li Jun Postle Anthony Fenning Robert S Bollinger James G Hoffman Bryan E Pelchovitz Daniel J Yang Jisheng Mirabile Rosanna C Webb Christine L Zhang LeFeng Zhang Ping Gelb Michael H Walker Max C Zalewski Andrew Macphee Colin H |
| |
Affiliation: | Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, Pennsylvania 19104, USA. robert.wilensky@uphs.upenn.edu |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|