Title : Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development - Wilensky_2008_Nat.Med_14_1059 |
Author(s) : Wilensky RL , Shi Y , Mohler ER, 3rd , Hamamdzic D , Burgert ME , Li J , Postle A , Fenning RS , Bollinger JG , Hoffman BE , Pelchovitz DJ , Yang J , Mirabile RC , Webb CL , Zhang L , Zhang P , Gelb MH , Walker MC , Zalewski A , Macphee CH |
Ref : Nat Med , 14 :1059 , 2008 |
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. |
PubMedSearch : Wilensky_2008_Nat.Med_14_1059 |
PubMedID: 18806801 |
Gene_locus related to this paper: human-PLA2G7 |
Gene_locus | human-PLA2G7 |
Wilensky RL, Shi Y, Mohler ER, 3rd, Hamamdzic D, Burgert ME, Li J, Postle A, Fenning RS, Bollinger JG, Hoffman BE, Pelchovitz DJ, Yang J, Mirabile RC, Webb CL, Zhang L, Zhang P, Gelb MH, Walker MC, Zalewski A, Macphee CH (2008)
Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development
Nat Med
14 :1059
Wilensky RL, Shi Y, Mohler ER, 3rd, Hamamdzic D, Burgert ME, Li J, Postle A, Fenning RS, Bollinger JG, Hoffman BE, Pelchovitz DJ, Yang J, Mirabile RC, Webb CL, Zhang L, Zhang P, Gelb MH, Walker MC, Zalewski A, Macphee CH (2008)
Nat Med
14 :1059