Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development

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Abstract
Although increased levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with cardiac disease, whether this enzyme has a causal role in the development of atherosclerosis has not been clear. Wilensky et al. now show in a pig model of atherosclerosis that a selective Lp-PLA2 inhibitor reduces progression to complex atherosclerotic lesion formation, an effect that is associated with decreased infiltration of inflammatory cells into the lesions. These results support the use of Lp-PLA2 inhibitors for the treatment of atherosclerotic cardiovascular disease. 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.