부산대학교 도서관

Increased lipoprotein-associated phospholipase [A.sub.2] (Lp-[PLA.sub.2]) activity is associated with increased risk of cardiac events, but it is not known whether Lp-[PLA.sub.2] is a causative agent. Here we show that selective inhibition of Lp-[PLA.sub.2] with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-[PLA.sub.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.sub.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.
Atherosclerosis, the most common cause of myocardial infarction, stroke and cardiovascular death, is an inflammatory-immunomodulatory disease (1,2). A key early step in its development is the accumulation and subsequent oxidation [...]