No abstract

Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.

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.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 of low-density lipoproteins COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/. Lp-PLA 2 , also known as platelet-activating factor acetylhydrolase or type VIIA PLA 2 , is a calcium-independent phospholipase A 2 . In humans, Lp-PLA 2 is secreted by leukocytes and is associated with circulating LDL and macrophages in atherosclerotic plaques. Although some have hypothesized that Lp-PLA 2 has a protective role in atherosclerotic lesion development 9,10 , the preponderance of recent data suggests that Lp-PLA 2 has an active role in atherosclerotic development and progression [11][12][13] . Elevated circulating Lp-PLA 2 activity predicts increased cardiovascular risk 14 . A proatherogenic role for Lp-PLA 2 has been postulated on the basis of its ability to generate two key proinflammatory mediators, lysophosphatidylcholine (LPC) and oxidized nonesterified fatty acids (oxNEFAs), through the cleavage of oxidized or polar phospholipids generated during LDL oxidation 15,16 . Evidence exists for a regulatory role of these proinflammatory lipids, particularly of LPC 12,13,17 , in promoting atherosclerotic plaque development that can ultimately lead to the formation of a necrotic core. These steps include recruitment and activation of leukocytes 12,18 , induction of apoptosis 12,19 and impaired removal of dead cells 20,21 . The demonstration that Lp-PLA 2 is highly upregulated in macrophages undergoing apoptosis within the necrotic core and fibrous cap of vulnerable and ruptured plaques, ...

Background-Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Synthetic LXR agonists have been shown to inhibit the progression of atherosclerosis in mice, but the mechanism is uncertain. LXR agonism upregulates the genes encoding ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1) in macrophages, thus promoting efflux of cholesterol; it also upregulates liver and intestinal ABCG5 and ABCG8, helping to promote biliary and fecal excretion of cholesterol. Thus, LXR agonism may inhibit atherosclerosis through promotion of reverse cholesterol transport (RCT) in vivo, but this has not been proven. We previously described an in vivo method to trace the movement of cholesterol from 3 H-cholesterol-labeled J774 macrophages into plasma, into liver, and ultimately into the bile and feces as free cholesterol or bile acids. In the present study we used this approach to test the hypothesis that administration of the synthetic LXR agonist GW3965 would increase the rate of macrophage RCT in vivo. Methods and Results-Three different mouse models-wild-type C57BL/6 mice, LDLR/apobec-1 double knockout mice, and human apolipoprotein (apo)B/cholesteryl ester transfer protein (CETP) double transgenic mice-were treated with either vehicle or GW3965. Mice were injected intraperitoneally with 3 H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of 3 H-tracer in plasma, liver, and feces. Administration of GW3965 significantly increased the levels of 3 H-tracer in plasma and feces in all 3 mouse models. Conclusions-These