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, ...

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomalrecessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor α (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADα normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADα expression. STRADα-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADα in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADα deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.

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Objective-To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging. Methods and Results-Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma (P=0.0001) containing larger plaque (P<0.0001) and necrotic core areas (P<0.0019) and thinner fibrous caps (P=0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity (P=0.006), and proliferating (P=0.016), and apoptotic cells (P=0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months (P<0.01). By multivariate analysis NIRS positivity at 6 months predicted the subsequent presence of a fibroatheroma at 9 months (P=0.005; odds ratio, 2.71). Conclusion-The