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Translational studies of lipoprotein-associated phospholipase A? in inflammation and atherosclerosis.

ABSTRACT: This study sought to examine the role of lipoprotein-associated phospholipase A? (Lp-PLA?/PLA2G7) in human inflammation and coronary atherosclerosis.Lp-PLA? has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA? are indirect and confounded by species differences; whether Lp-PLA? is causal in coronary heart disease remains in question.We examined inflammatory regulation of Lp-PLA? during experimental endotoxemia in humans, probed the source of Lp-PLA? in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA?, with coronary artery calcification.In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA? messenger ribonucleic acid decreased transiently, and plasma Lp-PLA? mass declined modestly during endotoxemia. In vitro, Lp-PLA? expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA? activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification.Circulating Lp-PLA? did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA?. Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA? to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA? as a biomarker of Lp-PLA? actions in the vasculature.

SUBMITTER: Ferguson JF

PROVIDER: S-EPMC3285416 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Translational studies of lipoprotein-associated phospholipase A₂ in inflammation and atherosclerosis.

Ferguson Jane F JF Hinkle Christine C CC Mehta Nehal N NN Bagheri Roshanak R Derohannessian Stephanie L SL Shah Rhia R Mucksavage Megan I MI Bradfield Jonathan P JP Hakonarson Hakon H Wang Xuexia X Master Stephen R SR Rader Daniel J DJ Li Mingyao M Reilly Muredach P MP

Journal of the American College of Cardiology 20120201 8

<h4>Objectives</h4>This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis.<h4>Background</h4>Lp-PLA₂ has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA₂ are indirect and confounded by species differences; whether Lp-PLA₂ is causal in coronary heart disease remains in question.<h4>Methods</h4>We examined inflammatory regulation of Lp-PLA₂ during experimental e ...[more]

PMID: 22340269

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Project description:Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a unique member of the phospholipase A(2) superfamily. This enzyme is characterized by its ability to specifically hydrolyze PAF as well as glycerophospholipids containing short, truncated, and/or oxidized fatty acyl groups at the sn-2 position of the glycerol backbone. In humans, Lp-PLA(2) circulates in active form as a complex with low- and high-density lipoproteins. Clinical studies have reported that plasma Lp-PLA(2) activity and mass are strongly associated with atherogenic lipids and vascular risk. These observations led to the hypothesis that Lp-PLA(2) activity and/or mass levels could be used as biomarkers of cardiovascular disease and that inhibition of the activity could offer an attractive therapeutic strategy. Darapladib, a compound that inhibits Lp-PLA(2) activity, is anti-atherogenic in mice and other animals, and it decreases atherosclerotic plaque expansion in humans. However, disagreement continues to exist regarding the validity of Lp-PLA(2) as an independent marker of atherosclerosis and a scientifically justified target for intervention. Circulating Lp-PLA(2) mass and activity are associated with vascular risk, but the strength of the association is reduced after adjustment for basal concentrations of the lipoprotein carriers with which the enzyme associates. Genetic studies in humans harboring an inactivating mutation at this locus indicate that loss of Lp-PLA(2) function is a risk factor for inflammatory and vascular conditions in Japanese cohorts. Consistently, overexpression of Lp-PLA(2) has anti-inflammatory and anti-atherogenic properties in animal models. This thematic review critically discusses results from laboratory and animal studies, analyzes genetic evidence, reviews clinical work demonstrating associations between Lp-PLA(2) and vascular disease, and summarizes results from animal and human clinical trials in which administration of darapladib was tested as a strategy for the management of atherosclerosis.

Dataset Information

Translational studies of lipoprotein-associated phospholipase A? in inflammation and atherosclerosis.

Publications

Translational studies of lipoprotein-associated phospholipase A₂ in inflammation and atherosclerosis.

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