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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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<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]

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