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

Ferguson JF, Hinkle CC, Mehta NN, Bagheri R, Derohannessian SL, Shah R, Mucksavage MI, Bradfield JP, Hakonarson H, Wang X, Master SR, Rader DJ, Li M, Reilly MP
J Am Coll Cardiol. 2012 59 (8): 764-72

PMID: 22340269 · PMCID: PMC3285416 · DOI:10.1016/j.jacc.2011.11.019

OBJECTIVES - This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis.

BACKGROUND - 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.

METHODS - We examined inflammatory regulation of Lp-PLA₂ during experimental endotoxemia in humans, probed the source of Lp-PLA₂ in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA₂, with coronary artery calcification.

RESULTS - In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA₂ messenger ribonucleic acid decreased transiently, and plasma Lp-PLA₂ mass declined modestly during endotoxemia. In vitro, Lp-PLA₂ 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-PLA₂ 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.

CONCLUSIONS - Circulating Lp-PLA₂ 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-PLA₂. Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA₂ to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA₂ as a biomarker of Lp-PLA₂ actions in the vasculature.

© 2012 American College of Cardiology Foundation.

MeSH Terms (12)

1-Alkyl-2-acetylglycerophosphocholine Esterase Adult Biomarkers Coronary Artery Disease Female Gene Expression Regulation Humans Inflammation Male Polymorphism, Single Nucleotide Real-Time Polymerase Chain Reaction RNA, Messenger

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