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

Authors: 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 
Citation: Ferguson JF, etal., J Am Coll Cardiol. 2012 Feb 21;59(8):764-72.
Pubmed: (View Article at PubMed) PMID:22340269
DOI: Full-text: DOI:10.1016/j.jacc.2011.11.019

OBJECTIVES: This study sought to examine the role of lipoprotein-associated phospholipase A (Lp-PLA/PLA2G7) in human inflammation and coronary atherosclerosis. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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CRRD Object Information
CRRD ID: 6482770
Created: 2012-05-02
Species: All species
Last Modified: 2012-05-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.