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

Abstract

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.

• Authors: Jane F Ferguson, Christine C Hinkle, Nehal N Mehta, Roshanak Bagheri, Stephanie L Derohannessian, Rhia Shah, Megan I Mucksavage, Jonathan P Bradfield, Hakon Hakonarson, Xuexia Wang, Stephen R Master, Daniel J Rader, Mingyao Li, Muredach P Reilly
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 59 Issue 8 Pg. 764-72 (Feb 21 2012) ISSN: 1558-3597 [Electronic] United States
• PMID: 22340269 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 American College of Cardiology Foundation.

Chemical References

• Biomarkers
• RNA, Messenger
• 1-Alkyl-2-acetylglycerophosphocholine Esterase

Topics

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