Translational Studies of Lipoprotein-Associated Phospholipase A2 in Inflammation and Atherosclerosis

被引：91

作者：

Ferguson, Jane F. ^{[1
]}

Hinkle, Christine C. ^{[1
]}

Mehta, Nehal N. ^{[1
]}

Bagheri, Roshanak ^{[1
]}

DerOhannessian, Stephanie L. ^{[1
]}

Shah, Rhia ^{[1
]}

Mucksavage, Megan I. ^{[1
]}

Bradfield, Jonathan P. ^{[6
]}

Hakonarson, Hakon ^{[6
]}

Wang, Xuexia ^{[4
]}

Master, Stephen R. ^{[5
]}

Rader, Daniel J. ^{[1
,2
,3
]}

Li, Mingyao ^{[4
]}

Reilly, Muredach P. ^{[1
,2
,3
]}

机构：

[1] Univ Penn, Dept Med, Cardiovasc Inst, Sch Med, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[4] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[6] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2012年 / 59卷 / 08期

关键词：

coronary artery calcification; lipoprotein-associated phospholipase A(2); PLA2G7; CORONARY-HEART-DISEASE; ACTIVATING-FACTOR ACETYLHYDROLASE; C-REACTIVE PROTEIN; INDEPENDENT PREDICTOR; ARTERY CALCIFICATION; COMPUTED-TOMOGRAPHY; RISK; PLASMA; CALCIUM; GENE;

D O I：

10.1016/j.jacc.2011.11.019

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives This study sought to examine the role of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)/PLA2G7) in human inflammation and coronary atherosclerosis. Background Lp-PLA(2) has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA(2) are indirect and confounded by species differences; whether Lp-PLA(2) is causal in coronary heart disease remains in question. Methods We examined inflammatory regulation of Lp-PLA(2) during experimental endotoxemia in humans, probed the source of Lp-PLA(2) in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA(2), with coronary artery calcification. Results In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA(2) messenger ribonucleic acid decreased transiently, and plasma Lp-PLA(2) mass declined modestly during endotoxemia. In vitro, Lp-PLA(2) 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(2) 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(2) 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(2). Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA(2) to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA(2) as a biomarker of Lp-PLA(2) actions in the vasculature. (J Am Coll Cardiol 2012;59:764-72) (C) 2012 by the American College of Cardiology Foundation

引用

页码：764 / 772

页数：9

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