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

被引：90

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

共 48 条

[1] QUANTIFICATION OF CORONARY-ARTERY CALCIUM USING ULTRAFAST COMPUTED-TOMOGRAPHY [J].

AGATSTON, AS ;

JANOWITZ, WR ;

HILDNER, FJ ;

ZUSMER, NR ;

VIAMONTE, M ;

DETRANO, R .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1990, 15 (04) :827-832

[2] Innate immunity modulates adipokines in humans [J].

Anderson, Paul D. ;

Mehta, Nehal N. ;

Wolfe, Megan L. ;

Hinkle, Christine C. ;

Pruscino, Leticia ;

Comiskey, Lynne L. ;

Tabita-Martinez, Jennifer ;

Sellers, Kimberly F. ;

Rickels, Michael R. ;

Ahima, Rexford S. ;

Reilly, Muredach P. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2007, 92 (06) :2272-2279

[3]

[Anonymous], METAL MET AN HELP

[4] Association of Carotid Plaque Lp-PLA2 with Macrophages and Chlamydia pneumoniae Infection among Patients at Risk for Stroke [J].

Atik, Berna ;

Johnston, S. Claiborne ;

Dean, Deborah .

PLOS ONE, 2010, 5 (06)

[5] Relation of Plasma Fatty Acid Binding Proteins 4 and 5 With the Metabolic Syndrome, Inflammation and Coronary Calcium in Patients With Type-2 Diabetes Mellitus [J].

Bagheri, Roshanak ;

Qasim, Atif N. ;

Mehta, Nehal N. ;

Terembula, Karen ;

Kapoor, Shiv ;

Braunstein, Seth ;

Schutta, Mark ;

Iqbal, Nayyar ;

Lehrke, Michael ;

Reilly, Muredach P. .

AMERICAN JOURNAL OF CARDIOLOGY, 2010, 106 (08) :1118-1123

[6] Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study [J].

Ballantyne, CM ;

Hoogeveen, RC ;

Bang, H ;

Coresh, J ;

Folsom, AR ;

Heiss, G ;

Sharrett, AR .

CIRCULATION, 2004, 109 (07) :837-842

[7] Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidised LDL on human monocyte-macrophages [J].

Carpenter, KLH ;

Dennis, IF ;

Challis, IR ;

Osborn, DP ;

Macphee, CH ;

Leake, DS ;

Arends, MJ ;

Mitchinson, MJ .

FEBS LETTERS, 2001, 505 (03) :357-363

[8] PLA2G7 Genotype, Lipoprotein-Associated Phospholipase A2 Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry [J].

Casas, Juan P. ;

Ninio, Ewa ;

Panayiotou, Andrie ;

Palmen, Jutta ;

Cooper, Jackie A. ;

Ricketts, Sally L. ;

Sofat, Reecha ;

Nicolaides, Andrew N. ;

Corsetti, James P. ;

Fowkes, F. Gerry R. ;

Tzoulaki, Ioanna ;

Kumari, Meena ;

Brunner, Eric J. ;

Kivimaki, Mika ;

Marmot, Michael G. ;

Hoffmann, Michael M. ;

Winkler, Karl ;

Maerz, Winfred ;

Ye, Shu ;

Stirnadel, Heide A. ;

Khaw, Kay-Tee ;

Humphries, Steve E. ;

Sandhu, Manjinder S. ;

Hingorani, Aroon D. ;

Talmud, Philippa J. .

CIRCULATION, 2010, 121 (21) :2284-U74

[9] Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker [J].

Corson, Marshall A. ;

Jones, Peter H. ;

Davidson, Michael H. .

AMERICAN JOURNAL OF CARDIOLOGY, 2008, 101 (12A) :41F-50F

[10] Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population: The Rancho Bernardo study [J].

Daniels, Lori B. ;

Laughlin, Gall A. ;

Sarno, Mark J. ;

Bettencourt, Ricki ;

Wolfert, Robert L. ;

Barrett-Connor, Elizabeth .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2008, 51 (09) :913-919

← 1 2 3 4 5 →