Evidence Supporting a Key Role of Lp-PLA2-Generated Lysophosphatidylcholine in Human Atherosclerotic Plaque Inflammation

被引：208

作者：

Goncalves, Isabel ^{[1
,2
]}

Edsfeldt, Andreas ^{[1
]}

Ko, Na Young ^{[1
]}

Grufman, Helena ^{[1
,2
]}

Berg, Katarina ^{[1
]}

Bjoerkbacka, Harry ^{[1
]}

Nitulescu, Mihaela ^{[1
]}

Persson, Ana ^{[1
,2
]}

Nilsson, Marie ^{[1
,2
]}

Prehn, Cornelia ^{[3
]}

Adamski, Jerzy ^{[3
,4
]}

Nilsson, Jan ^{[1
]}

机构：

[1] Lund Univ, Clin Res Ctr, Expt Cardiovasc Res Grp, Malmo, Sweden

[2] Malmo Univ Hosp, Dept Cardiol, Malmo, Sweden

[3] German Res Ctr, Helmholtz Zentrum Munchen, Genome Anal Ctr, Inst Expt Genet, Neuherberg, Germany

[4] Tech Univ Munich, Inst Expt Genet, Life & Food Sci Ctr Weihenstephan, Freising Weihenstephan, Germany

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2012年 / 32卷 / 06期

基金：

瑞典研究理事会;

关键词：

atherosclerosis; carotid plaque; inflammation; lipoprotein-associated phospholipase A2; lysophosphatidylcholine; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; CORONARY-ARTERY-DISEASE; HUMAN ENDOTHELIAL-CELLS; PHOSPHOLIPASE A(2); DEPENDENT MECHANISM; HUMAN-MONOCYTES; T-LYMPHOCYTES; OXIDIZED LDL; EXPRESSION;

D O I：

10.1161/ATVBAHA.112.249854

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective-To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp-PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein-oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. Methods and Results-Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among lysoPC 16: 0, 18: 0, 18: 1, LPA, and Lp-PLA2 in plaques. LysoPC 16: 0, 18: 0, 18: 1, LPA, and Lp-PLA2 correlated with interleukin-1 beta, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 beta, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-alpha in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16: 0, 18: 0, and 18: 1, but not LPA were higher in symptomatic than in asymptomatic plaques. Conclusion-The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2012;32:1505-1512.)

引用

页码：1505 / +

页数：19

共 43 条

[1] Lysophosphatidylcholine induces inflammatory activation of human coronary artery smooth muscle cells [J].

Aiyar, Nambi ;

Disa, Jyoti ;

Ao, Zhaohui ;

Ju, Haisong ;

Nerurkar, Sandhya ;

Willette, Robert N. ;

Macphee, Colin H. ;

Johns, Douglas G. ;

Douglas, Stephen A. .

MOLECULAR AND CELLULAR BIOCHEMISTRY, 2007, 295 (1-2) :113-120

[2]

[Anonymous], METABOLOMICS

[3] LPA Receptors: Subtypes and Biological Actions [J].

Choi, Ji Woong ;

Herr, Deron R. ;

Noguchi, Kyoko ;

Yung, Yun C. ;

Lee, Charig-Wook ;

Mutoh, Tetsuji ;

Lin, Mu-En ;

Teo, Siew T. ;

Park, Kristine E. ;

Mosley, Alycia N. ;

Chun, Jerold .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2010, 50 :157-186

[4] 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

[5] MINIMALLY MODIFIED LOW-DENSITY-LIPOPROTEIN INDUCES MONOCYTE CHEMOTACTIC PROTEIN-1 IN HUMAN ENDOTHELIAL-CELLS AND SMOOTH-MUSCLE CELLS [J].

CUSHING, SD ;

BERLINER, JA ;

VALENTE, AJ ;

TERRITO, MC ;

NAVAB, M ;

PARHAMI, F ;

GERRITY, R ;

SCHWARTZ, CJ ;

FOGELMAN, AM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (13) :5134-5138

[6] Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease [J].

Emanuele, E ;

Falcone, C ;

D'Angelo, A ;

Minoretti, P ;

Buzzi, MP ;

Bertona, M ;

Geroldi, D .

ATHEROSCLEROSIS, 2006, 186 (01) :140-145

[7] Oxidised LDL modulates immune-activation by an IL-12 dependent mechanism [J].

Fei, GZ ;

Huang, YH ;

Swedenborg, J ;

Frostegård, J .

ATHEROSCLEROSIS, 2003, 169 (01) :77-85

[8] Changes related to age and the extracellular matrix cerebrovascular symptoms in of human carotid plaques [J].

Gonçalves, I ;

Moses, J ;

Dias, N ;

Pedro, LM ;

Fernandes, JFE ;

Nilsson, J ;

Ares, MPS .

STROKE, 2003, 34 (03) :616-622

[9] Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice [J].

Gu, L ;

Okada, Y ;

Clinton, SK ;

Gerard, C ;

Sukhova, GK ;

Libby, P ;

Rollins, BJ .

MOLECULAR CELL, 1998, 2 (02) :275-281

[10]

Haley KJ, 2000, CIRCULATION, V102, P2185

← 1 2 3 4 5 →