Atherosclerosis 191 (2007) 54–62
Role of lipoprotein-associated phospholipase A
2
in leukocyte
activation and inflammatory responses
Yi Shi
a,∗
, Ping Zhang
a
, LiFeng Zhang
a
, Hashim Osman
b
, Emile R. Mohler III
b
,
Colin Macphee
c
, Andrew Zalewski
a,c
, Anthony Postle
d
, Robert L. Wilensky
b
a
Thomas Jefferson University, Philadelphia, PA, United States
b
University of Pennsylvania, Philadelphia, PA, United States
c
GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, United States
d
University of Southampton, UK
Received 21 November 2005; received in revised form 4 April 2006; accepted 1 May 2006
Available online 9 June 2006
Abstract
Background: Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
) is an emerging cardiovascular risk marker. To explore the biologic role of
Lp-PLA
2
in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions.
Methods and results: Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA
2
activity was observed at 1 month. This was accompanied by upregulated Lp-PLA
2
mRNA expression by peripheral blood mononuclear cells
(PBMC) at 3 months, and elevated Lp-PLA
2
mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased
inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of
inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA
2
. Furthermore,
lysophosphatidylcholine (lysoPC), a product of Lp-PLA
2
activity, induced an increase in several inflammatory cytokines (IL-1, IL-6, TNF-)
in a concentration-dependent manner. In contrast, Lp-PLA
2
inhibition (SB677116; 1 M) abrogated the inflammatory response elicited by
oxidized LDL.
Conclusions: In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA
2
expression. In vitro, Lp-PLA
2
activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA
2
inhibition abolished
inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA
2
.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Atherosclerosis; Hypercholesterolemia; Diabetes; Inflammation; Lipoprotein-associated phospholipase A
2
1. Introduction
Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
),
also known as platelet activating factor acetylhydrolase,
belongs to the large family of phospholipases that liberate
bioactive molecules through the hydrolysis of a wide range
of phospholipids [1]. Lp-PLA
2
is unique among members of
phospholipase A
2
superfamily due to its origin (secreted from
∗
Correspondence to: Department of Surgery, Thomas Jefferson Univer-
sity, Suite 623, 1025 Walnut Street, Philadelphia, PA 19107, United States.
Tel.: +1 215 955 2693; fax: +1 215 955 2878.
E-mail address: yi.shi@jefferson.edu (Y. Shi).
bone marrow-derived cells, mainly leukocytes), its associa-
tion with circulating lipoproteins, and its substrate preference
for polar phospholipids including those generated during the
oxidation of LDL [2]. Several studies have demonstrated
higher levels of circulating Lp-PLA
2
(mass or activity) in
individuals who subsequently develop cardiovascular events
[3–8]. In most studies, Lp-PLA
2
remained an independent
predictor of future events even after adjustment for several
conventional risk factors. Furthermore, higher levels of circu-
lating Lp-PLA
2
appear to be associated with atherosclerotic
burden, as assessed by extent of coronary artery calcifications
or the angiographic extent of coronary artery disease [9,10].
Although the emerging epidemiologic data provide evidence
0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2006.05.001