Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses.
BACKGROUND
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA2 in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions.


RESULTS
Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA2 activity was observed at 1 month. This was accompanied by upregulated Lp-PLA2 mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA2 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-PLA2. Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA2 activity, induced an increase in several inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) in a concentration-dependent manner. In contrast, Lp-PLA2 inhibition (SB677116; 1 microM) abrogated the inflammatory response elicited by oxidized LDL.


CONCLUSIONS
In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA2 expression. In vitro, Lp-PLA2 activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA2 inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA2.
Shi
Yi
Y
Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA. yi.shi@jefferson.edu
Zhang
Ping
P
Zhang
LiFeng
L
Osman
Hashim
H
Mohler
Emile R
ER
Macphee
Colin
C
Zalewski
Andrew
A
Postle
Anthony
A
Wilensky
Robert L
RL
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood* / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology; D003324:Coronary Artery Disease / Q000276:immunology; D003331:Coronary Vessels / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000276:immunology*; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000502:physiology*; D008297:Male; D054467:Phospholipases A2; D013552:Swine
D015850:Interleukin-6; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase