Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses

Autor: Anthony D. Postle, Robert L. Wilensky, Colin H. Macphee, Andrew Zalewski, Yi Shi, LiFeng Zhang, Ping Zhang, Emile R. Mohler, Hashim Osman
Rok vydání: 2007
Předmět:
Male
medicine.medical_specialty
Swine
medicine.medical_treatment
Hypercholesterolemia
Inflammation
Coronary Artery Disease
macromolecular substances
Peripheral blood mononuclear cell
Diabetes Mellitus
Experimental
Proinflammatory cytokine
chemistry.chemical_compound
Phospholipase A2
stomatognathic system
Internal medicine
medicine
Animals
Phospholipase A
biology
Interleukin-6
Lipoprotein-associated phospholipase A2
respiratory system
Atherosclerosis
Intercellular Adhesion Molecule-1
Coronary Vessels
Lipoproteins
LDL
Disease Models
Animal
Phospholipases A2
Endocrinology
Cytokine
Lysophosphatidylcholine
chemistry
1-Alkyl-2-acetylglycerophosphocholine Esterase
Leukocytes
Mononuclear
biology.protein
Diet
Atherogenic
lipids (amino acids
peptides
and proteins)
medicine.symptom
Cardiology and Cardiovascular Medicine
Zdroj: Atherosclerosis. 191:54-62
ISSN: 0021-9150
DOI: 10.1016/j.atherosclerosis.2006.05.001
Popis: 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-1β, IL-6, TNF-α) in a concentration-dependent manner. In contrast, Lp-PLA 2 inhibition (SB677116; 1 μM) 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 .
Databáze: OpenAIRE
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