This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our understanding of atherosclerosis has progressed in the last century. Two hypotheses have been proposed to explain this malady; the inflammatory response to injury and lipid oxidation, and response to lipid retention in the arterial wall. These two hypotheses recognize oxidized low density lipoprotein (ox-LDL)as a major contributor in the inflammatory cascade. Lp-PLA2, a 45.4 KDa calcium-independent phospholipase, is a member of the phospholipase A2 super family. It was initially known as platelet activating factor acetylhydrolase (PAF-AH), and thought to have an anti-inflammatory properties by hydrolyzing the platelet activating factor. Recently, it has been recognized to have pro-inflammatory properties, as well. Lp-PLA2 hydrolyzes oxidized phospholipids at sn-2 site and generates strong pro-inflammatory and pro-atherogenic products, lysophosphatidylcholine (Lyso-PC) and oxidized fatty acids (OxFA). Lp-PLA2 is secreted by several cell lineages; monocytes, macrophages, T lymphocytes, and mast cells. Carboxy terminus of LDL-contained apolipoprotein B-100 (apoB-100) attaches to two domains on the enzyme protein. This explains why 80-90% of the mass circulating Lp-PLA2 in plasma is bound to LDL. 10-20% of the enzyme mass is bound to high density lipoprotein (HDL) and the rest is found in very low density lipoprotein (VLDL). Lp-PLA2 stays latent on the LDL moiety till LDL becomes modified then becomes active and hydrolyzes the LDL-contained oxidized phospholipids at sn-2 location. Lyso-PC has significant pro-atherogenic properties including impairment of endothelium- dependant relaxation, up-regulation of vascular and cellular adhesion molecules, CD40 ligand expression, and chemoattractant cytokines, and downregulation of nitric oxide production(15). Little is known about the biologic effects of OxFA, though it has been associated with high pro-inflammatory potential. Aspirin not only acetylates cyclo-oxygenase and inhibits platelet aggregation, but also exerts anti-oxidant effect. Although the exact mechanism of its anti-oxidant properties has not been clearly identified, several explanations were proposed. Oberle et al. suggested that aspirin up-regulates ferritin biosynthesis which might provide protection against LDL oxidation. Hermann et al. found that salicylate moiety inhibits superoxide/nitric oxide effect on LDL. Exner et al. found gentisic acid (salicylate metabolite) is responsible for inhibiting glucose autoxidation-mediated LDL modification. Several clinical studies have shown increased level of Lp-PLA2 in patients with atherosclerosis and CAD. In a nested cohort study from the West of Scotland Coronary prevention Study (WOSCOPS), 580 men suffering a cardiac event (myocardial infarction, percutaneous coronary intervention, or death) were compared to 1160 age and smoking-matched controls. A 2-fold increase in CAD risk was found in the highest quintile of Lp-PLA2 compared to the lowest. Findings from the Atherosclerosis Risk in Communities (ARIC) study have supported the hypothesis that Lp-PLA2 is an independent risk factor for CAD and has a complementary effect to CRP in identifying high risk patients who have normal to low LDL. Steer et al.reported in an elegant study that giving 300 mg of aspirin to ten normolipidimic healthy subjects for 2 weeks has protected LDL oxidation in vitro. No study has as yet looked at the effect of aspirin on Lp-PLA2 levels.
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