LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2, ACETYLSALICYLIC ACID AND ATHEROSCLEROSI

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们对动脉粥样硬化的认识在上个世纪有了进展。已经提出了两种假说来解释这种疾病;损伤和脂质氧化的炎症反应，以及对动脉壁中脂质滞留的反应。这两种假说认为氧化低密度脂蛋白（ox-LDL）是炎症级联反应的主要贡献者。Lp-PLA 2是磷脂酶A2超家族的一员，分子量为45.4KDa，不依赖钙离子。它最初被称为血小板活化因子乙酰水解酶（PAF-AH），并被认为通过水解血小板活化因子而具有抗炎特性。最近，它也被认为具有促炎特性。Lp-PLA 2在sn-2位点水解氧化磷脂并产生强促炎和促动脉粥样硬化产物溶血磷脂酰胆碱（Lyso-PC）和氧化脂肪酸（OxFA）。Lp-PLA 2由几种细胞谱系分泌;单核细胞、巨噬细胞、T淋巴细胞和肥大细胞。含LDL的载脂蛋白B-100（apo B-100）的羧基末端连接到酶蛋白上的两个结构域。这解释了为什么血浆中循环的Lp-PLA 2的80-90%的质量与LDL结合。10-20%的酶质量与高密度脂蛋白（HDL）结合，其余的存在于极低密度脂蛋白（VLDL）中。Lp-PLA 2在LDL部分上保持潜伏，直到LDL被修饰，然后变得有活性并在sn-2位置水解含有LDL的氧化磷脂。Lyso-PC具有显著的促动脉粥样硬化特性，包括内皮依赖性舒张受损、血管和细胞粘附分子、CD 40配体表达和化学引诱细胞因子的上调以及一氧化氮产生的下调（15）。关于OxFA的生物学作用知之甚少，尽管它与高促炎潜力有关。阿司匹林不仅能乙酰化环氧合酶，抑制血小板聚集，而且具有抗氧化作用。虽然其抗氧化特性的确切机制尚未明确确定，但提出了几种解释。Oberle等人认为阿司匹林上调铁蛋白的生物合成，这可能提供对LDL氧化的保护。Hermann等人发现水杨酸酯部分抑制超氧化物/一氧化氮对LDL的作用。Exner等人发现龙胆酸（水杨酸代谢物）负责抑制葡萄糖自氧化介导的LDL修饰。一些临床研究表明，动脉粥样硬化和CAD患者的Lp-PLA 2水平升高。在苏格兰西部冠状动脉预防研究（WOSCOPS）的一项嵌套队列研究中，将580名患有心脏事件（心肌梗死、经皮冠状动脉介入治疗或死亡）的男性与1160名年龄和吸烟匹配的对照组进行了比较。与最低水平相比，在Lp-PLA 2的最高五分位数中发现CAD风险增加2倍。来自社区动脉粥样硬化风险（ARIC）研究的结果支持了Lp-PLA 2是CAD的独立风险因素的假设，并且在识别具有正常至低LDL的高风险患者时对CRP具有补充作用。Steer等人在一项出色的研究中报道，给予10名正常血脂的健康受试者300 mg阿司匹林2周，在体外保护了LDL氧化。目前还没有研究观察阿司匹林对Lp-PLA 2水平的影响。

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.