脂蛋白相关磷脂酶A2:一种独立血管风险预测因子和治疗新靶点

脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,Lp-PLA2)可快速水解氧化低密度脂蛋白和脂蛋白(a)中的氧化磷脂分子,生成可溶性促炎和促凋亡介质-溶血卵磷脂和氧化游离脂肪酸,刺激单核巨噬细胞系统聚集和激活,诱导细胞凋亡和破坏死亡细胞的清除,在动脉粥样硬化脂质坏死核心的发展中起重要作用.Lp-PLA2不仅是冠状动脉疾病和缺血性卒中的独立风险标志物,而且在动脉粥样硬化斑块进展中起重要作用.选择性Lp-PLA2抑制剂可减少坏死核心的发展,可能对动脉粥样斑块起稳定作用,同时可能代表着一种动脉粥样硬化的治疗新靶点.     

脂蛋白相关磷脂酶A2在动脉粥样硬化中的作用

人血浆脂蛋白相关磷脂酶A2(Lp-PLA2)又称血小板活化因子乙酰水解酶(PAF-AH),主要由巨噬细胞合成和分泌.大部分Lp-PLA2与低密度脂蛋白结合,能水解灭活血小板活化因子,水解低密度脂蛋白上的氧化磷脂,生成溶血卵磷脂和氧化型游离脂肪酸,因此既有抗炎抗动脉粥样硬化,又有促炎促动脉粥样硬化的作用.近年来,越来越多的研究表明,Lp-PLA2具有促动脉粥样硬化作用,是心血管病的风险预测因子,可能成为心血管病新的治疗目标.     

脂蛋白相关磷脂酶A2在颈动脉粥样硬化和缺血性卒中中的作用

脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,Lp-PLA2)是磷脂酶A2超家族的一个亚型,主要由巨噬细胞和淋巴细胞产生.Lp-PLA2选择性水解低密度脂蛋白颗粒表面的氧化型磷脂,产生溶血磷脂胆碱和氧化型游离脂肪酸.Lp-PLA2表达于动脉粥样硬化斑块和不稳定斑块纤维帽内的巨噬细胞.研究表明,缺血性卒中患者血浆Lp-PLA2活性显著增高,而Lg-PLA2可能成为预测缺血性脑血管事件的独立危险因素.选择性LP-PLA2抑制剂可减轻炎症反应,增强斑块稳定性,抑制动脉粥样硬化斑块形成,有可能成为抗动脉粥样硬化斑块形成的一类新型药物.     

脂蛋白相关磷脂酶A_2在动脉粥样硬化中的作用

人血浆脂蛋白相关磷脂酶A2(Lp-PLA2)又称血小板活化因子乙酰水解酶(PAF-AH),主要由巨噬细胞合成和分泌。大部分Lp-PLA2与低密度脂蛋白结合,能水解灭活血小板活化因子,水解低密度脂蛋白上的氧化磷脂,生成溶血卵磷脂和氧化型游离脂肪酸,因此既有抗炎抗动脉粥样硬化,又有促炎促动脉粥样硬化的作用。近年来,越来越多的研究表明,Lp-PLA2具有促动脉粥样硬化作用,是心血管病的风险预测因子,可能成为心血管病新的治疗目标。     

脂蛋白相关磷脂酶A2与颈动脉粥样硬化

脂蛋白相关磷脂酶A2(lipowotein-associated phospholipase A2, Lp-PLA2)是心血管疾病的一种新型生物学标志物.它在有症状颈动脉粥样硬化斑块中的表达高于无症状颈动脉粥样硬化斑块,其产物溶血磷脂胆碱与组织氧化应激和炎症有关.另外,Lp-PLA2在颈动脉粥样硬化斑块的不稳定性差异中起着较为独特的作用.     

脂蛋白相关磷脂酶A2与冠状动脉粥样硬化的相关性

动脉粥样硬化斑块的形成与血管内膜炎症反应和氧化应激密切相关.脂蛋白相关磷脂酶A2(Lp-PLA2)是较新的一个炎症因子,与冠状动脉粥样硬化的形成密切相关.     

细胞水平胰岛素抵抗导致动脉粥样硬化斑块进展的研究

近期提出细胞水平胰岛素抵抗包括内皮细胞、平滑肌细胞和巨噬细胞,即粥样硬化斑块病变内细胞自身存在胰岛素信号通路的缺陷导致细胞生物学性能的改变,在动脉粥样硬化斑块进展中起关键作用.如斑块内细胞自身胰岛素抵抗可降低内皮细胞的舒张功能、平滑肌细胞的增殖、迁移并增加巨噬细胞凋亡和吞噬缺陷,导致粥样硬化斑块坏死核心的扩大.因此,深入了解细胞水平胰岛素抵抗参与动脉粥样硬化疾病发生、发展的机制为未来研发新型药物开辟新方向.     

脂蛋白相关磷脂酶A2在急性冠状动脉综合征中的研究进展

脂蛋白相关磷脂酶A2(Lp-PLA2)由炎症细胞产生,可以水解氧化型低密度脂蛋白(ox-LDL)产生炎症介质促进动脉粥样硬化。Lp-PLA2存在于不稳定斑块以及破裂斑块中,与急性冠状动脉综合征的发病机制有关。LpPLA2作为心血管事件的独立预测因子而受到广泛关注。Darapladib是一种特异性Lp-PLA2抑制剂,其Ⅲ期临床试验已完成,结果对于以粥样硬化炎症成份为新型治疗靶点的探索提出了新的挑战。     

颈动脉粥样硬化斑块与血浆脂蛋白相关磷脂酶A2的关系

选择103例心内科住院患者行颈动脉超声检查，测量颈动脉四组血管内径、内中膜厚度（IMT），估测血管狭窄程度，计算粥样硬化斑块的Crouse积分，并根据有无斑块将患者分为斑块组和对照组，检测两组血浆脂蛋白相关磷脂酶A2（Lp-PLA2）浓度，用线形回归模型来估计动脉斑块与Lp-PL如及其他危险因子的线形关系。结果斑块组与对照组的IMT、Lp-PLA2均有统计学差异（P均〈0.05）；Lp-PLA2浓度与颈动脉IMT、斑块积分呈正相关。认为Lp-PLA2与颈动脉IMT一样，可作为早期动脉粥样硬化的判断指标。     

基于Lp-PLA2水平分析急性脑梗死与颈动脉粥样硬化斑块的关系

目的探讨急性脑梗死患者脂蛋白相关磷脂酶A2(Lp-PLA2)水平的变化特点及其与颈动脉粥样硬化斑块的关系。方法选取2013年6月至2014年10月来我院就诊确诊的82例急性脑梗死患者作为脑梗死组,并选取同期我院体检者82例作为对照组,彩色多普勒超声检测颈总动脉粥样硬化斑块,ELISA检测血清Lp-PLA2水平,Spearman相关分析急性脑梗死患者血清Lp-PLA2水平变化特点及其与梗死面积、颈动脉粥样硬化斑块Crouse积分之间的关系。结果脑梗死组Lp-PLA2、hs-CRP、TG、TC及LDLC的水平显著高于对照组,HDLC水平显著低于对照组(P0.05);颈动脉粥样硬化斑块Ⅰ级、Ⅱ级和Ⅲ级三组间Crouse积分、Lp-PLA2水平比较具有显著性差异,且随分级增加Lp-PLA2水平升高(P0.05);急性脑梗死患者Lp-PLA2水平随神经功能损伤程度增加而升高,Lp-PLA2水平与Crouse积分、梗死面积呈正相关(r=0.823和r=0.879,P0.05)。结论 Lp-PLA2水平与动脉粥样硬化性脑梗死有关,可反映患者颈动脉粥样硬化斑块及脑梗死面积情况,可作为脑梗死预测指标。     

Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target

The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA2 mediated by products of the Lp-PLA2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA2, in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients.     

Vaccines in development to prevent and treat atherosclerotic disease

Coronary heart disease (CHD) remains the leading cause of death in the United States. Immune mechanisms have been recently proposed to play an important role in the development of atherosclerotic plaques in CHD. Heat shock proteins and oxidized low-density lipoprotein are proinflammatory substances that have been shown to have an important role in the pathogenesis of atherosclerosis, and are now targets for clinical vaccine development. In addition, a vaccine has been developed to inhibit cholesteryl ester transfer protein. It is now recognized that many medications used to combat plaque development and rupture have significant anti-inflammatory effects and these effects are critical for drug efficacy. The influenza vaccine is associated with an atheroprotective effect. In addition, a nicotine vaccine, an antiangiotensin vaccine, and an anti-obesity vaccine may play a therapeutic role in modifying known risk factors for the development of atherosclerosis and its complications. This article reviews these vaccines as possible additions to the armamentarium of atheroprotective treatment modalities.     

Recent Developments with Lipoprotein-Associated Phospholipase A<Subscript>2</Subscript> Inhibitors

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a calcium-independent phospholipase A₂ enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA₂ in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA₂ generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA₂. Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA₂ reduces plasma Lp-PLA₂ activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA₂ inhibitors.     

慢性肾衰患者血浆脂蛋白相关磷脂酶A2与动脉粥样硬化的关系

目的研究慢性肾功能衰竭患者血浆脂蛋白相关磷脂酶A2(Lp-PLA2)水平与动脉粥样硬化的关系。方法选择慢性肾功能衰竭患者100例和健康对照40例采用酶联免疫吸附(ELISA)法测定血浆脂蛋白相关磷脂酶A2水平,超声技术检测颈动脉内膜中膜厚度和粥样硬化斑块。比较慢性肾衰患者与对照组血浆Lp-PLA2水平及慢性肾功能衰竭患者不同分组间Lp-PLA2水平,并对影响颈动脉颈动脉内膜中膜厚度的多因素进行逐步回归分析。结果慢性肾功能衰竭患者血浆Lp-PLA2水平明显高于健康对照组(232.16±59.36μg/L比129.47±29.72μg/L,P<0.01);透析者血浆Lp-PLA2水平明显高于未透析者(261.84±50.82μg/L比204.73±53.95μg/L,P<0.01);未透析者血浆Lp-PLA2水平与内生肌酐清除率呈负相关(r=-0.567,P<0.01)。有颈动脉粥样斑块者血浆Lp-PLA2水平明显高于无动脉粥样斑块者(281.33±39.72μg/L比188.46±35.02μg/L,P<0.01)。多因素逐步回归分析均显示血浆Lp-PLA2水平与颈动脉内膜中膜厚度呈正相关(β=0.735,P<...     

Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway

Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, -tocopherol, but not β-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.     

脂蛋白相关磷脂酶A2与缺血性卒中

人血浆脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipese A2,LP-PLA2)由成熟的巨噬细胞和淋巴细胞分泌,主要与低密度脂蛋白结合.近年来的研究表明,Lp-PLA2在动脉粥样硬化形成过程中起着重要作用,其基因多态性与缺血性卒中发生相关,其特异性抑制剂具有抗动脉粥样硬化作用.Lp-PLA2可能是缺血性卒中的新型独立危险因素和治疗靶标.