Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses
Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses
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DOI：
10.1016/j.atherosclerosis.2006.05.001
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发表时间：
2007-03-01
期刊：
影响因子：
5.3
通讯作者：
Wilensky, Robert L.
中科院分区：
文献类型：
--
作者：
Shi, Yi;Zhang, Ping;Wilensky, Robert L.
背景：脂蛋白相关磷脂酶A（2）（Lp-PLA（2））是一种新兴的心血管风险标志物。为了探索Lp-PLA（2）在动脉粥样硬化中的生物学作用，我们检测了其在致动脉粥样硬化条件下的表达和对白细胞活化的贡献。方法和结果：在猪模型中诱导糖尿病和高胆固醇血症后，在1个月时观察到血浆Lp-PLA（2）活性迅速增加。3个月时外周血单核细胞（PBMC）的Lp-PLA（2）mRNA表达上调，6个月时冠状动脉中Lp-PLA（2）mRNA表达升高。这些变化被循环PBMC（ICAM-1，IL-6）的增加的炎症反应所掩盖。在冠状动脉组织中（ICAM-1，VCAM-1），以及随后的炎症细胞积累。在人PBMC中，促炎介质增加了功能性Lp-PLA的合成和释放（2）。此外，Lp-PLA（2）活性产物溶血磷脂酰胆碱（lysoPC）以浓度依赖性方式诱导几种炎性细胞因子（IL-1 β、IL-6、TNF-α）增加。相反，Lp-PLA（2）抑制（SB 677116; 1 μ M）消除了氧化LDL引起的炎症反应。结论：在糖尿病和高胆固醇血症的实验模型中，白细胞活化与Lp-PLA（2）表达增加有关。在体外，Lp-PLA（2）活性介导白细胞活化和炎症反应，而Lp-PLA（2）抑制则消除氧化LDL诱导的炎症反应。总之，这些观察结果支持Lp-PLA的促动脉粥样硬化作用（2）。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
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-1 beta, IL-6, TNF-alpha) in a concentration-dependent manner. In contrast, Lp-PLA(2) inhibition (SB677116; 1 mu M) 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). (c) 2006 Elsevier Ireland Ltd. All rights reserved.