Smith Camilla, Damås Jan K, Otterdal Kari, Øie Erik, Sandberg Wiggo J, Yndestad Arne, Waehre Torgun, Scholz Hanne, Endresen Knut, Olofsson Peder S, Halvorsen Bente, Gullestad Lars, Frøland Stig S, Hansson Gøran K, Aukrust Pål
Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway.
J Am Coll Cardiol. 2006 Oct 17;48(8):1591-9. doi: 10.1016/j.jacc.2006.06.060. Epub 2006 Sep 27.
We sought to investigate the role of the CXC chemokine neutrophil-activating peptide-2 (NAP-2) in atherogenesis and plaque destabilization.
Chemokines are involved in atherogenesis, but the role of NAP-2 in atherosclerotic disorders is unclear. Based on its potential pro-atherogenic properties, we hypothesized a pathogenic role for NAP-2 in coronary artery disease.
We tested this hypothesis by differential experimental approaches including studies in patients with stable (n = 40) and unstable angina (n = 40) and healthy control subjects (n = 20).
The following results were discovered: 1) patients with stable, and particularly those with unstable, angina had markedly raised plasma levels of NAP-2 compared with control subjects, accompanied by increased expression of CXC receptor 2 in monocytes; 2) platelets, but also peripheral blood mononuclear cells (PBMCs), released large amounts of NAP-2 upon stimulation, with a particularly prominent PBMC response in unstable angina; 3) NAP-2 protein was detected in macrophages and smooth muscle cells of atherosclerotic plaques and in monocytes and platelets of coronary thrombi; 4) in vitro, recombinant and platelet-derived NAP-2 increased the expression of adhesion molecules and chemokines in endothelial cells; and 5) whereas aspirin reduced plasma levels of NAP-2, statin therapy increased NAP-2 with stimulating effects both on platelets and leukocytes.
Our findings suggest that NAP-2 has the potential to induce inflammatory responses within the atherosclerotic plaque. By its ability to promote leukocyte and endothelial cell activation, such a NAP-2-driven inflammation could promote plaque rupture and acute coronary syndromes.
我们旨在研究CXC趋化因子中性粒细胞激活肽-2（NAP-2）在动脉粥样硬化形成和斑块不稳定中的作用。
趋化因子参与动脉粥样硬化形成，但NAP-2在动脉粥样硬化疾病中的作用尚不清楚。基于其潜在的促动脉粥样硬化特性，我们推测NAP-2在冠状动脉疾病中具有致病作用。
我们通过不同的实验方法来验证这一假设，包括对稳定型心绞痛患者（n = 40）、不稳定型心绞痛患者（n = 40）和健康对照者（n = 20）进行研究。
发现以下结果：1）与对照者相比，稳定型心绞痛患者，尤其是不稳定型心绞痛患者的血浆NAP-2水平显著升高，同时单核细胞中CXC受体2的表达增加；2）血小板以及外周血单个核细胞（PBMC）在受到刺激后会释放大量NAP-2，在不稳定型心绞痛中PBMC的反应尤为突出；3）在动脉粥样硬化斑块的巨噬细胞和平滑肌细胞以及冠状动脉血栓的单核细胞和血小板中检测到NAP-2蛋白；4）在体外，重组NAP-2和血小板衍生的NAP-2可增加内皮细胞中黏附分子和趋化因子的表达；5）阿司匹林可降低血浆NAP-2水平，而他汀类药物治疗则会增加NAP-2水平，对血小板和白细胞均有刺激作用。
我们的研究结果表明，NAP-2有可能在动脉粥样硬化斑块内诱导炎症反应。通过其促进白细胞和内皮细胞活化的能力，这种由NAP-2驱动的炎症可能会促进斑块破裂和急性冠状动脉综合征。
