Wittwer Jonas, Hersberger Martin
Institute of Clinical Chemistry, Center for Integrative Human Physiology, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
Prostaglandins Leukot Essent Fatty Acids. 2007 Aug;77(2):67-77. doi: 10.1016/j.plefa.2007.08.001. Epub 2007 Sep 14.
Chronic inflammation plays a major role in atherogenesis and understanding the role of inflammation and its resolution will offer novel approaches to interfere with atherogenesis. The 15(S)-lipoxygenase (15-LOX) plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell cultures and primary cells and even opposite effects on atherosclerosis in two different animal species. There is evidence for a pro-atherosclerotic effect of 15-LOX including the direct contribution to LDL oxidation and to the recruitment of monocytes to the vessel wall, its role in angiotensin II mediated mechanisms and in vascular smooth muscle cell proliferation. In contrast to the pro-atherosclerotic effects of 15-LOX, there is also a broad line of evidence that 15-LOX metabolites of arachidonic and linoleic acid have anti-inflammatory effects. The 15-LOX arachidonic acid metabolite 15-HETE inhibits superoxide production and polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium and can be further metabolized to the anti-inflammatory lipoxins. These promote vasorelaxation in the aorta and counteract the action of most other pro-inflammatory factors like leukotrienes and prostanoids. Anti-atherogenic properties are also reported for the linoleic acid oxidation product 13-HODE through inhibition of adhesion of several blood cells to the endothelium. Furthermore, there is evidence that 15-LOX is involved in the metabolism of the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) leading to a family of anti-inflammatory resolvins and protectins. From these cell culture and animal studies the role of the 15-LOX in human atherosclerosis cannot be predicted. However, recent genetic studies characterized the 15-LOX haplotypes in Caucasians and discovered a functional polymorphism in the human 15-LOX promoter. This will now allow large studies to investigate an association of 15-LOX with coronary artery disease and to answer the question whether 15-LOX is pro- or anti-atherogenic in humans.
慢性炎症在动脉粥样硬化形成过程中起主要作用，了解炎症及其消退的作用将为干预动脉粥样硬化形成提供新方法。15（S）-脂氧合酶（15-LOX）在炎症中扮演着两面性的角色，在细胞培养和原代细胞中具有促炎和抗炎作用，甚至在两种不同动物物种中对动脉粥样硬化有相反的影响。有证据表明15-LOX具有促动脉粥样硬化作用，包括对低密度脂蛋白氧化的直接作用以及单核细胞向血管壁的募集，其在血管紧张素II介导的机制和血管平滑肌细胞增殖中的作用。与15-LOX的促动脉粥样硬化作用相反，也有大量证据表明花生四烯酸和亚油酸的15-LOX代谢产物具有抗炎作用。15-LOX花生四烯酸代谢产物15-HETE可抑制超氧化物的产生以及多形核中性粒细胞（PMN）穿过细胞因子激活的内皮细胞的迁移，并可进一步代谢为抗炎性脂氧素。这些物质可促进主动脉血管舒张，并抵消大多数其他促炎因子如白三烯和前列腺素的作用。亚油酸氧化产物13-HODE通过抑制几种血细胞与内皮细胞的黏附也具有抗动脉粥样硬化特性。此外，有证据表明15-LOX参与长链ω-3脂肪酸二十二碳六烯酸（DHA）的代谢，产生一系列抗炎性消退素和保护素。从这些细胞培养和动物研究中无法预测15-LOX在人类动脉粥样硬化中的作用。然而，最近的基因研究对高加索人的15-LOX单倍型进行了特征分析，并在人类15-LOX启动子中发现了一个功能性多态性。这现在将允许进行大规模研究，以调查15-LOX与冠状动脉疾病的关联，并回答15-LOX在人类中是促动脉粥样硬化还是抗动脉粥样硬化的问题。
