Qiu Hong, Gabrielsen Anders, Agardh Hanna E, Wan Min, Wetterholm Anders, Wong Chi-Huey, Hedin Ulf, Swedenborg Jesper, Hansson Göran K, Samuelsson Bengt, Paulsson-Berne Gabrielle, Haeggström Jesper Z
Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8161-6. doi: 10.1073/pnas.0602414103. Epub 2006 May 12.
Leukotrienes (LT) are a group of proinflammatory lipid mediators that are implicated in the pathogenesis and progression of atherosclerosis. Here we report that mRNA levels for the three key proteins in LTB4 biosynthesis, namely 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTA4 hydrolase (LTA4H), are significantly increased in human atherosclerotic plaque (n = 72) as compared with healthy controls (n = 6). Neither LTC4 synthase nor any of the LT receptors exhibits significantly increased mRNA levels. Immunohistochemical staining revealed abundant expression of 5-LO, FLAP, and LTA4H protein, colocalizing in macrophages of intimal lesions. Human lesion tissue converts arachidonic acid into significant amounts of LTB4, and a selective, tight-binding LTA4H inhibitor can block this activity. Furthermore, expression of 5-LO and LTA4H, but not FLAP, is increased in patients with recent or ongoing symptoms of plaque instability, and medication with warfarin correlates with increased levels of FLAP mRNA. In contrast to human plaques, levels of 5-LO mRNA are not significantly increased in plaque tissues from two atherosclerosis-prone mouse strains, and mouse plaques exhibit segregated cellular expression of LTA4H and 5-LO as well as strong increases of CysLT1 and CysLT2 mRNA. These discrepancies indicate that phenotypic changes in the synthesis and action of LT in specific mouse models of atherosclerosis should be cautiously translated into human pathology. The abundant expression of LTA4H and correlation with plaque instability identify LTA4H as a potential target for pharmacological intervention in treatment of human atherosclerosis.
白三烯（LT）是一类促炎脂质介质，与动脉粥样硬化的发病机制和进展有关。在此我们报告，与健康对照者（n = 6）相比，人类动脉粥样硬化斑块（n = 72）中白三烯B4（LTB4）生物合成过程中三种关键蛋白，即5-脂氧合酶（5-LO）、5-脂氧合酶激活蛋白（FLAP）和LTA4水解酶（LTA4H）的mRNA水平显著升高。LTC4合酶和任何一种LT受体的mRNA水平均未显著升高。免疫组织化学染色显示5-LO、FLAP和LTA4H蛋白表达丰富，在内膜病变的巨噬细胞中共定位。人类病变组织可将花生四烯酸转化为大量LTB4，一种选择性、紧密结合的LTA4H抑制剂可阻断该活性。此外，在有近期或持续斑块不稳定症状的患者中，5-LO和LTA4H（而非FLAP）的表达增加，使用华法林治疗与FLAP mRNA水平升高相关。与人类斑块不同，在两种易患动脉粥样硬化的小鼠品系的斑块组织中，5-LO mRNA水平未显著升高，且小鼠斑块中LTA4H和5-LO呈细胞分离表达，同时半胱氨酰白三烯1（CysLT1）和半胱氨酰白三烯2（CysLT2）mRNA强烈增加。这些差异表明，在特定动脉粥样硬化小鼠模型中LT合成和作用的表型变化应谨慎地外推至人类病理学。LTA4H的丰富表达及其与斑块不稳定的相关性表明LTA4H是人类动脉粥样硬化治疗中药理学干预的潜在靶点。
