Division of Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21093-7. doi: 10.1073/pnas.1015166107. Epub 2010 Nov 15.
Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC(4), LTD(4), and LTE(4) are important mediators of asthma, and LTB(4) has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC(4) synthase (LTC(4)S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB(4), are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC(4)S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB(4). Furthermore, challenge of AAA wall tissue with exogenous LTD(4) increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC(4)S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.
白细胞三烯（LTs）是一种源自花生四烯酸的脂质介质，参与多种炎症性疾病的发病机制和进展。半胱氨酰白三烯 LTC（4）、LTD（4）和 LTE（4）是哮喘的重要介质，而 LTB（4）最近被牵连到动脉粥样硬化中。在这里，我们报告在人类腹主动脉瘤（AAA）壁中，半胱氨酰白三烯生物合成的三个关键酶/蛋白（5-脂氧合酶（5-LO）、5-LO 激活蛋白（FLAP）和 LTC（4）合酶（LTC（4）S）的 mRNA 水平显著增加。相比之下，负责 LTB（4）生物合成的 LTA（4）水解酶的 mRNA 水平没有增加。AAA 壁的免疫组织化学染色显示 5-LO、FLAP 和 LTC（4）S 蛋白在中膜和外膜中呈局灶性表达，定位于富含炎症细胞的区域，包括巨噬细胞、中性粒细胞和肥大细胞。人 AAA 壁组织将花生四烯酸和不稳定的环氧化物 LTA（4）转化为大量的半胱氨酰白三烯，并且在较小程度上转化为 LTB（4）。此外，外源性 LTD（4）对 AAA 壁组织的挑战增加了基质金属蛋白酶（MMP）2 和 9 的释放，而孟鲁司特对 CysLT1 受体的选择性抑制阻断了这种作用。LTC（4）S 的表达增加，加上半胱氨酰白三烯的主要形成和对 MMP 产生的影响，提示 LTs 可能通过促进 AAA 壁基质降解的机制起作用，并将半胱氨酰白三烯途径的成分确定为 AAA 预防和治疗的潜在靶点。
