Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, United States.
Atherosclerosis. 2010 May;210(1):107-13. doi: 10.1016/j.atherosclerosis.2009.11.031. Epub 2009 Nov 26.
Leukotriene B(4) (LTB(4)) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA(4)-hydrolase. LTB(4) signals primarily through its G protein-coupled receptor BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominal aortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe(-/-) mice were treated with a 4-week infusion of Angiotensin II (AngII, 1000 ng/(kg min)) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical.
白三烯 B(4)(LTB(4))是一种由 5-脂氧合酶(5-LO)和 LTA(4)-水解酶生成的促炎脂质介质。LTB(4)主要通过其 G 蛋白偶联受体 BLT1 信号转导，BLT1 在特定白细胞亚群中高度表达。最近在人类中的遗传研究以及在小鼠中的基因敲除研究表明，白三烯合成途径与几种血管病变有关。在这里，我们检验了这样一个假设，即 BLT1 的药理学抑制可减少腹主动脉瘤(AAA)的形成，AAA 是与动脉粥样硬化血管疾病相关的主要并发症。10 周龄时，用 Angiotensin II(AngII，1000ng/(kg min))进行 4 周输注，在一种成熟的小鼠 AAA 模型中，对 Chow 喂养的 Apoe(-/-)小鼠进行处理。同时给予 BLT1 选择性拮抗剂 CP-105,696 进行治疗，可使 AAA 的形成发生率从 82%降低至 40%(p<0.05)。最大主动脉直径也从 2.35mm 减少到 1.56mm(p<0.05)。虽然在 AngII 输注开始后第 14 天给予拮抗剂可减少病变处巨噬细胞的积累，但到第 42 天时，它并未显著改变 AAA 的大小。因此，BLT1 的药理学抑制可能具有临床应用前景，但早期干预可能至关重要。
