Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation.
Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation.
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DOI：
10.1016/j.atherosclerosis.2009.11.031
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发表时间：
2010-05
期刊：
影响因子：
5.3
通讯作者：
Gerszten, Robert E.
中科院分区：
文献类型：
--
作者：
Kristo, Fjoralba;Hardy, Gregory J.;Anderson, Thomas J. T.;Sinha, Sumita;Ahluwalia, Neil;Lin, Alexander Y.;Passeri, Jonathan;Scherrer-Crosbie, Marielle;Gerszten, Robert E.
白三烯B4（LTB 4）是由酶5-脂氧合酶（5-LO）和LTA 4-水解酶产生的促炎脂质介质。LTB 4主要通过其G蛋白偶联受体BLT 1发出信号，BLT 1在特定的白细胞亚群上高度表达。最近的人类遗传学研究以及小鼠基因敲除研究表明，白三烯合成途径与几种血管病变有关。在这里，我们测试的假设，药理学抑制BLT 1减少腹主动脉瘤（AAA）的形成，一个主要的并发症与动脉粥样硬化性血管疾病。在良好建立的鼠AAA模型中，从10周龄开始，用血管紧张素II（AngII，1000 ng/kg/min）输注饲料喂养的Apoe-/-小鼠4周。与AngII输注同时开始的选择性BLT 1拮抗剂CP-105，696的给药将AAA形成的发生率从82%降低到40%（p<0.05）。主动脉最大直径从2.35 mm降低到1.56 mm（p<0.05）。虽然在AngII输注开始后第14天给予拮抗剂减少了病变巨噬细胞的积聚，但到第42天，它并没有显著改变AAA的大小。因此，BLT 1的药理学抑制可能最终具有临床前景，但早期干预可能至关重要。
Leukotriene B4 (LTB4) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA4-hydrolase. LTB4 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.
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