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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Leukotriene B-4 signaling through NF-kappa B-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia
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Leukotriene B-4 signaling through NF-kappa B-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia

机译：白三烯B-4通过动脉粥样硬化和内膜增生中的血管平滑肌细胞上的NF-κB依赖性BLT1受体进行信号传导

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摘要

Leukotriene B-4 (LTB4) a potent leukocyte chemoattractant derived from the 5-lipoxygenase metabolism of arachidonic acid, exerts its action by means of specific cell surface receptors, denoted BLT1 and BLT2. In this study, BLT1 receptor proteins were detected in human carotid artery atherosclerotic plaques, colocalizing with markers for macrophages, enclothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB4 or U75302, a partial agonist that is selective for the BLT1 receptor, induced an approximate to 4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT1 receptors. LTB4 induced migration and proliferation of SMC in vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injury in vivo inhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT1 receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1 beta in vitro, were prevented by transfection with a dominantnegative form of I kappa kinase beta carried by adenovirus, indicating that BLT1 receptor expression depends on NF-kappa B. These results show that LTB4 activates functional BLT1 receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT, receptors were up-regulated through an I kappa kinase P/NF-kappa B-dependent pathway. Inhibition of LTB4/BLT1 signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.
机译：白三烯B-4（LTB4）是一种有效的白细胞化学引诱剂，来自花生四烯酸的5-脂氧合酶代谢，通过特定的细胞表面受体（称为BLT1和BLT2）发挥作用。在这项研究中，在人的颈动脉粥样硬化斑块中检测到BLT1受体蛋白，并与巨噬细胞，肾上腺细胞和血管平滑肌细胞（SMC）的标志物共定位。通过使用膜片钳技术，对LLT4或U75302（对BLT1受体具有选择性的部分激动剂）对人冠状动脉SMC的攻击诱导了全细胞电流的约4倍增加，表明这些细胞表达了功能性BLT1受体。 LTB4体外诱导SMC迁移和增殖，并在体内颈动脉球囊损伤后用BLT受体拮抗剂BIIL 284（10 mg / kg，每天一次）治疗14天，抑制大鼠内膜增生。在后一种模型中，与内侧SMC相比，源自内膜的SMC表现出更高水平的BLT1受体mRNA。腺病毒携带的显性阴性形式的Iκ激酶β转染可防止体内BLT受体在体内内膜上调以及在体外由IL-1β上调，表明BLT1受体表达依赖于NF-这些结果表明LTB4激活血管SMC上的功能性BLT1受体，诱导趋化性和增殖，并且BLT受体通过Iκ激酶P /NF-κB依赖性途径上调。在对血管损伤的反应过程中对LTB4 / BLT1信号的抑制减少了内膜增生，提示该途径可能是治疗的靶标。

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