Losartan inhibits monocytic adhesion induced by ADMA via downregulation of chemokine receptors in monocytes
Losartan inhibits monocytic adhesion induced by ADMA via downregulation of chemokine receptors in monocytes
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DOI：
10.1007/s00228-008-0607-2
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发表时间：
2009-05-01
影响因子：
2.9
通讯作者：
Xie, Xiu-Mei
中科院分区：
文献类型：
--
作者：
Chen, Mei-Fang;Li, Yuan-Jian;Xie, Xiu-Mei
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，可以诱导单核细胞与血管内皮的粘附，趋化因子在此过程中发挥重要作用。本研究旨在测试氯沙坦对ADMA诱导的单核细胞粘附的抑制作用是否是由趋化因子受体介导的。在不存在或存在氯沙坦的情况下，将人单核细胞（THP-1）与外源ADMA（30μM）一起孵育4或24小时。测定单核细胞粘附、趋化因子水平和趋化因子受体的表达。还探讨了可能的信号通路。在培养的单核细胞中，ADMA（30μM）显着增加单核细胞与内皮细胞的粘附，升高单核细胞趋化蛋白-1（MCP-1）和白细胞介素-8（IL-8）的水平，并上调趋化因子受体CCR2和CXCR2的mRNA表达。暴露于 ADMA (30 μM) 显着诱导细胞内活性氧 (ROS) 的产生和核因子 (NF)-kappa B 的激活。用 AT(1) 受体阻断剂 (ARB) 氯沙坦 (1、3、10 μM) 预处理可减弱 ADMA 引起的单核细胞粘附性，并下调 CCR2 和 CXCR2 mRNA 的表达，同时 ROS 生成和 NF-kappa 显着减少B活性和表达。本研究表明氯沙坦对ADMA诱导的单核细胞粘附的抑制作用可能与通过抑制ROS/NF-kappa B途径下调趋化因子受体有关。
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, can induce the adhesiveness of monocytes to vascular endothelium, and chemokines play an important role in this process. The present study was carried out to test whether the inhibitory effect of losartan on ADMA-induced monocytic adhesion is mediated by chemokine receptors.Human monocytoid cells (THP-1) were incubated with exogenous ADMA (30 mu M) for 4 or 24 h in the absence or presence of losartan. The monocytic adhesion, the levels of chemokines, and the expression of chemokine receptors were determined. The possible signal pathway was also explored.In cultured monocytes, ADMA (30 mu M) markedly increased monocytic adhesion to endothelial cells, elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and upregulated the mRNA expression of chemokine receptors CCR2 and CXCR2. Exposure to ADMA (30 mu M) significantly induced the generation of intracellular reactive oxygen species (ROS) and activation of nuclear factor (NF)-kappa B. Pretreatment with AT(1) receptor blocker (ARB) losartan (1, 3, 10 mu M) attenuated monocytic adhesiveness elicited by ADMA and downregulated the expression of CCR2 and CXCR2 mRNA, accompanied by a significant decrease in ROS generation and NF-kappa B activity and expression.The present study suggests that the inhibitory effect of losartan on ADMA-induced monocytic adhesion may be related to downregulation of chemokine receptors by inhibiting the ROS/NF-kappa B pathway.