MCP-1-induced enhancement of THP-1 adhesion to vascular endothelium was modulated by HMG-CoA reductase inhibitor through RhoA GTPase-, but not ERK1/2-dependent pathway
MCP-1-induced enhancement of THP-1 adhesion to vascular endothelium was modulated by HMG-CoA reductase inhibitor through RhoA GTPase-, but not ERK1/2-dependent pathway
复制标题
DOI：
10.1016/j.lfs.2004.02.028
复制
发表时间：
2004-07-30
期刊：
影响因子：
6.1
通讯作者：
Yoshida, M
中科院分区：
文献类型：
--
作者：
Hiraoka, M;Nitta, N;Yoshida, M
单核细胞-内皮细胞相互作用在动脉粥样硬化中起着关键作用。我们之前的研究表明，HMG CoA还原酶抑制剂在体外可以减少单核细胞与血管内皮细胞的黏附，但不能减少单核细胞与血管内皮的滚动。在本研究中，我们观察了一种新型的HMG CoA还原酶抑制剂匹伐他汀在血流(切应力=1.0dyne/cm(2))下对MCP-1诱导的单核细胞对血管内皮细胞的滚动向稳定黏附转变的影响。加入50 nM的单核细胞趋化蛋白-1(P<；0.002)后，对照THP-1细胞在活化(IL-1β，4h)的人脐静脉内皮细胞上的滚动数和贴壁细胞数均显著增加。相反，在加入MCP-1之前，MCP-1未能将经匹伐他汀处理(10微米，48小时)的THP-1滚动到稳定的粘附力，与基线粘附力相比(p>；0.4)。甲伐他汀是胆固醇生物合成的中间体，10微米甲伐他汀可逆转匹伐他汀诱导的THP-1细胞改变。为了阐明Pitavastatin调节MCP-1诱导的THP-1黏附作用的机制，检测了细胞外信号调节激酶1/2(ERK1/2)的可能参与。用抗ERK1/2抗体和抗磷酸化ERK1/2抗体(PERK)进行免疫印迹分析表明，匹伐他汀显著抑制MCP-1诱导的ERK1/2的磷酸化。此外，RhoA下拉实验表明RhoA被激活。匹伐他汀治疗后GTP酶活性降低。有趣的是，RBOA GTPase的抑制剂，而不是ERK1/2途径的抑制剂，减弱了THP-1细胞对HUVEC的MCP-1依赖的黏附。这些发现表明，他汀类药物在调节MCP-1诱导的单核细胞-内皮细胞相互作用的表型变化中起作用，这可能是他汀类药物抗炎作用的原因。(C)2004 Elsevier Inc.保留所有权利。
Monocyte-endothelial interaction plays a pivotal role in atherosclerosis. We previously showed that HMG CoA reductase inhibitor reduces adhesion, however, not the rolling of monocytes to vascular endothelium under flow in vitro. In the present study, we investigated the effect of pitavastatin, a novel HMG CoA reductase inhibitor, on the transition from monocyte rolling on vascular endothelium to stable adhesion induced by MCP-1 under flow (shear stress = 1.0 dyne/cm(2)). Control THP-1 cells rolled on activated (IL-1beta, 4 hours) human umbilical vein endothelial cells (HUVEC) and the number of adhered THP-1 cells were significantly enhanced following the addition of 50 nM of MCP-1 (p < 0.002). In contrast, MCP-1 failed to convert pitavastatin-treated (10 muM, 48 hours) THP-1 rolling to stable adhesion, as compared to baseline adhesion, prior to the addition of MCP-1 (p > 0.4). Pitavastatin-induced changes in THP-1 cells were reversed by treatment with 10 muM of mevalonate, the intermediate of cholesterol biosynthesis. To elucidate the mechanism by which pitavastatin modulates MCP-1-induced THP-1 adhesive interactions, the possible involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) was examined. Western blotting analysis using an anti-ERK1/2 Ab and an antibody against phosphorylated-ERK1/2 (pERK) revealed that pitavastatin treatment significantly inhibited the MCP-1 induced phosphorylation of ERK1/2. Further, a RhoA pull-down assay revealed that activation of RhoA. GTPase was reduced after pitavastatin treatment. Interestingly, an inhibitor of RboA GTPase, but not that of the ERK1/2 pathway, attenuated MCP-1-dependent adhesion of THP-1 cells to HUVEC. These findings indicate a role for pitavastatin in modulating the MCP-1-induced phenotypic changes of monocyte-endothelial interactions, which may account for the anti-inflammatory effects of statins. (C) 2004 Elsevier Inc. All rights reserved.