Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells
Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells
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DOI：
10.1016/j.bbrc.2006.07.204
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发表时间：
2006-10-06
影响因子：
3.1
通讯作者：
Saito, Yasushi
中科院分区：
文献类型：
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作者：
Jiang, Meizi;Bujo, Hideaki;Saito, Yasushi
他汀类药物是HMG-CoA还原酶的抑制剂，对血管细胞有多种作用，包括调节平滑肌细胞（SMC）的增殖和迁移。在这里，我们已经阐明了他汀类药物，特别是匹伐他汀，减弱平滑肌细胞迁移活性的机制。LR 11是LDL受体家族的成员，也是尿激酶型纤溶酶原激活物受体（uPAR）细胞表面定位的增强剂，其表达在培养的SMC中通过PDGF-BB处理而增加。匹伐他汀减弱PDGF-BB诱导的LR 11和uPAR的表面表达。在LR 11过表达和通过刺激可溶性LR 11分泌时观察到的SMC迁移增加不被匹伐他汀逆转。体内研究表明，斑块中表达LR 11的SMC几乎与表达非肌肉肌球蛋白重链（SMemb）的内膜细胞一致。匹伐他汀降低LR 11和SMemb的表达，培养的内膜SMC中LR 11、uPAR和SMemb的水平降低至中膜SMC中的水平。我们认为，这种他汀类药物通过减弱SMC中的LR 11/uPAR系统来减少PDGF诱导的迁移。用他汀类药物调节LR 11/uPAR系统提示了一种基于抑制内膜SMC迁移的动脉粥样硬化形成的新治疗策略。(c)2006年爱思唯尔公司All rights reserved.
Statins, inhibitors of HMG-CoA reductase, elicit various actions on vascular cells including the modulation of proliferation and migration of smooth muscle cells (SMCs). Here, we have elucidated the mechanism by which statins, in particular pitavastatin, attenuate the migration activity of SMCs. The expression of LR11, a member of the LDL receptor family and an enhancer of cell surface localization of urokinase-type plasminogen activator receptor (uPAR), is increased in cultured SMCs by treatment with PDGF-BB. Pitavastatin attenuates the PDGF-BB-induced surface expression of LR11 and uPAR. The increased migration of SMCs observed both upon overexpression of LR11 and via stimulation of secretion of soluble LR11 is not reversed by pitavastatin. In vivo studies showed that the SMCs expressing LR11 in plaques are almost congruent with intimal cells expressing nonmuscle myosin heavy chain (SMemb). Pitavastatin reduced the expression of LR11 and SMemb, and the levels of LR11, uPAR, and SMemb in cultured intimal SMCs were reduced to those seen in medial SMCs. We propose that this statin reduces PDGF-induced migration through the attenuation of the LR11/uPAR system in SMCs. Modulation of the LR11/uPAR system with statins suggests a novel treatment strategy for atherogenesis based on suppression of intimal SMC migration. (c) 2006 Elsevier Inc. All rights reserved.