Contribution of Rho A and Rho kinase to platelet-derived growth factor-BB-induced proliferation of vascular smooth muscle cells.
Contribution of Rho A and Rho kinase to platelet-derived growth factor-BB-induced proliferation of vascular smooth muscle cells.
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DOI：
10.5551/jat.10.117
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发表时间：
2003-04
影响因子：
4.4
通讯作者：
M. Kamiyama;K. Utsunomiya;Kanta Taniguchi;T. Yokota;H. Kurata;N. Tajima;K. Kondo
中科院分区：
文献类型：
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作者：
M. Kamiyama;K. Utsunomiya;Kanta Taniguchi;T. Yokota;H. Kurata;N. Tajima;K. Kondo
为了鉴定有助于血管平滑肌细胞（VSMC）增殖的小G蛋白，我们检测了HMG-CoA还原酶抑制剂（西立伐他汀）、法尼基转移酶抑制剂（FTI-277）、香叶基香叶基转移酶抑制剂（GGTI-286）和Rho激酶抑制剂（Y-27632）对培养的大鼠VSMC增殖的影响20ng/ml 血小板衍生生长因子 (PDGF)-BB。西立伐他汀和 GGTI-286（而非 FTI-277）抑制 PDGF-BB 诱导的细胞外信号相关激酶 (ERK1/2) 的激活。添加香叶基香叶基焦磷酸 (GGPP) 后，西立伐他汀对 PDGF-BB 诱导的 ERK1/2 激活的抑制作用可完全恢复，但法呢基焦磷酸 (FPP) 则不能。西立伐他汀和 GGTI-286（而非 FTI-277）抑制 PDGF-BB 诱导的 [3H] 胸苷掺入和鸟氨酸脱羧酶 (ODC) 的激活，这两种情况均通过添加 GGPP（而非 FPP）完全恢复。这些数据表明PDGF-BB诱导的ERK1/2激活和VSMC增殖依赖于香叶基香叶基化的小G蛋白。免疫印迹分析显示，PDGF-BB 刺激的 VSMC 膜部分中 Rho A 蛋白上调。此外，Y-27632 抑制 PDGF-BB 诱导的 ERK1/2 激活和 VSMC 增殖。基于这些数据，我们得出结论，PDGF-BB通过激活Rho A来刺激VSMC的增殖。Rho激酶作为Rho A的效应子在此过程中发挥着重要作用。
In order to identify small G protein (s) which contributes to the proliferation of vascular smooth muscle cells (VSMCs), we examined the effect of an HMG-CoA reductase inhibitor (cerivastatin), a farnesyltransferase inhibitor (FTI-277), a geranyl geranyl transferase inhibitor (GGTI-286) and a Rho kinase inhibitor (Y-27632) on the proliferation of cultured rat VSMCs stimulated with 20ng/ml platelet-derived growth factor (PDGF)-BB. Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced activation of extracellular signal related kinase (ERK1/2). The inhibitory effect of cerivastatin on the PDGF-BB-induced activation of ERK1/2 was fully recovered by the addition of geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP). Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced [3H] thymidine incorporation and activation of ornitine decarboxylase (ODC), both of which were fully recovered by the addition of GGPP, but not FPP. These data indicate that the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs depend upon geranylgeranylated small G protein. Immunoblotting analysis revealed the upregulation of Rho A protein in the membrane fractions of VSMCs stimulated by PDGF-BB. Furthermore, Y-27632 suppressed the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs. On the basis of these data, we conclude that PDGF-BB stimulates the proliferation of VSMCs via the activation of Rho A. Rho kinase plays an important role in this process as an effector of Rho A.