RhoA-dependent PAI-1 gene expression induced in endothelial cells by monocyte adhesion mediates geranylgeranyl transferase I and Ca2+ signaling
RhoA-dependent PAI-1 gene expression induced in endothelial cells by monocyte adhesion mediates geranylgeranyl transferase I and Ca2+ signaling
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DOI：
10.1016/j.atherosclerosis.2006.08.036
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发表时间：
2007-07-01
期刊：
影响因子：
5.3
通讯作者：
Maruyama, Yukio
中科院分区：
文献类型：
--
作者：
Sakamoto, Takayuki;Ishibashi, Toshiyuki;Maruyama, Yukio
我们研究了 RhoA 激活的作用及其在内皮细胞单核细胞粘附诱导的纤溶酶原激活物抑制剂 1 (PAI-1) 基因表达中的作用及其机制。将分离的人外周血单核细胞添加到培养的人冠状动脉内皮细胞中。单核细胞与内皮细胞的粘附增加了转录水平上的 PAI-1 表达并激活了 RhoA，同时香叶基香叶基转移酶 I (GGTase 1)（一种负责香叶基香叶基化和肌动蛋白应激纤维形成的酶）活性增加。 C3 外切酶或腺病毒介导的 N19RhoA 表达以及普伐他汀抑制 RhoA，可防止单核细胞粘附诱导的 PAI-1 上调。 GGTI-286 是一种 GGTase 1 抑制剂，可阻止单核细胞诱导的 RhoA 激活和内皮细胞中 PAI-1 的表达。单核细胞粘附诱导内皮细胞内Ca2+浓度([Ca(2+)])增加，Ca2+螯合阻止单核细胞粘附诱导的启动子活性和PAI-1表达的增加。 0 外切酶和 GGTI-286 还抑制单核细胞诱导的内皮细胞内 Ca2+ 动员和 Ca2+ 进入。本研究表明，GGTase I 在单核细胞粘附诱导的内皮细胞 RhoA 激活中发挥作用，并且 GGTase I 介导的 Ca2+ 信号传导可能有助于 RhoA 依赖性 PAI-1 基因表达。 (c) 2006 Elsevier Ireland Ltd. 保留所有权利。
We investigated the role of RhoA activation and its mechanism in plasminogen activator inhibitor-1 (PAI-1) gene expression induced in endothelial cells by monocyte adhesion. Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased PAI- 1 expression at the transcriptional level and activated RhoA which was accompanied by an increase in the activity of geranylgeranyl transferase I (GGTase 1), an enzyme responsible for geranylgeranylation, and actin stress fiber formation. Inhibition of RhoA by C3 exoenzyme or by adenovirus-mediated expression of N19RhoA, as well as by pravastatin, prevented the upregulation of PAI-1 induced by monocyte adhesion. GGTI-286, an inhibitor of GGTase 1, prevented the monocyte-induced RhoA activation and PAI- 1 expression in endothelial cells. Monocyte attachment induced an increase in intracellular Ca2+ concentration ([Ca (2+)],) in endothelial cells and Ca2+ chelation prevented the increased promoter activity and expression of PAI- 1 induced by monocyte adhesion. 0 exoenzyme and GGTI-286 also suppressed endothelial intracellular Ca2+ mobilization and Ca2+ entry induced by monocytes. The present study shows that GGTase I plays a role in the RhoA activation in endothelial cells induced by monocyte adhesion and that GGTase I-mediated Ca2+ signaling may contribute to RhoA-dependent PAI- 1 gene expression. (c) 2006 Elsevier Ireland Ltd. All rights reserved.