Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells
Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells
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DOI：
10.1016/j.yjmcc.2004.05.008
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发表时间：
2004-08-01
影响因子：
5
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Hiroki, J;Shimokawa, H;Takeshita, A
最近的研究表明，上调的Rho-Kinase在动物和人类的动脉硬化和血管痉挛的发病机制中发挥着重要作用。然而，关于Rho-Kinase上调的分子机制(S)却知之甚少。由于炎症机制与动脉硬化和血管痉挛的发病机制有关，我们在体外和体内检测了炎症刺激是否上调了Rho-Kinase。在培养的人冠状动脉血管平滑肌细胞(HcVSMC)中，炎症刺激，如血管紧张素II和白介素1β，以时间和浓度依赖的方式增加Rho-Kinase的表达(在mRNA和蛋白质水平)和功能(通过Rho-Kinase底物ERM(ezrin/Radioxin/moesin)家族的磷酸化程度来评估)。阻断蛋白激酶C(PKC)(GF109253或佛波醇醋酸酯作用24小时)和腺病毒介导的显性活性Ikappa-B基因转移可抑制Rho-Kinase的表达，提示PKC和NF-kappaB参与了Rho-Kinase表达的细胞内信号转导途径。此外，长期给予血管紧张素II诱导的冠状动脉病变形成(以中层增厚和血管周围纤维化为特征)在体内Rho-Kinase表达和活性降低的情况下，显著抑制了NF-kappaB(-/-)小鼠的冠状动脉病变形成。这些结果表明，炎症刺激(如血管紧张素II和IL-1β)在体外和体内均上调了PKC和NF-kappaB参与的hcVSMC中Rho-Kinase的表达和功能。(C)2004爱思唯尔有限公司。保留所有权利。
Recent studies have demonstrated that upregulated Rho-kinase plays an important role in the pathogenesis of arteriosclerosis and vasospasm in both animals and humans. However, little is known about the molecular mechanism(s) involved in the Rho-kinase upregulation. Since inflammatory mechanisms have been implicated in the pathogenesis of arteriosclerosis and vasospasm, we examined whether inflammatory stimuli upregulate Rho-kinase in vitro and in vivo. In cultured human coronary vascular smooth muscle cells (hcVSMC), inflammatory stimuli, such as angiotensin II and interleukin-1beta, increased Rho-kinase expression (at both mRNA and protein levels) and function (as evaluated by the extent of the phosphorylation of the ERM (the ezrin/radixin/moesin) family, substrates of Rho-kinase) in a time-and concentration-dependent manner. The expression of Rho-kinase was inhibited by blockades of protein kinase C (PKC) (by either GF109253 or prolonged treatment with phorbol myristate acetate for 24 h) and an adenovirus-mediated gene transfer of dominant-active Ikappa-B, suggesting an involvement of PKC and NF-kappaB in the intracellular signal transduction pathway for the Rho-kinase expression. Furthermore, coronary vascular lesion formation (characterized by medial thickening and perivascular fibrosis) induced by a long-term administration of angiotensin II was markedly suppressed in NF-kappaB(-/-) mice with reduced expression and activity of Rho-kinase in vivo. These results indicate that the expression and function of Rho-kinase are upregulated by inflammatory stimuli (e.g. angiotensin II and IL-1beta) in hcVSMC with an involvement of PKC and NF-kappaB both in vitro and in vivo. (C) 2004 Elsevier Ltd. All rights reserved.