Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells
Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells
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DOI：
10.1016/j.ejphar.2005.11.023
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发表时间：
2006-01-13
影响因子：
5
通讯作者：
Lee, WS
中科院分区：
文献类型：
--
作者：
Juan, SH;Lee, JL;Lee, WS
2，3，7，8-四氯二苯并对二恶英（TCDD，dioxin）和多环芳烃对心血管疾病的影响越来越受到关注。它们的化学结构相似，但多环芳烃不像四氯二苯并对二恶英那样含有氯。其作用的生化机制主要是由芳香烃受体介导的。此外，氧化应激也在这些化学物质的生物和毒性效应中发挥作用。在这项研究中，我们使用芳香烃受体激动剂，3-甲基胆蒽（3-MC），研究其对人脐血管内皮细胞增殖和血管生成的影响。[3 H]胸腺嘧啶核苷掺入法测定3-MC浓度依赖性地抑制人脐静脉内皮细胞DNA合成，并使细胞阻滞于细胞周期的G 0/G1期。有趣的是，3-MC的DNA合成的抑制被消除在更大程度上由芳香烃受体拮抗剂，α-NF（0.5和1 μ M）和白藜芦醇（5和10 μ M），比由抗氧化剂，N-乙酰半胱氨酸（5和10 mM）。3-MC可使人脐静脉内皮细胞的通透性、粘附性和管腔形成呈浓度依赖性降低。我们还证明，细胞粘附信号（磷酸化粘着斑激酶（FAK））减少后3-MC处理，表明细胞粘附抑制3-MC可能是由于抑制细胞粘附信号。此外，α-萘酮（α-NF）改善3-MC对细胞渗透性，粘附和管形成的影响，表明芳烃受体参与血管生成。结果表明，3-MC的不利影响主要是通过芳香烃受体介导的，而不是通过增加氧化应激。(c)2005 Elsevier B. V.保留所有权利。
There is increasing interest in the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and polycyclic aromatic hydrocarbons on cardiovascular diseases. Their chemical structures are similar, although polycyclic aromatic hydrocarbons contain no chlorine as does TCDD. The biochemical mechanism of their action is mainly mediated by the aryl hydrocarbon receptor. In addition, oxidative stress also plays a role in the biological and toxic effects of these chemicals. In this study, we used an aryl hydrocarbon receptor agonist, 3-methylcholanthrene (3-MC), to investigate its effect on the proliferation and angiogenesis of human umbilical vascular endothelial cells. 3-MC suppressed DNA synthesis of human umbilical vascular endothelial cells as determined by [3 H]thymidine incorporation in a concentration-dependent fashion and arrested cells at the G0/G1 phase of the cell cycle. Interestingly, the inhibition of DNA synthesis by 3-MC was eliminated to a greater extent by aryl hydrocarbon receptor antagonists, alpha-NF (0.5 and I mu M) and resveratrol (5 and 10 mu M), than by the antioxidant, N-acetylcysteine (5 and 10 mM). Cell permeability, adhesion, and tube formation in human umbilical vascular endothelial cells exposed to 3-MC decreased in concentration-dependent manners. We also demonstrated that cell adhesion signaling (phosphorylated focal adhesion kinase (FAK)) decreased upon 3-MC treatment, suggesting that cell adhesion inhibited by 3-MC might be due to inhibition of cell adhesion signaling. Additionally, alpha-naphthoflavon (alpha-NF) ameliorated the effects of 3-MC on cell permeability, adhesion and tube formation, indicating the involvement of the aryl hydrocarbon receptor in angiogenesis. The results suggest that the adverse effects of 3-MC are mainly mediated by the aryl hydrocarbon receptor and not via increased oxidative stress. (c) 2005 Elsevier B.V. All rights reserved.