人脐静脉内皮细胞中海马型血红素加氧酶-1 表达对槟榔碱诱导的氧化应激的反应。
Hemeoxygenase-1 expression in response to arecoline-induced oxidative stress in human umbilical vein endothelial cells.
机构信息
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
出版信息
Int J Cardiol. 2011 Sep 1;151(2):187-94. doi: 10.1016/j.ijcard.2010.05.015. Epub 2010 Jun 17.
BACKGROUND
Arecoline, the most abundant areca alkaloid, has been reported to stimulate reactive oxygen species (ROS) production in several cell types. Overproduction of ROS has been implicated in atherogenesis. Hemeoxygenase-1 (HO-1) has cytoprotective activities in vascular tissues. This study investigated the effect of arecoline on adhesion molecule expression and explored the role of HO-1 in this process.
METHODS
Human umbilical vein endothelial cells (HUVECs) were treated with arecoline, then ROS levels and the expression of adhesion molecules and HO-1 were analyzed and potential signaling pathways investigated.
RESULTS
After 2h of arecoline treatment, ROS production was stimulated and reached a maximum at 12h. Expression of the adhesion molecules ICAM and VCAM was also induced. Glutathione pretreatment completely blocked arecoline-stimulated ROS production and VCAM expression, but not ICAM expression. Arecoline also induced HO-1 expression and this effect was partly due by ROS stimulation. Inhibition of c-jun N-terminal kinase (JNK) by SP600125, p38 by SB 203580, or tyrosine kinase by genistein reduced arecoline-induced HO-1 expression. In contrast, inhibition of ERK (extracellular signal-related MAP kinase) by PD98059 had no effect. Transfection of HUVECs with the GFP/HO-1 gene, which resulted in a 5-fold increase in HO-1 activity, markedly, but not completely, inhibited the decrease in cell viability caused by arecoline.
CONCLUSIONS
This study demonstrates that, in HUVECs, arecoline stimulates ROS production and ICAM and VCAM expression. HO-1 expression is also upregulated through the ROS, tyrosine kinase, and MAPK (JNK and p38) signaling pathways.
背景
作为最丰富的槟榔生物碱，槟榔碱已被报道能刺激几种细胞类型中活性氧物质（ROS）的产生。ROS 的过度产生与动脉粥样硬化的形成有关。血红素加氧酶-1（HO-1）在血管组织中具有细胞保护活性。本研究探讨了槟榔碱对黏附分子表达的影响，并探索了 HO-1 在这一过程中的作用。
方法
用槟榔碱处理人脐静脉内皮细胞（HUVEC），然后分析 ROS 水平和黏附分子及 HO-1 的表达，并探讨潜在的信号通路。
结果
槟榔碱处理 2h 后，ROS 生成被刺激，并在 12h 时达到最大值。黏附分子 ICAM 和 VCAM 的表达也被诱导。谷胱甘肽预处理完全阻断了槟榔碱刺激的 ROS 生成和 VCAM 表达，但不能阻断 ICAM 表达。槟榔碱还诱导了 HO-1 的表达，这种作用部分是由于 ROS 的刺激。用 SP600125 抑制 c-jun N 末端激酶（JNK）、用 SB 203580 抑制 p38 或用 genistein 抑制酪氨酸激酶，均可减少槟榔碱诱导的 HO-1 表达。相反，用 PD98059 抑制 ERK（细胞外信号相关 MAP 激酶）则没有影响。用 GFP/HO-1 基因转染 HUVEC，导致 HO-1 活性增加 5 倍，显著但不完全抑制了槟榔碱引起的细胞活力下降。
结论
本研究表明，在 HUVEC 中，槟榔碱刺激 ROS 生成以及 ICAM 和 VCAM 的表达。HO-1 的表达也通过 ROS、酪氨酸激酶和 MAPK（JNK 和 p38）信号通路被上调。
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