VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) GENE-TRANSCRIPTION AND EXPRESSION ARE REGULATED THROUGH AN ANTIOXIDANT SENSITIVE MECHANISM IN HUMAN VASCULAR ENDOTHELIAL-CELLS
VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) GENE-TRANSCRIPTION AND EXPRESSION ARE REGULATED THROUGH AN ANTIOXIDANT SENSITIVE MECHANISM IN HUMAN VASCULAR ENDOTHELIAL-CELLS
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DOI：
10.1172/jci116778
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发表时间：
1993-10-01
影响因子：
15.9
通讯作者：
MEDFORD, RM
中科院分区：
文献类型：
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作者：
MARUI, N;OFFERMANN, MK;MEDFORD, RM
氧化应激和血管内皮细胞上血管细胞粘附分子-1（VCAM-1）的表达是动脉粥样硬化和其他炎性疾病发病机制的早期特征。VCAM-1基因表达的调节可能通过特异性的还原-氧化（氧化还原）敏感性转录或转录后调节因子与氧化应激偶联。在培养的人脐静脉内皮（HUVE）细胞中，细胞因子白细胞介素1 β（IL-1 β）通过一种机制激活VCAM-1基因表达，该机制被抗氧化剂吡咯烷二硫代氨基甲酸酯（PDTC）和N-乙酰半胱氨酸（NAC）抑制约90%。此外，PDTC选择性地抑制VCAM-1的诱导，但不是细胞间粘附分子-1（ICAM-1），mRNA和蛋白质积累的细胞因子肿瘤坏死因子-α（TNF α）以及非细胞因子细菌内毒素脂多糖（LPS）和双链RNA，聚（I：C）（PIC）。PDTC还显著减弱TNF α诱导VCAM-1介导的细胞粘附。在一个独特的模式，PDTC部分抑制E-选择素基因表达的TNF α，但不LPS，IL-1 β，或PIC。TNF α和LPS通过NF-κ B样DNA增强子元件和相关NF-κ B样DNA结合蛋白介导的人VCAM-1启动子的转录激活被PDTC抑制。这些研究表明，抗氧化剂敏感的转录调控机制和VCAM-I基因表达之间的分子联系，扩大了氧化应激作为动脉粥样硬化发病机制中的重要调控信号的概念。
Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation(redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1beta (IL-1beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNFalpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNFalpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNFalpha but not to LPS, IL-1beta, or PIC. TNFalpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappaB-like DNA enhancer elements and associated NF-kappaB-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-I gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.