The up-regulation of monocyte chemoattractant protein-1 (MCP-1) in Ea.hy 926 endothelial cells under long-term low folate stress is mediated by the p38 MAPK pathway.
The up-regulation of monocyte chemoattractant protein-1 (MCP-1) in Ea.hy 926 endothelial cells under long-term low folate stress is mediated by the p38 MAPK pathway.
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DOI：
10.1016/j.atherosclerosis.2008.12.008
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发表时间：
2009-07
期刊：
影响因子：
5.3
通讯作者：
Whitehead, Alexander S.
中科院分区：
文献类型：
--
作者：
Lu, Zhi-Yong;Jensen, Liselotte E.;Huang, Yuehua;Kealey, Carmel;Blair, Ian A.;Whitehead, Alexander S.
由CCL 2基因编码的单核细胞趋化蛋白-1（MCP-1）在动脉粥样硬化的发生和发展中起重要作用。在低叶酸条件下生长的Ea.hy926内皮细胞（LO细胞）比叶酸充足的对照细胞（HI细胞）合成更多的MCP-1 mRNA并分泌更多的MCP-1蛋白。我们研究了长期“叶酸胁迫”对MCP-1表达的调节机制。使用启动子-报告基因分析评估，CCL 2转录在LO细胞中相对于HI细胞上调，而MCP-1 mRNA稳定性不变。在慢性低叶酸条件下的这种定量转录偏倚不是由于活性NF-κB的差异，而是与总p38和磷酸化p38的升高水平相关，这可以通过Western免疫印迹检测到。短暂的急性甲氨蝶呤介导的叶酸耗竭或暴露于高浓度的同型半胱氨酸（Hcy）对Ea.hy 926细胞的MCP-1合成没有影响。p38抑制剂SB-203580可抑制LO细胞产生MCP-1。在大量TNF-α诱导后，LO细胞中CCL 2的定量转录偏好性得以保留。在长期叶酸胁迫期间，p38是CCL 2转录的主要决定因素。长期叶酸不足“引发”Ea.hy 926内皮细胞对精氨酸介导的炎性应激具有定量上更强烈的反应。
Monocyte chemoattractant protein-1 (MCP-1), encoded by the CCL2 gene, plays an important role in the initiation and progression of atherosclerosis. Ea.hy 926 endothelial cells grown under low folate conditions (LO cells) synthesize more MCP-1 mRNA and secrete more MCP-1 protein than folate-replete control cells (HI cells). We investigated the mechanisms underlying the modulation of MCP-1 expression by long-term “folate stress”. CCL 2 transcription, assessed using promoter-reporter assays, is up-regulated in LO cells relative to HI cells, whereas MCP-1 mRNA stability is unchanged. This quantitative transcriptional bias under chronic low folate conditions is not attributable to differences in active NF-κB, but is associated with elevated levels of both total p38 and phospho-p38 that are detectable by Western immunoblotting. Transient, acute methotrexate-mediated folate depletion or exposure to high concentrations of homocysteine (Hcy) had no effect on MCP-1 synthesis by Ea.hy 926 cells. The p38 inhibitor SB-203580 abolished the excess MCP-1 production by LO cells. The quantitative transcriptional bias of CCL2 in LO cells was retained following massive induction by TNF-α. During long-term folate stress, p38 is the primary determinant of CCL2 transcription. Long-term folate insufficiency “primes” Ea.hy 926 endothelial cells to have a quantitatively more vigorous response to cytokine-mediated inflammatory stress.
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