Regulatory role of endothelium in the expression of genes affecting arterial calcification
Regulatory role of endothelium in the expression of genes affecting arterial calcification
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DOI：
10.1016/j.bbrc.2004.05.181
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发表时间：
2004-07-23
影响因子：
3.1
通讯作者：
Mehta, JL
中科院分区：
文献类型：
--
作者：
Cola, C;Almeida, M;Mehta, JL
血管钙化是一个高度调节的过程，具有骨矿化的特征。由于内皮细胞调节动脉粥样硬化形成过程中的许多过程，我们监测了人类冠状动脉内皮细胞（HCAECs）暴露于动脉粥样硬化刺激后钙化相关基因的表达。研究的基因是：核心结合因子α-1（Cbfa 1/Runx 2），骨生成的关键转录调节因子;骨形态发生蛋白-2（BMP 2），软骨和骨的诱导剂;以及基质gla蛋白（MGP），钙化的有效抑制剂，其通过阻断BMP 2发挥其作用。用氧化低密度脂蛋白（ox-LDL，80 μ g/mL）或肿瘤坏死因子-α（TNF α，10 ng/mL）处理HCAEC，并通过实时PCR定量Cbfa 1，BMP 2和MGP的表达。Cbfa 1在未处理的HCAEC中呈低水平表达，其表达不受ox-LDL或TNF α的影响。BMP 2和MGP在ox-LDL或TNF α处理后早期（2-8 h）表达增加，24 h增加不明显。Ox-LDL对NIGP表达的影响强于对BMP 2表达的影响。用针对LOX-1（ox-LDL的凝集素样受体）的抗体（10 μ g/mL）预处理细胞，可抑制ox-LDL（而非TNF α）对NIGP和BMP 2表达的影响。因此，当暴露于致动脉粥样硬化的刺激物，特别是ox-LDL时，内皮通过增强骨抑制性MGP的表达来调节钙化过程，而Cbfa 1的表达保持不变。BMP 2的上调可能代表响应于NIGP增加的反馈上调。ox-LDL的作用似乎是通过LOX-1活化介导的。(C)2004年爱思唯尔公司All rights reserved.
Vascular calcification is a highly regulated process sharing features of bone mineralization. Since endothelium regulates many of the processes during atherogenesis, we monitored the expression of genes involved in calcification upon exposure of human coronary artery endothelial cells (HCAECs) to atherogenic stimuli. Genes studied were: core binding factor alpha-1 (Cbfa1/Runx2), a pivotal transcriptional regulator of osteogenesis; bone morphogenetic protein-2 (BMP2), an inducer of cartilage and bone; and matrix gla-protein (MGP), a potent inhibitor of calcification, which exerts its action by blocking BMP2. HCAECs were treated with oxidized-low density lipoprotein (ox-LDL, 80 mug/mL) or tumor necrosis factor-alpha (TNFalpha, 10 ng/mL), and the expression of Cbfa1, BMP2, and MGP was quantified by real-time PCR. Cbfa1 was expressed at low levels in untreated HCAECs, and its expression did not change with ox-LDL or TNFalpha treatment, The expression of BMP2 and MGP increased early after exposure to ox-LDL or TNFalpha (at 2-8 h), and the increase was not evident at 24 h. Ox-LDL exerted a stronger effect on NIGP than on BMP2 expression. The effects of ox-LDL, but not TNFalpha, on NIGP and BMP2 expression were inhibited by pretreatment of cells with an antibody directed at LOX-1, a lectin-like receptor for ox-LDL (10 mug/mL). Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged. Upregulation of BMP2 may represent a feedback upregulation in response to increase in NIGP. The effect of ox-LDL appears to be mediated by LOX-1 activation. (C) 2004 Elsevier Inc. All rights reserved.