1&agr;,25-Dihydroxyvitamin D3 and Its Potent Synthetic Analogs Downregulate Tissue Factor and Upregulate Thrombomodulin Expression in Monocytic Cells, Counteracting the Effects of Tumor Necrosis Factor and Oxidized LDL
1&agr;,25-Dihydroxyvitamin D3 and Its Potent Synthetic Analogs Downregulate Tissue Factor and Upregulate Thrombomodulin Expression in Monocytic Cells, Counteracting the Effects of Tumor Necrosis Factor and Oxidized LDL
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1
DOI：
10.1161/01.cir.102.23.2867
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
R. Kamiyama
中科院分区：
文献类型：
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作者：
M. Ohsawa;T. Koyama;Keiko Yamamoto;S. Hirosawa;S. Kamei;R. Kamiyama
背景我们最近发现，维生素D的一种药物活性形式，1，25-二羟基维生素D3 [1，25（OH）2D 3]，通过在包括人外周单核细胞的单核细胞中上调抗凝糖蛋白血栓调节蛋白（TM）的表达和下调关键凝血因子组织因子（TF）的表达而发挥抗凝作用。在这项研究中，我们研究了1，25（OH）2D 3及其有效的类似物对TF诱导和TM下调肿瘤坏死因子和氧化LDL在单核细胞和TF和TM表达的有效类似物的调节作用的抵消作用。方法和结果检测了1，25（OH）2D 3及其有效的合成类似物（22 R）-22-甲基-20-表-1，25（OH）2D 3（KY 3）和22-oxacalcitriol对单核细胞TF和TM抗原水平、细胞表面活性和mRNA水平的影响。1，25（OH）2D 3及其有效类似物通过下调TF和上调TM表达在单核细胞中显示抗凝作用，抵消肿瘤坏死因子和氧化LDL的作用。KY 3对TF和TM表达的调节作用最强。结论由于KY 3与维生素D受体的亲和力最高，我们的研究结果表明，TF和TM的1，25（OH）2D 3类似物的调节也是由维生素D受体介导的。1，25（OH）2D 3类似物KY 3和22-oxacalcitriol可能有潜力作为预防和治疗动脉粥样硬化和其他精氨酸介导的血栓性疾病的药物，并作为研究TF和TM调节的分子机制的工具。
BackgroundWe have recently found that a hormonally active form of vitamin D, 1&agr;,25-dihydroxyvitamin D3 [1,25(OH)2D3], exerts anticoagulant effects by upregulating the expression of an anticoagulant glycoprotein, thrombomodulin (TM), and downregulating the expression of a critical coagulation factor, tissue factor (TF), in monocytic cells including human peripheral monocytes. In this study, we investigated the counteracting effects of 1,25(OH)2D3 and its potent analogs on TF induction and TM downregulation by tumor necrosis factor and oxidized LDL in monocytic cells and the modulatory effects of potent analogs on TF and TM expression. Methods and ResultsEffects of 1,25(OH)2D3 and its potent synthetic analogs (22R)-22-methyl-20-epi-1,25(OH)2D3 (KY3) and 22-oxacalcitriol on TF and TM antigen levels, cell surface activities, and mRNA levels in monocytic cells were examined. 1,25(OH)2D3 and its potent analogs showed anticoagulant effects in monocytic cells by downregulating TF and upregulating TM expression, counteracting the effects of tumor necrosis factor and oxidized LDL. KY3 was most potent in its regulatory effect on TF and TM expression. ConclusionsBecause KY3 has the highest affinity for vitamin D receptor, our findings suggest that TF and TM regulation by 1,25(OH)2D3 analogs is also mediated by vitamin D receptor. The 1,25(OH)2D3 analogs KY3 and 22-oxacalcitriol may have the potential to serve as an agent for preventing and treating atherosclerotic and other cytokine-mediated thrombotic diseases and as a tool for studying the molecular mechanisms of TF and TM regulation.