Dilazep, an antiplatelet agent, inhibits tissue factor expression in endothelial cells and monocytes
Dilazep, an antiplatelet agent, inhibits tissue factor expression in endothelial cells and monocytes
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DOI：
10.1182/blood.v90.6.2345.2345_2345_2356
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发表时间：
1997-09-15
期刊：
影响因子：
20.3
通讯作者：
Suzuki, K
中科院分区：
文献类型：
--
作者：
Deguchi, H;Takeya, H;Suzuki, K
地拉西普是一种抗血小板药物，临床上通常用作抗血栓药物。地拉西普还可以对内皮细胞发挥细胞保护和抗氧化作用。然而，其对内皮或单核细胞促凝血活性的影响尚不清楚。在本研究中，评估了地拉西普对肿瘤坏死因子-α（TNF）、凝血酶或佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）刺激后人脐静脉内皮细胞（HUVEC）中组织因子（TF）表达的影响。我们还评估了地拉西普对 TNF (1,000 U/mL) 诱导的单核细胞 TF 表达的影响。 Dilazep 以剂量依赖性方式（7 至 100 μg/mL）抑制每种刺激剂 TNF (1000 U/mL)、凝血酶 (25 nmol/L) 或 PMA (5 nmol/L) 在 HUVEC 上诱导的 TF 活性。用100μg/mL地拉西普处理后，TF活性降低至约10%。通过流式细胞术分析确定，地拉西普还阻断了每种刺激剂在 HUVEC 表面诱导的 TF 抗原的表达。此外，在 HUVEC 中，它显着降低了凝血酶或 PMA 诱导的 TF mRNA 和总 TF 抗原的表达，但不降低 TNF 诱导的 TF mRNA 和总 TF 抗原的表达，表明地拉西普在转录水平阻断 PMA 或凝血酶诱导的 TF 表达，并在转录后水平阻断 TNF 诱导的 TF 表达。蛋白质印迹分析表明，地拉西普可减少天然 TF 的积累，但会增加低分子量 TF 衍生物的积累。腺苷受体拮抗剂 8-(对磺苯基)茶碱部分抵消了地拉西普对 HUVEC 的抗凝活性，从而表明地拉西普对 HUVEC 中 TF 表达的抑制作用至少部分取决于其腺苷增强活性。 Dilazep 还以剂量依赖性方式（0.1 至 100 μg/mL）抑制单核细胞上 TNF 诱导的 TF 表达。简而言之，本研究首次表明常用抗血小板药物地拉西普强烈抑制HUVEC和单核细胞中的TF表达。地拉西普因其对内皮细胞和单核细胞促凝血活性的抑制特性而可能对高凝状态患者具有有效的治疗价值。 (C) 1997 年，美国血液学会。
Dilazep, an antiplatelet agent, is generally used as an antithrombotic drug in clinical practice. Dilazep is also known to exert cytoprotective and antioxidant effects on endothelial cells. However, its effect on the endothelial or monocyte procoagulant activity is unknown. In the current study, the effect of dilazep on the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) after the stimulation with tumor necrosis factor-alpha (TNF), thrombin, or phorbol 12-myristate 13-acetate (PMA) was evaluated. We also evaluated the effect of dilazep on TNF (1,000 U/mL)induced TF expression on monocytes. Dilazep inhibited TF activity induced on HUVECs by each stimulant, TNF (1000 U/mL), thrombin (25 nmol/L), or PMA (5 nmol/L) in a dose-dependent fashion (7 to 100 mu g/mL). TF activity decreased to approximately 10% after treating with 100 mu g/mL of dilazep. Dilazep also blocked the expression of TF antigen induced by each stimulant on the surface of HUVECs as determined by flow cytometric analysis. In addition, in HUVECs, it significantly decreased the expression of TF mRNA and the total TF antigen induced by thrombin or PMA, but not those induced by TNF, suggesting that dilazep blocks the TF expression induced by PMA or thrombin at a transcriptional level and that induced by TNF at a posttranscriptional level. Western blot analysis showed that dilazep reduces the accumulation of native TF but increases that in lower molecular weight TF derivatives. The adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline, partially counteracted the anticoagulant activity of dilazep on HUVECs, thereby suggesting that the inhibitory effect of dilazep on TF expression in HUVECs depends, at least in part, on its adenosine potentiating activity. Dilazep also inhibited TNF-induced TF expression on monocytes in a dose-dependent fashion (0.1 to 100 mu g/mL). In brief, the current study showed for the first time that dilazep, a commonly used antiplatelet drug, strongly inhibits the TF expression in HUVECs and monocytes. Dilazep may have a potent therapeutic value in patients with hypercoagulable state for its inhibitory property on the procoagulant activity of endothelial cells and monocytes. (C) 1997 by The American Society of Hematology.