Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Eur Heart J. 2010 Jul;31(14):1780-91. doi: 10.1093/eurheartj/ehp598. Epub 2010 Jan 29.
Amphetamine intake is associated with acute vascular syndromes. Since these events are caused by arterial thrombosis and this in turn is triggered by tissue factor (TF), this study examines whether amphetamines regulate TF in human endothelial cells.
Amphetamine (10(-7)-10(-4) mol/L) enhanced thrombin- and tumour necrosis factor (TNF)-alpha-induced as well as basal TF expression (P = 0.029, 0.0003, and 0.003 at maximal concentration), and TNF-alpha-induced plasminogen activator inhibitor (PAI)-1 expression (P = 0.003), whereas tissue factor pathway inhibitor expression was impaired (P = 0.008). Similarly, 3,4-methylenedioxymethamphetamine (10(-7)-10(-4) mol/L) enhanced TF expression (P = 0.046). These effects were paralleled by an increased TF activity (P = 0.002); moreover, clotting time of human plasma was accelerated by supernatant from amphetamine-treated cells (P = 0.03). Amphetamine enhanced TF mRNA expression via phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38 (P = 0.03 and 0.033), but not c-Jun NH(2)-terminal kinase (JNK; P = 0.81). The effect of amphetamine on TF expression was abrogated by the dopamine D4 receptor antagonists L-745,870 and L-750,667, but not D2 or D3 receptor antagonists; furthermore, L-745,870 blunted the amphetamine-induced activation of ERK and p38, but not JNK.
Amphetamines induce endothelial TF expression via stimulation of dopamine D4 receptor and activation of the MAPKs p38 and ERK. These effects occur at clinically relevant amphetamine concentrations and may account for the increased incidence of acute vascular syndromes after amphetamine consumption.
安非他命的摄入与急性血管综合征有关。由于这些事件是由动脉血栓形成引起的，而血栓形成反过来又是由组织因子（TF）触发的，因此本研究检查安非他命是否调节人内皮细胞中的 TF。
安非他命（10(-7)-10(-4)mol/L）增强了凝血酶和肿瘤坏死因子（TNF）-α诱导的以及基础 TF 表达（在最大浓度时 P = 0.029、0.0003 和 0.003），并增强了 TNF-α诱导的纤溶酶原激活物抑制剂（PAI）-1 表达（P = 0.003），而组织因子途径抑制剂的表达受到损害（P = 0.008）。同样，3,4-亚甲二氧基甲基苯丙胺（10(-7)-10(-4)mol/L）增强了 TF 表达（P = 0.046）。这些作用伴随着 TF 活性的增加（P = 0.002）；此外，用安非他命处理过的细胞上清液加速了人血浆的凝固时间（P = 0.03）。安非他命通过丝裂原激活的蛋白激酶（MAPKs）细胞外信号调节激酶（ERK）和 p38 的磷酸化增强 TF mRNA 表达（P = 0.03 和 0.033），但不增强 c-Jun NH(2)-末端激酶（JNK；P = 0.81）。多巴胺 D4 受体拮抗剂 L-745,870 和 L-750,667 阻断了安非他命对 TF 表达的影响，但多巴胺 D2 或 D3 受体拮抗剂没有；此外，L-745,870 阻断了安非他命诱导的 ERK 和 p38 的激活，但没有 JNK 的激活。
安非他命通过刺激多巴胺 D4 受体和激活 MAPKs p38 和 ERK 诱导内皮 TF 表达。这些作用发生在临床上相关的安非他命浓度下，可能解释了安非他命摄入后急性血管综合征发生率的增加。
