Tafamidis 是一种分子伴侣，可稳定转甲状腺素蛋白 (TTR) 同源四聚体，防止其解离并随后在器官组织中以淀粉样原纤维的形式沉积。 Tafamidis 可降低 TTR 淀粉样蛋白 (ATTR) 心肌病患者的死亡率和因心血管原因住院的发生率。由于 ATTR 心肌病与血栓栓塞并发症的高风险相关，我们假设 tafamidis 可能具有直接的辅助抗血栓作用。在使用临床相关浓度的 tafamidis 和患者血浆之前，对原代人主动脉内皮细胞 (HAEC) 进行处理以及开始使用他法米迪治疗后。通过与肿瘤坏死因子 α (TNFα) 一起孵育来诱导 TF 的表达。通过蛋白质印迹测量组织因子（TF）的细胞内表达。 TF 活性通过比色测定来测量。通过定量聚合酶链反应测量 TF 的基因表达。tafamidis 治疗剂量依赖性地降低 TNFα 诱导的 TF 的表达和活性。这种效应在用患者血浆处理的细胞中得到了证实。 tafamidis 显着抑制信号转导和转录激活剂 3 (STAT3) 磷酸化。 HAEC 与 tafamidis 和 STAT3 激活剂 colivelin 一起孵育可部分挽救 TF 的表达。用 tafamidis 治疗可通过降低 TF 表达和活性来降低人原代内皮细胞的血栓形成潜力。这种先前未知的脱靶效应可能为接受 tafamidis 治疗的 ATTR 心肌病患者血栓栓塞并发症数量减少提供了新的机制解释。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect.Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction.Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF.Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.Copyright © 2024 Elsevier Inc. All rights reserved.