School of Pharmacy, Taipei Medical University, 110, Taipei, Taiwan.
J Thromb Thrombolysis. 2010 Jan;29(1):52-9. doi: 10.1007/s11239-009-0318-2. Epub 2009 Mar 31.
Carvedilol, a nonselective beta-adrenoceptor antagonist, has been shown to possess antioxidant effects and reduce the risk of hospitalization and death in patients with severe congestive heart failure, which is featured by the activation of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), and leads to thrombotic complications. Thrombomodulin (TM) plays protective roles against thrombosis. Treatment of ECs with TNF-alpha resulted in a down-regulation in the TM expression in a time-dependent manner. Pre-treatment of ECs with carvedilol (1 and 10 microM) for 1 h significantly up-regulated the TM expression in ECs in response to TNF-alpha. When ECs were pre-treated with a nuclear factor-kappaB (NF-kappaB) inhibitor, i.e., parthenolide, their TNF-alpha-mediated down-regulation of TM expression was inhibited. Pre-treatment of ECs with carvedilol inhibited the NF-kappaB-DNA binding activity in ECs induced by TNF-alpha. Our findings provide insights into the mechanisms by which carvedilol exerts anti-thrombotic effects by inducing TM expression in ECs in response to pro-inflammatory stimulation.
卡维地洛是一种非选择性的β肾上腺素受体拮抗剂，已被证明具有抗氧化作用，并降低严重充血性心力衰竭患者住院和死亡的风险，这种心力衰竭的特征是促炎细胞因子（包括肿瘤坏死因子-α（TNF-α））的激活，导致血栓并发症。血栓调节蛋白（TM）在对抗血栓形成方面发挥保护作用。TNF-α 处理 ECs 会导致 TM 表达随时间呈下调趋势。用卡维地洛（1 和 10 μM）预处理 ECs 1 小时，可显著上调 ECs 对 TNF-α的 TM 表达。当用核因子-κB（NF-κB）抑制剂即小白菊内酯预处理 ECs 时，其 TNF-α 介导的 TM 表达下调受到抑制。卡维地洛预处理可抑制 TNF-α诱导的 ECs 中 NF-κB-DNA 结合活性。我们的研究结果提供了深入了解卡维地洛通过诱导 TM 表达来发挥抗血栓作用的机制，这种作用是对促炎刺激的反应。
