Holy Erik W, Akhmedov Alexander, Lüscher Thomas F, Tanner Felix C
Cardiovascular Research, Physiology Institute, University of Zürich, Switzerland.
J Mol Cell Cardiol. 2009 Feb;46(2):234-40. doi: 10.1016/j.yjmcc.2008.10.011. Epub 2008 Oct 30.
Berberine (BBR) is a novel natural hypolipidemic agent. This study investigates whether BBR, similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. BBR enhanced tumor necrosis factor-alpha (TNF-alpha) and thrombin induced TF expression in human endothelial cells by 3.5-fold. These effects were paralleled by an enhanced TF surface activity. In contrast, expression of TF pathway inhibitor was impaired. BBR enhanced TNF-alpha induced TF mRNA expression; however, TF promoter activity was inhibited. Activation of ERK and p38 remained unaffected, while c-Jun terminal NH(2) kinase was inhibited. BBR reduced TF mRNA degradation rates, prolonging its half-life from 1.1 to 4.3 h. The HMG-CoA reductase inhibitor simvastatin impaired thrombin induced TF expression, and BBR blunted this inhibition. Simvastatin did not affect TNF-alpha induced TF expression, and BBR enhanced TF under these conditions. Administration of BBR (100 mg/kg/d) increased TF activity and impaired TFPI expression in carotid artery of ApoE(-/-) mice. BBR enhances TF via mRNA stabilization at clinically relevant concentrations. Clinical application of BBR, either as an alternative to or in combination with statins, should be considered with caution.
黄连素（BBR）是一种新型天然降血脂药物。本研究调查了BBR是否与他汀类药物类似，对内皮组织因子（TF）表达具有多效性作用。BBR使肿瘤坏死因子-α（TNF-α）和凝血酶诱导的人内皮细胞中TF表达增加了3.5倍。这些作用伴随着TF表面活性的增强。相反，TF途径抑制剂的表达受损。BBR增强了TNF-α诱导的TF mRNA表达；然而，TF启动子活性受到抑制。ERK和p38的激活未受影响，而c-Jun末端NH2激酶受到抑制。BBR降低了TF mRNA的降解速率，使其半衰期从1.1小时延长至4.3小时。HMG-CoA还原酶抑制剂辛伐他汀削弱了凝血酶诱导的TF表达，而BBR减弱了这种抑制作用。辛伐他汀不影响TNF-α诱导的TF表达，在这些条件下BBR增强了TF表达。给予BBR（100mg/kg/d）可增加ApoE（-/-）小鼠颈动脉中的TF活性并损害TFPI表达。BBR在临床相关浓度下通过mRNA稳定作用增强TF表达。BBR作为他汀类药物的替代品或与之联合应用的临床应用应谨慎考虑。
