Monraats Pascalle S, Pires Nuno M M, Schepers Abbey, Agema Willem R P, Boesten Lianne S M, de Vries Margreet R, Zwinderman Aeilko H, de Maat Moniek P M, Doevendans Pieter A F M, de Winter Robbert J, Tio René A, Waltenberger Johannes, 't Hart Leen M, Frants Rune R, Quax Paul H A, van Vlijmen Bart J M, Havekes Louis M, van der Laarse Arnoud, van der Wall Ernst E, Jukema J Wouter
Department of Cardiology, Leiden University Medical Center, The Netherlands.
FASEB J. 2005 Dec;19(14):1998-2004. doi: 10.1096/fj.05-4634com.
Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFalpha, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNFalpha gene was performed. The role of TNFalpha in restenosis was also assessed in ApoE*3-Leiden mice, TNFalpha knockout mice, and by local delivery of a TNFalpha biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNFalpha gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNFalpha mRNA was significantly time-dependently up-regulated. Mice lacking TNFalpha or treated locally with thalidomide showed a reduction in reactive stenosis (P=0.01 and P=0.005, respectively). Clinical and preclinical data indicate that TNFalpha plays an important role in restenosis. Therefore, TNFalpha genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNFalpha may be an anti-restenotic target strategy.
遗传因素在经皮冠状动脉介入治疗（PCI）后的再狭窄过程中似乎很重要，在炎症（再狭窄的一个关键因素）中也是如此。肿瘤坏死因子α（TNFα）是炎症反应的关键调节因子，可能对PCI后再狭窄的发生发展产生关键影响。再狭窄的遗传决定因素（GENDER）项目纳入了3104例成功接受PCI的患者。对TNFα基因的六个多态性进行了系统基因分型。还在载脂蛋白E*3-莱顿小鼠、TNFα基因敲除小鼠中，以及通过局部递送TNFα生物合成抑制剂沙利度胺，评估了TNFα在再狭窄中的作用。TNFα基因的-238G-1031T单倍型增加了再狭窄的临床和血管造影风险（分别为P=0.02和P=0.002）。在反应性狭窄的小鼠模型中，动脉TNFα mRNA随时间显著上调。缺乏TNFα或局部用沙利度胺治疗的小鼠反应性狭窄减少（分别为P=0.01和P=0.005）。临床和临床前数据表明，TNFα在再狭窄中起重要作用。因此，TNFα基因型可作为再狭窄的风险标志物，并可能有助于在临床实践中对PCI术前的个体患者进行筛查。抑制TNFα可能是一种抗再狭窄的靶向策略。
