Monraats Pascalle S, Rana Jamal S, Nierman Melchior C, Pires Nuno M M, Zwinderman Aeilko H, Kastelein John J P, Kuivenhoven Jan Albert, de Maat Moniek P M, Rittersma Saskia Z H, Schepers Abbey, Doevendans Pieter A F, de Winter Robbert J, Tio René A, Frants Rune R, Quax Paul H A, van der Laarse Arnoud, van der Wall Ernst E, Jukema J Wouter
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
J Am Coll Cardiol. 2005 Sep 20;46(6):1093-100. doi: 10.1016/j.jacc.2005.05.071.
We sought to identify polymorphisms in genes that predispose to restenosis.
Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis.
The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process.
Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement.
The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.
我们试图鉴定易导致再狭窄的基因中的多态性。
脂蛋白脂肪酶（LPL）基因的变异与许多与冠心病相关的病理生理状况有关。本研究在接受经皮冠状动脉介入治疗（PCI）的大量患者群体中，检测LPL基因多态性对再狭窄（通过靶血管再血管化[TVR]定义）的影响。使用再狭窄小鼠模型进一步研究LPL在再狭窄中的作用。
再狭窄的遗传决定因素（GENDER）项目是一项多中心前瞻性研究设计，纳入了3104例成功接受PCI后的连续患者。对这些患者进行了四种不同LPL基因多态性的基因分型。在载脂蛋白E（ApoE）*3 - 莱顿转基因小鼠中，使用动脉信使核糖核酸（mRNA）评估袖带诱导的再狭窄过程中的LPL表达。
通过多变量分析，与447Ser纯合子相比，LPL酶447Ter等位基因携带者的TVR风险较低（p = 0.005）。在小鼠模型中，袖带放置后6小时，与对照动脉相比，LPL mRNA水平增加了40倍。
LPL C/G多态性（Ser447Ter）导致成熟LPL蛋白的两个C末端氨基酸截短，似乎是人类TVR的重要保护因素。在小鼠模型中进一步确定了LPL在此过程中的作用，其中LPL表达在靶动脉壁中非常强烈地上调，表明这种脂解酶对再狭窄有贡献。可能，LPL Ser447Ter基因分型可能导致在PCI后预防再狭窄方面有更好的风险分层和个性化治疗。
