Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA.
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1628-33. doi: 10.1161/ATVBAHA.110.205740. Epub 2010 May 27.
To investigate the genetic contributions to the expression of cell surface adhesion molecules on endothelial cells (ECs) and to the release by ECs of chemokines, which are responsible for local inflammation.
Monocyte adhesion to ECs and transmigration across the endothelial barrier are the key steps in the formation of atherosclerotic plaques and the rupture of the existing plaques. Biopsy specimens were obtained from the femoral arteries of 131 pedigreed baboons (65 males and 66 females) aged 10.4+/-1.5 years (mean+/-SD); arterial ECs were harvested and cultured up to the second passage and then subjected to in vitro challenge with tumor necrosis factor (TNF) alpha, 10 ng/mL, or vehicle for 4 hours. Endothelial surface adhesion molecules were measured using flow cytometry, and chemokines released by the ECs were measured by immunoassay. In response to TNF-alpha treatment, interleukin 8 and monocyte chemoattractant protein-1 released by ECs were increased 3.4- and 26-fold, respectively (P<0.001). The expressions of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 were increased 12.2-, 41.4-, and 3.5-fold, respectively (P<0.001). The quantitative levels of several traits were heritable after TNF-alpha stimulation: h(2)=0.24 (P=0.02) for interleukin 8 and h(2)=0.28 (P=0.003) for E-selectin in culture medium; h(2)=0.21 (P=0.03) for intercellular adhesion molecule-1; and h(2)=0.37 (P<0.001) for vascular cell adhesion molecule-1 expression on EC surfaces. Furthermore, significant heritability was observed for lysate protein level, which is a measure of cell growth rate, with (h(2)=0.64, P<0.001) or without (h(2)=0.51, P<0.001) TNF-alpha stimulation.
This study reports on the heritability of adhesion molecules in ECs when activated by TNF-alpha. This finding suggests genetic regulation of key arterial wall inflammatory processes that are responsible for the initiation of atherosclerotic lesions and the plaque rupture of existing atheromas.
探讨细胞表面黏附分子在血管内皮细胞（ECs）中的表达以及趋化因子释放的遗传贡献，这些趋化因子负责局部炎症。
单核细胞黏附到 ECs 并穿过内皮屏障是形成动脉粥样硬化斑块和现有斑块破裂的关键步骤。从 131 只 10.4+/-1.5 岁（均值+/-标准差）的 pedigreed 狒狒的股动脉中获取活检样本；分离动脉 ECs 并培养至第二代，然后用肿瘤坏死因子（TNF）α，10ng/ml 或载体进行体外刺激 4 小时。通过流式细胞术测量内皮表面黏附分子，通过免疫测定法测量 EC 释放的趋化因子。用 TNF-α处理后，EC 释放的白细胞介素 8 和单核细胞趋化蛋白-1 分别增加了 3.4 倍和 26 倍（P<0.001）。E-选择素、细胞间黏附分子-1 和血管细胞黏附分子-1 的表达分别增加了 12.2 倍、41.4 倍和 3.5 倍（P<0.001）。TNF-α刺激后，几种性状的定量水平具有遗传性：培养物中白细胞介素 8 的 h(2)=0.24（P=0.02）和 E-选择素的 h(2)=0.28（P=0.003）；细胞间黏附分子-1 的 h(2)=0.21（P=0.03）；以及 EC 表面血管细胞黏附分子-1 的 h(2)=0.37（P<0.001）。此外，在有或没有 TNF-α刺激时，裂解物蛋白水平（一种细胞生长速度的测量值）也表现出显著的遗传性，（h(2)=0.64，P<0.001）或（h(2)=0.51，P<0.001）。
本研究报告了 TNF-α激活时 ECs 中黏附分子的遗传性。这一发现表明，遗传调控是负责动脉壁炎症过程的关键，这些炎症过程是动脉粥样硬化病变和现有动脉粥样硬化斑块破裂的启动因素。
