McCaffrey T A, Fu C, Du B, Eksinar S, Kent K C, Bush H, Kreiger K, Rosengart T, Cybulsky M I, Silverman E S, Collins T
Department of Medicine, Division of Hematology/Oncology, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Clin Invest. 2000 Mar;105(5):653-62. doi: 10.1172/JCI8592.
To understand the mRNA transcript profile in the human atherosclerotic lesion, RNA was prepared from the fibrous cap versus adjacent media of 13 patients undergoing carotid endarterectomy. cDNA expression arrays bearing 588 known genes indicated that lesions express unexpectedly high levels of the early growth response gene, Egr-1 (NGFI-A), a zinc-finger transcription factor that modulates a cluster of stress-responsive genes including PDGF and TGF-beta. Expression of Egr-1 was an average of 5-fold higher in the lesion than in the adjacent media, a result confirmed by RT-PCR, and many Egr-1-inducible genes were also strongly elevated in the lesion. Time-course analyses revealed that Egr-1 was not induced ex vivo. Immunocytochemistry indicated that Egr-1 was expressed prominently in the smooth muscle-actin positive cells, particularly in areas of macrophage infiltration, and in other cell types, including endothelial cells. Induction of atherosclerosis in LDL receptor-null mice by feeding them a high-fat diet resulted in a progressive increase in Egr-1 expression in the aorta. Thus, induction of Egr-1 by atherogenic factors may be a key step in coordinating the cellular events that result in vascular lesions.
为了解人类动脉粥样硬化病变中的mRNA转录谱，从13例行颈动脉内膜切除术患者的纤维帽和相邻中膜制备了RNA。包含588个已知基因的cDNA表达阵列显示，病变中早期生长反应基因Egr-1（NGFI-A）表达意外地高，Egr-1是一种锌指转录因子，可调节包括血小板衍生生长因子（PDGF）和转化生长因子-β（TGF-β）在内的一组应激反应基因。Egr-1在病变中的表达平均比相邻中膜高5倍，这一结果经逆转录聚合酶链反应（RT-PCR）证实，许多Egr-1诱导型基因在病变中也显著升高。时间进程分析显示，Egr-1在体外未被诱导。免疫细胞化学表明，Egr-1在平滑肌肌动蛋白阳性细胞中显著表达，尤其是在巨噬细胞浸润区域，以及包括内皮细胞在内的其他细胞类型中。通过给低密度脂蛋白受体缺失小鼠喂食高脂饮食诱导动脉粥样硬化，导致主动脉中Egr-1表达逐渐增加。因此，致动脉粥样硬化因子诱导Egr-1可能是协调导致血管病变的细胞事件的关键步骤。
