Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Cardiovasc Res. 2010 May 1;86(2):321-9. doi: 10.1093/cvr/cvq032. Epub 2010 Jan 28.
Early growth response gene-1 (Egr-1) regulates the expression of genes important to cardiovascular disease. Within atherosclerotic lesions, Egr-1 is expressed in smooth muscle cells, endothelial cells, and macrophages. Since macrophages play a pivotal role in atherosclerotic lesion initiation and progression, this study investigated the effects of Egr-1 deficiency within bone marrow-derived cells on the development of atherosclerosis in a hyperlipidaemic mouse model.
Bone marrow from Egr-1-deficient mice and wild-type controls was transplanted into lethally irradiated LDL receptor null mice. After 26 weeks on a high fat diet, atherosclerotic lesion size within the aortic sinus of recipients was evaluated. Mice receiving Egr-1-deficient bone marrow had significantly decreased lesion size compared with controls. Lesions of these mice contained fewer macrophages and had reduced expression of vascular cell adhesion molecule-1 (VCAM-1), tissue factor, as well as transforming growth factor receptor type II, which are target genes of Egr-1. These results were validated by in vitro analysis of Egr-1-deficient peritoneal macrophages which, after lipopolysaccharide stimulation, had decreased VCAM-1 and tissue factor mRNA expression compared with wild-type controls.
This study demonstrates that bone marrow-derived Egr-1 promotes macrophage accumulation, atherosclerotic lesion development, and lesion complexity.
早期生长反应基因-1（Egr-1）调节对心血管疾病重要的基因的表达。在动脉粥样硬化病变中，Egr-1 在平滑肌细胞、内皮细胞和巨噬细胞中表达。由于巨噬细胞在动脉粥样硬化病变的起始和进展中起着关键作用，本研究探讨了骨髓源性细胞中 Egr-1 缺失对高脂血症小鼠模型中动脉粥样硬化发展的影响。
从 Egr-1 缺陷型小鼠和野生型对照的骨髓中分离出骨髓细胞，然后移植到致死性辐射 LDL 受体缺失型小鼠体内。在高脂肪饮食 26 周后，评估接受者主动脉窦中的动脉粥样硬化病变大小。与对照组相比，接受 Egr-1 缺陷型骨髓的小鼠的病变大小明显减小。这些小鼠的病变中巨噬细胞数量减少，血管细胞黏附分子-1（VCAM-1）、组织因子以及转化生长因子受体 II 型的表达降低，这些都是 Egr-1 的靶基因。这些结果通过体外分析 Egr-1 缺陷型腹膜巨噬细胞得到了验证，与野生型对照相比，这些巨噬细胞在脂多糖刺激后，VCAM-1 和组织因子 mRNA 的表达降低。
本研究表明，骨髓源性 Egr-1 促进了巨噬细胞的积累、动脉粥样硬化病变的发展和病变的复杂性。
