Early growth response-1 promotes atherogenesis - Mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation
Early growth response-1 promotes atherogenesis - Mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation
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DOI：
10.1161/01.res.0000112405.61577.95
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发表时间：
2004-02-20
影响因子：
20.1
通讯作者：
Yan, SF
中科院分区：
文献类型：
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作者：
Harja, E;Bucciarelli, LG;Yan, SF
早期生长反应-1（Egr-1）调节急性细胞应激中促炎和促凝血基因的表达。实验证据表明，Egr-1转录上调人类动脉粥样硬化斑块与相邻的未受影响的组织。为了测试Egr-1对慢性血管应激的影响，我们研究了它在动脉粥样硬化小鼠模型中的作用。与从C57 BL/6对照动物中提取的DNA相比，从apoE（-/-）小鼠中提取的DNA的实时PCR分析表明Egr-1转录物以年龄依赖性方式增加。因此，将纯合子Egr-1（-/-）小鼠与apoE（-/-）背景交配。在C57 BL/6背景中的纯合双敲除小鼠（Egr-1（-/-）/apoE（-/-））维持正常食物饮食。在14和24周龄时，与apoE单独缺陷的小鼠相比，Egr-1和apoE缺陷的小鼠主动脉根部的动脉粥样硬化病变面积和复杂性显著降低。与此同时，Egr-1（-/-）/apoE（-/-）血小板与apoE（-/-）相比，调节炎症/血栓前反应的基因转录物减少。在体外，氧化低密度脂蛋白（OxLDL），一个关键因素，刺激动脉粥样硬化的机制，在血管，上调Egr-1表达单核细胞通过MEK-ERK 1/2途径。我们的结论是，Egr-1广泛调节与动脉粥样硬化形成和病变进展密切相关的分子的表达。
Early growth response-1 (Egr-1) regulates expression of proinflammatory and procoagulant genes in acute cell stress. Experimental evidence suggested that Egr-1 transcripts were upregulated in human atherosclerotic plaques versus adjacent unaffected tissue. To test the impact of Egr-1 in chronic vascular stress, we examined its role in a murine model of atherosclerosis. Real-time PCR analysis of aortae retrieved from apoE(-/-) mice demonstrated increased Egr-1 transcripts in an age-dependent manner, compared with aortae retrieved from C57BL/6 control animals. Therefore, homozygous Egr-1(-/-) mice were bred into the apoE(-/-) background. Homozygous double-knockout mice (Egr-1(-/-)/apoE(-/-)) in the C57BL/6 background were maintained on normal chow diet. At age 14 and 24 weeks, atherosclerotic lesion area and complexity at the aortic root were strikingly decreased in mice deficient in both Egr-1 and apoE compared with mice deficient in apoE alone. In parallel, transcripts for genes regulating the inflammatory/prothrombotic response were diminished in Egr-1(-/-)/apoE(-/-) aortae versus apoE(-/-). In vitro, oxidized low-density lipoprotein (OxLDL), a key factor inciting atherogenic mechanisms in the vasculature, upregulated Egr-1 expression in monocytes via the MEK-ERK1/2 pathway. We conclude that Egr-1 broadly regulates expression of molecules critically linked to atherogenesis and lesion progression.