Early Growth Response-1 Promotes Atherogenesis: Mice Deficient in Early Growth Response-1 and Apolipoprotein E Display Decreased Atherosclerosis and Vascular Inflammation

• Published in: Circulation research 2004-02, Vol.94 (3), p.333-339
• Main Authors: Harja, Evis, Bucciarelli, Loredana G., Lu, Yan, Stern, David M., Zou, Yu Shan, Schmidt, Ann Marie, Yan, Shi-Fang
• Format: Article
• Language: English
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; Apolipoproteins E - genetics; Apolipoproteins E - physiology; Arteriosclerosis - genetics; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Glucose - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiology. Vascular system; Cell Line; Chemokine CCL2 - genetics; Cholesterol - blood; Disease Progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Early Growth Response Protein 1; Enzyme Inhibitors - pharmacology; Female; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression; Immediate-Early Proteins - genetics; Immediate-Early Proteins - physiology; Intercellular Adhesion Molecule-1 - genetics; Interleukin-1 - genetics; Lipoproteins, LDL - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation - drug effects; Plasminogen Activator Inhibitor 1 - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thromboplastin - genetics; Time Factors; Transcription Factors - genetics; Transcription Factors - physiology; Triglycerides - blood; Vascular Cell Adhesion Molecule-1 - genetics; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000112405.61577.95

ABSTRACT—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.