Egr-1, an inducible switch in the cardiovascular response to injury
The vascular system normally facilitates the passage of blood, nutrients and oxygen throughout the body whilst maintaining a non-thrombogenic surface. Our blood vessels therefore play a key role in homeostasis. In response to vascular injury however there is a prompt sequence of molecular events that involve multiple signaling and transcriptional pathways that can lead to disease. Recent work indicates that Egr-1 is among the most responsive immediate early genes across a range of human cell types and has helped redefine our understanding of these key genes into classifications.
Early growth response-1 (Egr-1) is not generally expressed in normal arteries but is rapidly induced after injury. Egr-1 is also inducibly expressed in the myocardium after ischemic reperfusion injury. There are hundreds of genes that are stimulated by Egr-1, including growth factors, extracellular matrix proteins and transcriptional regulators such as Egr-1 itself. Egr-1 is one of many zinc finger transcription factors that belong to the Cys2-His2 subtype. Egr-1 binds to GC-rich elements in the promoters of responsive genes and in concert with other interacting proteins, drives gene expression. Egr-1 itself can undergo a range of post-translational modifications including acetylation, ubiquitination, phosphorylation, and SUMOylation to modulate gene expression.
This review compiles a wide range of findings obtained from different laboratories on the role played by Egr-1 in the pathogenesis of vascular disorders. Approaches that have been used to explore the functions of Egr-1 have included shRNA, siRNA, microRNA, DNAzymes, oligonucleotide decoy strategies as well as mice deficient in Egr-1.
For example, we recently reported that miR-191 negatively regulates Egr-1 in SMCs and controls neointima formation after balloon injury in rat carotid arteries. miR-191 suppresses Egr-1 expression and inhibits ki-67 proliferation marker expression. Secondly, in pig myocardium subjected to ischaemia-reperfusion injury, Egr-1 DNAzymes reduce infarct size and improve cardiac functional recovery. The DNAzyme inhibits Egr-1 and intercellular adhesion molecule-1 expression. It also reduces tumor necrosis factor-alpha, tissue factor, plasminogen activator inhibitor-1 expression and myocardial myeloperoxidase activity. Thirdly, a lentiviral vector carrying Egr-1 shRNA reduces intimal thickening in iliac arteries after balloon injury in rats induced by nicotine. Finally, Egr-1 decoy oligonucleotides inhibit expression of Egr-1 and hyperplasia in vein grafts of hypercholesterolemic and non-hypercholesterolemic rabbits.
This review also cites observations using Egr-1 deficient mice. Whereas Egr-1 expression increases in vein grafts in wild-type mice, neointimal area in vein grafts in Egr-1 knockout mice is reduced by over 50%. Moreover Egr-1 deficiency in chimeric mice deficient in Egr-1 in their hematopoietic compartment show poor aneurysm formation in an angiotensin II-independent CaCl2-induced model of abdominal aortic aneurysm.
These findings, taken together indicate that Egr-1 may represent an attractive target for therapeutic intervention in vascular disease.
Levon Khachigian
Vascular Biology and Translational Research, Faculty of Medicine,
University of New South Wales, Sydney, Australia
Publication
Early growth response-1 in the pathogenesis of cardiovascular disease.
Khachigian LM
J Mol Med (Berl). 2016 Jul
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