Changes in the extracellular environment can trigger alterations in gene expression and eventually phenotype through the activity of transcription factors. One such “coupler” is early growth response (Egr)-1 (also known as Krox-24, zif268, NGFI-A, and TIS8), a 60- to 80-kDa zinc finger transcription factor of the C2H2 subtype and the product of an immediateearly gene (1). It belongs to a family of nuclear regulators that include Egr-2, Egr-3, and Egr-4, and its expression can be induced by a variety of pathophysiologic stimuli in endothelial cells (ECs) and other vascular cell types such as smooth muscle cells (SMCs), monocytes, and macrophages, as well as in a diverse range of nonvascular cells. In 1987, Egr-1 was independently cloned by a number of groups using differential screening strategies (2–5). It is comprised of 533 amino acids and contains an amino-terminal and a carboxyl-terminal activation domain, a repression domain, and a DNA-binding domain consisting of three conserved zinc fingers. Egr-1 also contains a bipartite nuclear localization signal (residues 315–330 and a section of the DNA-binding domain) (Figure 90.1) (1,6).

Egr-1 has been implicated in a panoply of cardiovascular pathologic processes, which include atherosclerosis, restenosis, ischemia, angiogenesis, allograft rejection, and cardiac hypertrophy (7). Triggers such as injury (8), altered biomechanical environment (9), growth factor/hormone and cytokine exposure (10–13), chemical challenge (such as lysophosphatidylcholine) (14), and hypoxia (15,16) are capable of rapidly inducing Egr-1 transcription. Once induced, Egr-1 regulates the expression of many genes through specific interactions with GC-rich motifs in the promoter regions of responsive genes. These include transcription factors, signaling molecules, cell cycle regulatory proteins, cytokines, growth factors, coagulation factors, and even Egr-1 itself.