Transcriptional Control of Cardiac Allograft Vasculopathy by Early Growth Response Gene-1 (Egr-1)

Abstract

Abstract-Expression of the zinc finger transcription factor early growth response gene-1 (Egr-1) is triggered rapidly after mechanical vascular injury or after a precipitous drop in ambient oxygen, whereupon it induces the expression of diverse gene families to elicit a pathological response. Initially characterized as an early response transcriptional activator, the role of Egr-1 in more chronic forms of vascular injury remains to be defined. Studies were designed to examine whether Egr-1 induction may serve as a causal link between early preservation injury and delayed vascular consequences, such as coronary allograft vasculopathy (CAV). The preservation and transplantation of heterotopic murine cardiac allografts strongly induce Egr-1 expression, leading to increased expression of its downstream target genes, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet-derived growth factor A chain. Expression of these Egr-1-inducible gene targets is virtually obliterated in homozygous Egr-1-null donor allografts, which also exhibit attenuated parenchymal rejection and reduced CAV as long as 60 days. Congruous data are observed by treating donor hearts with a phosphorothioate antisense oligodeoxyribonucleotide directed against Egr-1 before organ harvest, which blocks subsequent expression of Egr-1 mRNA and protein and suppresses the late development of CAV. These data indicate that Egr-1 induction represents a central effector mechanism in the development of chronic rejection characterized by CAV. Blocking the expression of this proximal transcription factor solely at the time of organ harvest elicits beneficial delayed consequences for the cardiac allograft.

Transforming Growth Factor β1-mediated Activation of the Smooth Muscle α-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-α via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor

“…Egr-1 is not expressed in normal tissue but rapidly induced by inflammatory cytokines released into damaged heart, lung, and kidney tissue beds as a result of mechanical trauma and hypoxia (McCaffrey et al, 2000;Yan et al, 2000;Okada et al, 2002;Autieri et al, 2004;Khachigian, 2006;Harada et al, 2007). Hypoxia induces Egr-1 expression in the microvascular endothelium and adventitial fibroblasts via protein kinase C␣-mediated Ras/Raf/Mek/Erk signaling (Khachigian, 2006).…”

Early Growth Response-1 in Cardiovascular Pathobiology

“…In contrast, these genes are poorly expressed in homozygous Egr-1-deficient donor allografts, in which parenchymal rejection and CAV are suppressed. 79 Antisense Egr-1 oligonucleotides delivered at the time of organ harvest inhibit Egr-1 expression and the development of CAV. 79 Antisense Egr-1 also block lung transplant leukostasis, inflammation, and thrombosis in rats together with improved graft function and recipient survival.…”

A novel chimeric promoter that is highly responsive to hypoxia and metals

“…12 More recently, we and others have focused on the role of Egr-1 in coordinating responses to hypoxia and vascular injury. [13][14][15][16] The potential roles of MTF-1 and Egr-1 in hypoxia are significant in that they may represent other types of host response mechanisms in the hypoxic milieu. The target genes regulated by these zinc-finger transcription factors are thought to differ from those under the control of the HIF-1 family.…”