Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress.
Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.
Yan
S F
SF
Department of Surgery, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, New York 10032, USA.
Fujita
T
T
Lu
J
J
Okada
K
K
Shan Zou
Y
Y
Mackman
N
N
Pinsky
D J
DJ
Stern
D M
DM
D000818:Animals; D001779:Blood Coagulation Factors / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005812:Genes, Switch; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008817:Mice, Mutant Strains; D015427:Reperfusion Injury / Q000209:etiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016335:Zinc Fingers / Q000235:genetics
D001779:Blood Coagulation Factors; D018925:Chemokines; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016228:Endothelial Growth Factors; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D008222:Lymphokines; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018799:Intercellular Adhesion Molecule-1