Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blood Coagulation Factors / biosynthesis
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Chemokines / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Early Growth Response Protein 1
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Endothelial Growth Factors / biosynthesis
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Genes, Switch
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Intercellular Adhesion Molecule-1 / biosynthesis
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Lipopolysaccharides / toxicity
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Lung / blood supply
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Lung / pathology*
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Lymphokines / biosynthesis
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Mice
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Mice, Mutant Strains
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Reperfusion Injury / etiology*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Up-Regulation
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Zinc Fingers / genetics
Substances
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Blood Coagulation Factors
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Chemokines
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DNA-Binding Proteins
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Early Growth Response Protein 1
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Egr1 protein, mouse
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Endothelial Growth Factors
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Immediate-Early Proteins
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Lipopolysaccharides
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Lymphokines
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Intercellular Adhesion Molecule-1