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1 Developmental Lung Biology Laboratory, Pediatric Critical Care, University of Colorado, Denver, Colorado, USA
* To whom correspondence should be addressed. E-mail: kurt.stenmark{at}UCHSC.edu.
In most mammalian species, chronic exposure to hypoxia leads to pulmonary hypertension and vascular remodeling. The adventitial fibroblast, because of its ability to proliferate in response to hypoxia, is thought to be a critical cell in the remodeling process. However, the transcription factors driving hypoxia-induced fibroblast proliferation have yet to be elucidated. Previous studies have demonstrated that the Early growth response-1 (Egr-1) transcription factor is upregulated by hypoxia in pulmonary artery adventitial fibroblasts. We therefore hypothesized that Egr-1 is directly involved in hypoxia-induced adventitial fibroblast proliferation. Immunohistochemical analysis of in vivo lung tissue from animals exposed to chronic hypoxia revealed increased expression of Egr-1 in pulmonary artery fibroblasts of hypoxic animals compared to normoxic controls. In fibroblasts cultured from chronically hypoxic animals, we found that exposure to 1% oxygen upregulated Egr-1 protein and cell proliferation. To evaluate the role of Egr-1 in hypoxia-induced proliferation, we employed an Egr-1 antisense strategy. The addition of antisense Egr-1 oligonucleotides, but not sense oligonucleotides, attenuated the hypoxia-induced upregulation of Egr-1 protein. Hypoxia-induced DNA synthesis was reduced by 50% in the presence of antisense Egr-1 oligonucleotides. Cell proliferation was also significantly inhibited by the addition of the antisense Egr-1 oligonucleotides while the sense oligonucleotides had no effect. In addition, the hypoxia-induced upregulation of Cyclin-D and Epidermal Growth Factor Receptor (EGFR) were attenuated by Egr-1 antisense oligonucleotides. We conclude that Egr-1 protein expression is very sensitive to upregulation by hypoxia in pulmonary artery adventitial fibroblasts and that it plays an important role in the autonomous growth phenotype induced by hypoxia in these cells.
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