Hypoxia enhances promoter activity of human endothelin-1 gene in transgenic mice

Academic Article

Abstract

  • We have previously demonstrated that hypoxic exposure significantly and selectively enhances endothelin-1 (ET-1) gene expression in rat lung and in cultured human pulmonary microvessel endothelial cells. To further study the effects of hypoxia on the promoter activity of the human ET-1 gene, transgenic mice harboring a luciferase reporter gene driven by a 2.45kb human ET-1 gene promoter (-2459 to +165 bp from the transcriptional start site) were exposed to hypoxia (10% O2 1 atm.) or room air for 24 hrs. Luciferase activity in various organs was measured and normalized by protein content. Results (mean±SE) in hypoxic rats (n=6) (expressed as fold increase compared to values in air controls [n-6]) are: Lung 6.99±1.34** Liver 2.20±0.15** Kidney 1.85±10.17** Spleen 1.86±0.18** Heart 1.53±0.19** Brain 2.31±0.14** Aorta 2.40±0.42** Tail 0.94±0.08 * p<0.05, ** p<0.01, compared to air control group. These data indicate that the 2.45 kb promoter region of the human ET-1 gene in the 5± flanking region adjacent to the transcriptional start site contains cis-regulatory sequences that mediate a hypoxia-inducible response. The greater magnitude of hypoxic stimulation of luciferase activity in lung is consistent with the pattern of selective increase of ET-1 mRNA levels in rat lung in our previous studies and suggests involvement of tissue specific hypoxia inducible transcription factor(s) in lung which mediate the hypoxic response.
  • Authors

    Published In

    Author List

  • Li H; Chen YF; Oparil S
  • Volume

  • 44
  • Issue

  • 1