Hypoxia stimulates human preproendothelin-1 (PPET-1) promoter activity in transgenic mice

Academic Article

Abstract

  • Significant elevations in circulating and tissue levels of endothelin-1 (ET-1) accompany many diseases, but the regulatory mechanisms underlying these disease-associated increases are unclear. In order to investigate the in vivo regulation of human preproendothelin-1 (PPET-1) gene expression, we examined the activity of the PPET-1 promoter in transgenic mice exposed to hypoxic conditions. Mien expressing one of three KT promoter-luciferase (PPET- l/LUC) reporter transgene constructs (2.5 kb, 138 bp. or none of the 5 flanking PPET-1 promoter sequence) were generated. The pattern of tissue expression of the PPET-1/LUC transgenes was consistent with expression of endogenous mouse PPET-1 mRNA. I.uciferase expression was reduced in mice with a truncated 138 bp PPET-1 promoter. Exposure of mice bearing the 2.5 kb PPET-1/LUC transgene to hypoxic conditions (10% O2/12 hours) increased luciferase expression 5-fold in pulmonary tissue and 2-fold in cardiac, renal, hepatic, or splenic tissue. In situ hybridization in tissue from hypoxic mice revealed strongest transgene expression in the pulmonary vasculature and bronchiolar epithelium. These data are consistent with the hypothesis that hypoxic induction of the PPET-1 gene leads to increased pulmonary ET-1 production in diseases associated with low oxygen tension, such as pulmonary hypertension and congestive heart failure.
  • Authors

    Published In

  • The FASEB Journal  Journal
  • Author List

  • Aversa CR; Oparil S; Caro J; Li H; Minchenko A; Sun S; Chen YF; Swerdel M; Webb ML; Lira SA
  • Volume

  • 10
  • Issue

  • 6