HYPOXIA STIMULATES HUMAN PREPROENDOTHELIN-1 PROMOTER ACTIVITY IN TRANSGENIC MICE

Significant elevations in endothelin (ET)-1 levels accompany many dise ases, but the underlying regulatory mechanisms are unclear. To investi gate the in vivo regulation of human preproendothelin-1 (PPET-1), we e xamined the activity of the PPET-1 promoter in transgenic mice exposed to hypoxia. Mice expressing one of three PPET-1 promoter-luciferase ( PPET-1/LUC) reporter transgenes (approximate to 2.5 kb, 138 bp, or non e of the 5'-flanking sequences of the PPET-1 gene) were generated. LUC expression was reduced in mice with a truncated 138-bp PPET-1 promote r. Exposure of mice bearing the 2.5-kb PPET-1/LUC transgene to hypoxia (10% O-2 for 24 h) increased LUC expression sixfold in pulmonary tiss ue but only twofold in other tissues. In situ hybridization revealed t he strongest transgene expression in the pulmonary vasculature and bro nchiolar epithelium. These data are consistent with the hypothesis tha t hypoxic induction of the PPET-1 gene leads to increased pulmonary pr oduction of ET-1 in diseases associated with low O-2 tension.