Hypoxia stimulates human preproendothelin-1 promoter activity in transgenic mice.
Significant elevations in endothelin (ET)-1 levels accompany many diseases, but the underlying regulatory mechanisms are unclear. To investigate the in vivo regulation of human preproendothelin-1 (PPET-1), we examined 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 (approximately 2.5 kb, 138 bp, or none 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 promoter. Exposure of mice bearing the 2.5-kb PPET-1/LUC transgene to hypoxia (10% O2 for 24 h) increased LUC expression sixfold in pulmonary tissue but only twofold in other tissues. In situ hybridization revealed the 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 production of ET-1 in diseases associated with low O2 tension.
Aversa
C R
CR
Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Oparil
S
S
Caro
J
J
Li
H
H
Sun
S D
SD
Chen
Y F
YF
Swerdel
M R
MR
Monticello
T M
TM
Durham
S K
SK
Minchenko
A
A
Lira
S A
SA
Webb
M L
ML
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019332:Endothelin-1; D016232:Endothelins / Q000096:biosynthesis* / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia; D008156:Luciferases / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics*; D011651:Pulmonary Artery; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D008156:Luciferases