Cyclosporin A induces prepro endothelin-1 gene transcription in human endothelial cells.
Cyclosporin A employed in treatment of organ allograft rejection, is associated with hypertension possibly due to endothelin-1. We studied transcriptional regulation of endothelin-1 by cyclosporin A in human endothelial cells using cell transfection experiments and reporter gene assays. Human umbilical vein endothelial cells were established expressing a fusion gene of the coding sequence of the firefly luciferase gene, placed under the control of the rat endothelin-1 promoter. Luciferase assays demonstrate 2.8-fold stimulation of the reporter gene by cyclosporin A (P < 0.01), and Northern blot analysis shows induction of prepro endothelin-1 mRNA. Transcription is tightly repressed in the absence of the immunosuppressant, its regulation occurs Ca(2+)-dependent. Lack of extra- or intracellular Ca2+ prevents cyclosporin A-dependent endothelin-1 gene transcription and mRNA induction. These data demonstrate transcriptional regulation of endothelin-1 over a range of several orders of magnitude in human umbilical vein endothelial cells by cyclosporin A via Ca(2+)-dependent mechanisms. They support the critical role of endothelin- in cyclosporin A-associated hypertension.
Marsen
T A
TA
Klinik IV für Innere Medizin, University of Cologne, Germany. tobias.marsen@uni-koeln.de
Weber
F
F
Egink
G
G
Suckau
G
G
Baldamus
C A
CA
D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics*; D004727:Endothelium / Q000187:drug effects*; D005260:Female; D005470:Fluorometry; D005696:Galactosidases / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D010957:Plasmids; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
D002614:Chelating Agents; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D004533:Egtazic Acid; D016572:Cyclosporine; D008156:Luciferases; D005696:Galactosidases; D002118:Calcium