Transcriptional control of deformation-induced preproendothelin-1 gene expression in endothelial cells

Citation
M. Lauth et al., Transcriptional control of deformation-induced preproendothelin-1 gene expression in endothelial cells, J MOL MED-J, 78(8), 2000, pp. 441-450
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Journal title
JOURNAL OF MOLECULAR MEDICINE-JMM
ISSN journal
0946-2716 → ACNP
Volume
78
Issue
8
Year of publication
2000
Pages
441 - 450
Database
ISI
SICI code
0946-2716(2000)78:8<441:TCODPG>2.0.ZU;2-X
Abstract
Deformation-induced synthesis of endothelin-1 (ET-1) in endothelial cells e xposed to high blood pressure may play an important role in vein graft dise ase and in restenosis following percutaneous transluminal angioplasty. Effe ctive inhibitors of preproendothelin ET-1 (ppET-1) processing to ET-1 are n ot available, and blockade of ppET-1 expression may therefore emerge as an alternative therapeutic approach. To evaluate this, we investigated deforma tion-sensitive transcription factors controlling ppET-1 expression in both native (rabbit carotid artery and jugular vein) and cultured endothelial ce lls (EC; porcine aorta and human umbilical vein). Deformation of both nativ e and cultured endothelial cells for 6 h resulted in a marked increase in E T-I synthesis which was preceded by a transient (30-60 min) activation of t ranscription factors activator protein-1 (AP-1) and CCAAT/enhancer-binding protein (C/EBP) beta and/or 6. A decoy oligodeoxynucleotide directed agains t AP-1 inhibited deformation-induced ppET-1 expression in the rabbit jugula r vein as well as in porcine aorta EC and human umbilical vein EC but not i n the rabbit carotid artery. Subsequent reporter gene analyses with differe nt rat ppET-1 promoter-luciferase constructs transiently transfected into p orcine aorta EC identified a single AP-1 binding site at -110 to -100 bp as the primary response element for deformation-induced ppET-1 expression. Mo reover, a C/EBP-specific decoy oligodeoxynucleotide abolished ppET-1 expres sion in the endothelium of the rabbit carotid artery, but not in the jugula r vein where basal ET-1 synthesis was greatly enhanced instead. These findi ngs suggest that the key transcription factors controlling deformation-indu ced ppET-1 expression in endothelial cells are blood vessel rather than spe cies-specific. In humans, adjunct treatment with an AP-1-specific decoy oli godeoxynucleotide may prove be an interesting gene therapeutic option for t he above cardiovascular interventions.