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
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
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.