Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis.
Early growth response factor-1 (Egr-1) controls the expression of a growing number of genes involved in the pathogenesis of atherosclerosis and postangioplasty restenosis. Egr-1 is activated by diverse proatherogenic stimuli. As such, this transcription factor represents a key molecular target in efforts to control vascular lesion formation in humans. In this study, we have generated DNAzymes targeting specific sequences in human EGR-1 mRNA. These molecules cleave in vitro transcribed EGR-1 mRNA efficiently at preselected sites, inhibit EGR-1 protein expression in human aortic smooth muscle cells, block serum-inducible cell proliferation, and abrogate cellular regrowth after mechanical injury in vitro. These DNAzymes also selectively inhibit EGR-1 expression and proliferation of porcine arterial smooth muscle cells and reduce intimal thickening after stenting pig coronary arteries in vivo. These findings demonstrate that endoluminally delivered DNAzymes targeting EGR-1 may serve as inhibitors of in-stent restenosis.
Lowe
H C
HC
Centre for Thrombosis and Vascular Research, University of New South Wales and Prince of Wales Hospital, Sydney, Australia.
Fahmy
R G
RG
Kavurma
M M
MM
Baker
A
A
Chesterman
C N
CN
Khachigian
L M
LM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D021881:DNA, Catalytic / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects; D006083:Graft Occlusion, Vascular / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D017874:Immediate-Early Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013552:Swine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D021881:DNA, Catalytic; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014157:Transcription Factors