Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis

H C Lowe; R G Fahmy; M M Kavurma; A Baker; C N Chesterman; L M Khachigian

doi:10.1161/hh2001.097867

Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis

Circ Res. 2001 Oct 12;89(8):670-7. doi: 10.1161/hh2001.097867.

Authors

H C Lowe¹, R G Fahmy, M M Kavurma, A Baker, C N Chesterman, L M Khachigian

Affiliation

¹ Centre for Thrombosis and Vascular Research, University of New South Wales and Prince of Wales Hospital, Sydney, Australia.

PMID: 11597989
DOI: 10.1161/hh2001.097867

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Division / drug effects
Cells, Cultured
Coronary Vessels / drug effects
Coronary Vessels / metabolism*
Coronary Vessels / pathology
DNA, Catalytic / pharmacology*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Disease Models, Animal
Dose-Response Relationship, Drug
Early Growth Response Protein 1
Gene Expression Regulation / drug effects
Graft Occlusion, Vascular / metabolism*
Graft Occlusion, Vascular / pathology
Graft Occlusion, Vascular / prevention & control*
Humans
Immediate-Early Proteins*
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
RNA, Messenger / antagonists & inhibitors
RNA, Messenger / metabolism
Swine
Transcription Factors / genetics
Transcription Factors / metabolism*
Tunica Intima / drug effects
Tunica Intima / metabolism
Tunica Intima / pathology

Substances

DNA, Catalytic
DNA-Binding Proteins
EGR1 protein, human
Early Growth Response Protein 1
Immediate-Early Proteins
RNA, Messenger
Transcription Factors