Published online before print September 27, 2001, doi: 10.1161/hh2001.097867
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Catalytic Oligodeoxynucleotides Define a Key Regulatory Role for Early Growth Response Factor-1 in the Porcine Model of Coronary In-Stent Restenosis
From the Centre for Thrombosis and Vascular Research, University of New South Wales and Prince of Wales Hospital (H.C.L., R.G.F., M.M.K., C.N.C., L.M.K.) and Johnson and Johnson Research Pty. Limited (A.B.), Sydney, Australia.
Correspondence to Levon M. Khachigian, PhD, Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales, Sydney NSW 2052, Australia. E-mail L.Khachigian{at}unsw.edu.au
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.
Key Words: catalytic DNA • transcription factors • early growth response factor-1 • stenting • gene therapy
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