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New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury

Nature Medicine volume 5, pages 1264–1269 (1999)Cite this article

An Erratum to this article was published on 01 December 1999

Abstract

Early growth response factor-1 (Egr-1) binds to the promoters of many genes whose products influence cell movement and replication in the artery wall. Here we targeted Egr-1 using a new class of DNA-based enzyme that specifically cleaved Egr-1 mRNA, blocked induction of Egr-1 protein, and inhibited cell proliferation and wound repair in culture. The DNA enzyme also inhibited Egr-1 induction and neointima formation after balloon injury to the rat carotid artery wall. These findings demonstrate the utility of DNA enzymes as biological tools to delineate the specific functions of a given gene, and implicate catalytic nucleic acid molecules composed entirely of DNA as potential therapeutic agents.

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Figure 1: In vitro cleavage of Egr-1 RNA.
Figure 2: Egr-1 DNA enzyme inhibits the induction of Egr-1 mRNA and protein by serum.
Figure 3: SMC proliferation is inhibited by Egr-1 DNA enzyme.
Figure 4: Cellular localization and stability of Egr-1 DNA enzymes.
Figure 5: Egr-1 DNA enzyme inhibits SMC repair after mechanical injury.
Figure 6: Sequence-specific inhibition of neointima formation by Egr-1 DNA enzyme in the rat carotid artery.
Figure 7: Immunoperoxidase detection of Egr-1 in balloon-injured carotid arteries treated with DNA enzyme.

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Acknowledgements

We thank A. Enno for advice on immunohistochemical analysis and P. Halasz for assistance with image analysis. This work was supported in part by a Strategic Partnership with Industry grant from the Australian Research Council (L.M.K.), and grants from the National Heart Foundation of Australia (L.M.K.), National Health and Medical Research Council of Australia (N.H.M.R.C) (L.M.K. and C.N.C.) and New South Wales Health Department. H.C.L. is supported by a Medical Postgraduate Research Scholarship (N.H.M.R.C.) and L.M.K. is the recipient of an R. Douglas Wright Fellowship (N.H.M.R.C.).

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Authors and Affiliations

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

    Fernando S. Santiago, Harry C. Lowe, Mary M. Kavurma, Colin N. Chesterman & Levon M. Khachigian

  2. Johnson and Johnson Research Pty. Limited, Sydney, Australia

    Andrew Baker & David G. Atkins

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  1. Fernando S. Santiago
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Correspondence to Levon M. Khachigian.

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Santiago, F., Lowe, H., Kavurma, M. et al. New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury. Nat Med 5, 1264–1269 (1999). https://doi.org/10.1038/15215

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