Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

In vivo transfection of cis element “decoy” against nuclear factor- κB binding site prevents myocardial infarction

Nature Medicine volume 3, pages 894–899 (1997)Cite this article

Abstract

The transcriptional factor nuclear factor-κB (NFκB) plays a pivotal role in the coordinated trans-activation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Therefore, we hypothesized that synthetic double-stranded DMA with high affinity for NFκB could be introduced in vivo as “decoy” cis elements to bind the transcriptional factor and to block the activation of genes mediating myocardial infarction, thus providing effective therapy for myocardial infarction. Treatment before and after infarction by transfection of NFκB decoy, but not scrambled decoy, oligodeoxynucleotides before coronary artery occlusion or immediately after reperfusion had a significant inhibitory effect on the area of infarction. Here, we report the first successful in vivo transfer of NFκB decoy oligodeoxynucleotides to reduce the extent of myocardial infarction following reperfusion, providing a new therapeutic strategy for myocardial infarction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Sullenger, B.A., Gallardo, H.F., Lingers, G.E. & Gilboa, E. Overexpression of TAR sequence renders cells resistant to human immunodeficiency virus replication. Cell 63, 601–608 (1990).

    Article  CAS  Google Scholar 

  2. Bielinska, A., Schivdasani, R.A., Zhang, L. & Nabel, G.J. Regulation of gene expression with double-stranded phosphorothioate oligonucleotides. Science 250, 997–1000 (1990).

    Article  CAS  Google Scholar 

  3. Yamada, T. et al. In vivo identification of a negative regulatory element in the mouse renin gene using direct gene transfer. J. Clin. Invest. 96, 1230–1237 (1995).

    Article  CAS  Google Scholar 

  4. Morishita, R. et al. Role of transcriptional cis-elements, angiotensinogen gene-activating element, of angiotensinogen gene in blood pressure regulation. Hypertension 27, 502–507 (1996).

    Article  CAS  Google Scholar 

  5. Morishita, R. et al. A novel molecular strategy using cis element “decoy” of E2F binding site inhibits smooth muscle proliferation in vivo. Proc. Natl. Acad. Sci. USA 92, 5855–5859 (1995).

    Article  CAS  Google Scholar 

  6. Billups, K.L., Palladino, M.A., Hinton, B.T. & Sherley, J.L. Expression of E-selectin mRNA during ischemia/reperfusion injury. J. Lab. Clin. Med. 125, 626–633 (1995).

    CAS  PubMed  Google Scholar 

  7. Kukielka, G.L. et al. Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation 92, 1866–1875 (1995).

    Article  CAS  Google Scholar 

  8. Oz, M.C. et al. Ischemia-induced interleukin 8 release after human heart transplantation: A potential role for endothelial cells. Circulation 92, II-428–II-432 (1995).

    Article  CAS  Google Scholar 

  9. Herskowitz, A., Choi, S., Ansari, A.A. & Wesselingh, S. Cytokine mRNA expression in postischemic/reperfused myocardium. Am. J. Pathol. 146, 419–428 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Youker, K.A. et al. Molecular evidence for induction of intracellular adhesion molecule-1 in the viable border zone associated with ischemia-reperfusion injury of the dog heart. Circulation 89, 2736–2746 (1994).

    Article  CAS  Google Scholar 

  11. Lenardo, M.J., Baltimore, D. NF-kappa B: A pleiotropic mediator of inducible and tissue-specific gene control. Cell 58, 227–229 (1989).

    Article  CAS  Google Scholar 

  12. Libermann, T.A., Baltimore, D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol. Cell. Biol. 10, 2327–2334 (1990).

    Article  CAS  Google Scholar 

  13. Satriano, J., Schlondroff . Activation and attenuation of transcription factor NF-κB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3′:5′-cyclic monophosphate: Evidence for involvement of reactive oxygen species. J. Clin. Invest. 94, 1629–1636 (1994).

    Article  CAS  Google Scholar 

  14. Brennan, D.C., Jevnikar, A.M., Takei, F. & Reubin-Kelley, V.E. Mesangial cell accessory functions: Mediation by intercellular adhesion molecule-1. Kidney Int. 38, 1039–1046 (1990).

    Article  CAS  Google Scholar 

  15. Neish, A.S., Williams, A.J., Palmer, H.J., Whitley, M.Z. & Collins, T. Functional analysis of the human vascular cell adhesion molecule 1 promoter. J. Exp. Med. 176, 1583–1593 (1992).

    Article  CAS  Google Scholar 

  16. Yamazaki, T. et al. Expression of intercellular adhesion molecule-1 in rat heart with ischemia/reperfusion and limitation of infarct size by treatment with antibodies against cell adhesion molecules. Am. J. Pathol. 143, 410–418 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sawa, Y. et al. Efficiency of in vivo gene transfection into transplanted rat heart by coronary infusion of HVJ liposome. Circulation 92, 11-479–11-482 (1995).

    Article  Google Scholar 

  18. Jang, Y., Lincoff, A.M., Plow, E.F. & Topol, E.J. Cell adhesion molecules in coronary artery disease. J. Am. Coll. Cardiol. 24, 1591–1601 (1994).

    Article  CAS  Google Scholar 

  19. Weyrich, A.S., Ma, X.Y., Lefer, D.J., Albertine, K.H. & Lefer, A.M. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J. Clin. Invest. 91, 2620–2629 (1993).

    Article  CAS  Google Scholar 

  20. Wilson, I. et al. Inhibition of neutrophil adherence improves postischemic ventricular performance of the neonatal heart. Circulation 88, 11372–379 (1993).

    Article  Google Scholar 

  21. Cotran, R.S., Mumar, V., Robins, S.L. Pathologic Basis of Disease, 4th edn. 611 (Saunders, Philadelphia, 1989).

    Google Scholar 

  22. Sobel, B.E., Bresnahan, G.F., Shell, W.E. & Yoder, R.D. Estimation of infarct size in man and its relation to prognosis. Circulation 106, 640–648 (1972).

    Article  Google Scholar 

  23. Thomae, K.R. et al. Antisense oligonucleotide to inducible nitric oxide synthase inhibits nitric oxide synthesis in rat pulmonary artery smooth muscle cells in culture. Surgery 114, 272–277 (1993).

    CAS  PubMed  Google Scholar 

  24. Morita, S., Kawashima, S., Ueno, M., Kubota, A. & Iwasaki, T. Effects of late reperfusion on infarct expansion and infarct healing in conscious rats. Am. J. Pathol. 143, 419–430 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Herskowitz, A., Choi, S., Ansari, A.A. & Wesselingh, S. Cytokine mRNA expression in postischemic/reperfusion myocardium. Am. J. Pathol. 146, 419–428 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Sawa, Y. et al. Myocardial protective effect and its mechanism of leukocyte-depleted reperfusion in neonatal rabbit hearts. Ann. Thorac. Surg. 58, 1386–1391 (1994).

    Article  CAS  Google Scholar 

  27. Newton, R.C., Dowling, R., Daulerio, A.J. & Culp, S. An ELISA assay for murine interleukin-1 beta. J. Immunol. Methods 161, 257–264 (1993).

    Article  CAS  Google Scholar 

  28. Morishita, R. et al. Autocrine and paracrine effects of atrial natriuretic peptide gene transfer on vascular smooth muscle and endothelial cellular growth. J. Clin. Invest. 94, 824–829 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Ryuichi Morishita and Toshiko Sugimoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita, 565, Japan

    Ryuichi Morishita, Motokuni Aoki, Iwao Kida, Naruya Tomita, Atsushi Moriguchi, Jitsuo Higaki & Toshio Ogihara

  2. Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Osaka, 532, Japan

    Toshiko Sugimoto & Kazuhiro Maeda

  3. First Department of Surgery, Osaka University Medical School, Yamada-oka 2-2, Suita, 565, Japan

    Yoshiki Sawa

  4. Institute for Cellular and Molecular Biology, Osaka University Medical School, Yamada-oka 2-2, Suita, 565, Japan

    Yasufumi Kaneda

Authors
  1. Ryuichi Morishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiko Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Motokuni Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iwao Kida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naruya Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atsushi Moriguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhiro Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshiki Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasufumi Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jitsuo Higaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Toshio Ogihara
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morishita, R., Sugimoto, T., Aoki, M. et al. In vivo transfection of cis element “decoy” against nuclear factor- κB binding site prevents myocardial infarction. Nat Med 3, 894–899 (1997). https://doi.org/10.1038/nm0897-894

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0897-894

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing