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:

Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress

Nature Medicine volume 6, pages 1355–1361 (2000)Cite this article

An Erratum to this article was published on 01 April 2001

Abstract

Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.

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

Figure 1: Ischemia/reperfusion induces and activates Egr-1 in murine lung.
Figure 2: Ischemia/reperfusion induces ICAM-1: effect of Egr-1.
Figure 3: Ischemia/reperfusion induces IL-1–β and chemokines: effect of Egr-1.
Figure 4: Ischemia/reperfusion induces TF, PAI-1, and VEGF: effect of Egr-1.
Figure 5: Murine model of lung ischemia/reperfusion: effect of Egr-1.
Figure 6: Hypoxia induces Egr-1–dependent expression of mRNA for IL-1–β, MIP-2 and JE/MCP-1(a) whereas expression of transcripts for LT-β, MIF and IL-7, (b) and L32 (a,b) remain unchanged.

Similar content being viewed by others

References

  1. Semenza, G. Perspectives on oxygen sensing. Cell 98, 281–284 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Zhu, H. & Bunn, H. Oxygen sensing and signaling: impact on the regulation of physiologically important genes. Respir. Physiol. 115, 239–247 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ratcliffe, P., O'Rourke, J., Maxwell, P. & Pugh, C. Oxygen sensing, HIF-1 and the regulation of mammalian gene expression. J. Exp. Biol. 201, 1153–1162 (1998).

    CAS  PubMed  Google Scholar 

  4. Yan, S.-F. et al. Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia. Proc. Natl. Acad. Sci. USA 95, 8298–8303 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Milbrandt, J. A nerve growth factor induced gene encodes a possible transcriptional regulatory factor. Science 238, 797–799 (1988).

    Article  Google Scholar 

  6. Gashler, A. & Sukhatme, V. Egr-1: prototype of a zinc finger family of transcription factors. Prog. Nucl. Acids Res. and Molec. Biol. 50, 191–224 (1995).

    Article  CAS  Google Scholar 

  7. Nguyen, H., Hoffman-Lieberman, B. & Liebermann, D. Egr-1 is essential for and restricts differentiation along the macrophage cell lineage. Cell 72, 197–209 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Yan, S-F. et al. Hypoxia-associated induction of Early Growth Response-1 gene expression. J. Biol. Chem. 274, 15030–15040 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Okada, K. et al. Potentiation of endogenous fibrinolysis and rescue from lung ischemia-reperfusion injury in IL-10-reconstituted IL-10 null mice. J. Biol. Chem. 275, 21468–21476, 2000.

    Article  CAS  PubMed  Google Scholar 

  10. Brand, T. et al. Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. Circ. Res. 71, 1351–1360 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Ouellette, A., Malt, R., Sukhatme, V. & Bonventre, J. Expression of two “immediate early” genes, Egr-1 and c-fos, in response to renal ischemia and during compensatory renal hypertrophy in mice. J. Clin. Invest. 85, 766–771 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Safirstein, R., Price, P., Saggi, S. & Harris, R. Changes in gene expression after temporary renal ischemia. Kidney Intl. 37, 1515–1521 (1990).

    Article  CAS  Google Scholar 

  13. Lee, S. et al. Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1). Science 273, 1219–1221 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Lefer, A. Role of the β2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion. Ann. Thorac. Surg. 68, 1920–1930 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Wang, C., et al. Cardiac graft ICAM-1 and IL-1 expression mediate primary isograft failure and induction of ICAM-1 in organs remote from the site of transplantation. Circ. Res. 82, 762–772 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Lemay, S., Rabb, H., Postler, G. & Singh, A. Prominent and sustained upregulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. Transplant 69, 959–963 (2000).

    Article  CAS  Google Scholar 

  17. Liu, P. et al. Role of endogenous nitric oxide in TNF-α and IL-1–β generation in hepatic ischemia-reperfusion. Shock 13, 217–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Touzani, O., Boutin, H., Chuquet, J. & Rothwell, N. Potential mechanisms of IL-1 involvement in cerebral ischemia. J. Neuroimmunol. 100, 203–215 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Mitsui, Y. The expression of proinflammatory cytokine mRNA in the sciatic-tibial nerve of ischemia-reperfusion injury. Brain Res. 844, 192–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Rollins, B. Chemokines. Blood 90, 909–928 (1997).

    CAS  PubMed  Google Scholar 

  21. Kunkel, S. Through the looking glass: the diverse in vivo activities of chemokines. J. Clin. Invest. 104, 1333–1334 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Colletti, L., Green, M., Burdick, M., Strieter, R. The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury following hepatic ischemia/reperfusion in the rat. Hepatology 31, 435–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Yoshidome, H., Kato, A., Edwards, M. & Lentsch, A. IL-10 inhibits pulmonary NF-kB activation and lung injury by hepatic ischemia-reperfusion. Am. J. Physiol. 277, L919–L923 (1999).

    CAS  PubMed  Google Scholar 

  24. Lentsch, A. et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for MIP-2 and KC. Hepatology 27, 1172–1177 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Bless, N. et al. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion. Am. J. Physiol. 276, L57–L63 (1999).

    CAS  PubMed  Google Scholar 

  26. Gourmala, N. et al. Differential and time-dependent expression of JE/MCP-1 mRNA by astrocytes and macrophages in rat brain: effects of ischemia and peripheral LPS administration. J. Neuroimmunol. 74, 35–44 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, X. et al. Prolonged expression of IP-10 in ischemic cortex after permanent occlusion of the middle cerebral artery in rat. J. Neurochem. 71, 1194–1204 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Collen, D. & Lijnen, H. Fibrin-specific fibrinolysis. Ann. N. Y. Acad. Sci. 667, 259–271 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Loskutoff, D., Sawdey, M., Keeton, M. & Schneiderman, J. Regulation of PAI-1 gene expression in vivo. Thromb. & Haemost. 70, 135–137 (1993).

    Article  CAS  Google Scholar 

  30. Leung, D. et al. VEGF is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. Dvorak, H., Brown, L., Detmar, M. & Dvorak, A. VPF/VEGF, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hayashi, T., Abe, K., Suzuki, H. & Itoyama, Y. Rapid induction of VEGF gene expression after transient middle cerebral artery occlusion in rats. Stroke 28, 2039–2044 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, S. et al. Early expression of angiogenesis factors in acute myocardial ischemia. N. Engl. J. Med. 342, 626–633 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. VanBruggen, N. et al. VEGF antagonism reduces edema formation and tissue damage in ischemia/reperfusion injury in the mouse brain. J. Clin. Invest. 104, 1613–1620 (1999).

    Article  CAS  Google Scholar 

  35. Weiss, S. Tissue destruction by neutrophils. N. Engl. J. Med. 320, 365–376 (1989).

    Article  CAS  PubMed  Google Scholar 

  36. Pober, J. & Cotran, R. Cytokines and endothelial cell biology. Physiol. Revs. 70, 427–451 (1990).

    Article  CAS  Google Scholar 

  37. Schechter, A. et al. Tissue factor is induced by MCP-1 in human aortic smooth muscle and THP-1 cells. J. Biol. Chem. 272, 28568–28573 (1997).

    Article  Google Scholar 

  38. Clauss, M. et al. VEGF: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J. Exp. Med. 172, 1535–1545 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Maltzman, J., Carmen, J. & Monroe, J. Transcriptional regulation of the ICAM-1 gene in antigen receptor- and phorbol ester-stimulated B lymphocytes: role for transcription factor Egr-1. J. Exp. Med. 183, 1747–1759 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Forsythe, J. et al. Activation of VEGF gene transcription by HIF-1. Molec. Cell. Biol. 16, 4604–4613 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Khachigian, L., Lindner, V., Williams, A. & Collins, T. Egr-1-induced endothelial gene expression: a common theme in vascular injury. Science 271, 1427–1431 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Svaren, J. et al. NAB2, a corepressor of NGFI-A (EGR-1), and Krox20, is induced by proliferative, and differentiative stimuli. Mol. Cell. Biol. 16, 3545–3553 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Morishita, R. et al. In vivo transfection of cis element “decoy” against NF-kB binding site prevents myocardial infarction. Nature Med. 3, 894–899 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Schneider, A. et al. NF-kB is activated and promotes cell death in focal cerebral ischemia. Nature Med. 5, 554–550 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Millet, I. et al. Inhibition of NF-kB activity and enhancement of apoptosis by neuropeptide CGRP. J. Biol. Chem. 275, 15114–15121 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Cahir-McFarland, E. NF-kB inhibition causes spontaneous apoptosis in EB virus-transformed lymphoblastoid cells. Proc. Natl. Acad. Sci. USA 97, 6055–6060 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Saadane, N., Alpert, L. & Chalifour, L. Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in Egr-1-deficient mice. Am. J. Physiol. 278, H796–805 (2000).

    CAS  Google Scholar 

  48. Cenci, S., Weitzmann, M., Gentile, M., Aisa, M. & Pacifici, R. M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced bone loss. J. Clin. Invest. 105, 1279–1287 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Goldblum, S., Wu, K. & Jay, M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J. App. Physiol. 59, 1978–1985 (1985).

    Article  CAS  Google Scholar 

  50. Ikomminoth, P. Detection of mRNA in tissue sections using DIG-labeled RNA and oligonucleotide probes. in, Nonradioactive In Situ Hybridization Application Manual, 2nd edition (Boehringer-Mannheim, Germany 126–135 (1996).

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the USPHS (HL63967, HL55397 and HL59488), the LeDucq Foundation and the Surgical Research Foundation.

Author information

Authors and Affiliations

  1. Department of Surgery, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, 10032, New York

    Shi-Fang Yan, Tomoyuki Fujita, Jiesheng Lu, Kenji Okada, Yu Shan Zou & David M. Stern

  2. Department of Physiology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, 10032, New York

    David M. Stern

  3. Department of Cellular Biophysics and Medicine, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, 10032, New York

    David J. Pinsky

  4. Department of Immunology and Vascular biology, Scripps Research Institute, La Jolla, 92037-1092, CA

    Nigel Mackman

Authors
  1. Shi-Fang Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoyuki Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiesheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Shan Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nigel Mackman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David J. Pinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David M. Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Fang Yan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yan, SF., Fujita, T., Lu, J. et al. Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med 6, 1355–1361 (2000). https://doi.org/10.1038/82168

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/82168

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