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Molecular and Cellular Biochemistry

, Volume 303, Issue 1–2, pp 259–262 | Cite as

Hypoxia and antioxidants enhance soluble ICAM-1 release from cardiac fibroblasts

  • S. Sapna
  • K. ShivakumarEmail author
Article

Abstract

Intercellular adhesion molecule-1 plays a key role in mediating inflammatory and immune responses. There is also increasing appreciation of the role of its soluble form, sICAM-1, in regulating inflammation. This study evaluated the effects of hypoxia and N-acetyl-L-cysteine on sICAM-1 production by adult rat cardiac fibroblasts. By ELISA, hypoxia was found to cause a 61% increase in sICAM-1 in cardiac fibroblast culture supernates. However, RT-PCR did not reveal a concomitant increase in cell surface ICAM-1 transcript levels, suggesting that the increase in sICAM-1 may involve post-transcriptional and/or post-translational mechanisms. Using pharmacological inhibitors, it was observed that p42/44 MAPK and PKC mediate the stimulatory effect of hypoxia on sICAM-1 production. Remarkably, N-acetyl-L-cysteine caused a 3-fold increase in sICAM-1 by p42/44 MAPK-, p38 MAPK- and PKC-independent mechanisms. Pyrrolidine dithiocarbamate, another potent antioxidant, also augmented sICAM-1. The findings presented in this communication underscore the link between redox status and sICAM-1 release from cardiac fibroblasts. Further, because hypoxia is a major component of myocardial ischemia and is pro-inflammatory, and both N-acetylcysteine and pyrrolidine dithiocarbamate are clinically used antioxidants, the observations may have clinical significance.

Keywords

Cardiac fibroblasts sICAM-1 Hypoxia N-acetyl-L-cysteine Pyrrolidine dithiocarbamate p42/44 MAPK Protein kinase C 

Notes

Acknowledgements

This work was supported by a research grant to K Shivakumar from the Department of Biotechnology, Government of India. S Sapna acknowledges the Research Fellowship from the Department of Biotechnology. The authors thank Dr Sankara Sarma of SCTIMST for statistical analysis of the data.

References

  1. 1.
    Tsakadze NL, Sithu SD, Sen U et al (2006) Tumor Necrosis Factor-α-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 281:3157–3164PubMedCrossRefGoogle Scholar
  2. 2.
    Tsakadze NL, Sen U, Zhao Z et al (2004) Signals mediating cleavage of intercellular adhesion molecule-1. Am J Physiol Cell Physiol 287:C55–C63PubMedCrossRefGoogle Scholar
  3. 3.
    Otto VI, Gloor SM, Frentzel S et al (2002) The production of macrophage inflammatory protein-2 induced by soluble intercellular adhesion molecule-1 in mouse astrocytes is mediated by src tyrosine kinases and p42/44 mitogen-activated protein kinase. J Neurochem 80:824–834PubMedCrossRefGoogle Scholar
  4. 4.
    Gho YS, Kleinman HK, Sosne G (1999) Angiogenic activity of human soluble intercellular adhesion molecule-1. Cancer Res 59:5128–5132PubMedGoogle Scholar
  5. 5.
    Garton KJ, Gough PJ, Raines EW (2006) Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J Leukoc Biol 79:1105–1116PubMedCrossRefGoogle Scholar
  6. 6.
    Hwang SJ, Ballantyne CM, Sharrett AR et al (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the atherosclerosis risk in communities (ARIC) study. Circulation 96:4219–4225PubMedGoogle Scholar
  7. 7.
    Miwa K, Igawa A, Inoue H (1997) Soluble E-selectin, ICAM-1 and VCAM-1 levels in systemic and coronary circulation in patients with variant angina. Cardiovasc Res 36:37–44PubMedCrossRefGoogle Scholar
  8. 8.
    Niessen HWM, Krijnen PAJ, Visser CA et al (2002) Intercellular adhesion molecule-1 in the heart. Annals N Y Acad Sci 973:573–585CrossRefGoogle Scholar
  9. 9.
    Blann AD, McCollum CN (1994) Circulating endothelial cell/leukocyte adhesion molecules in atherosclerosis. Thromb Haemost 72:151–154PubMedGoogle Scholar
  10. 10.
    Zund G, Uezono S, Stahl GL et al (1997) Hypoxia enhances induction of endothelial ICAM-1: role for metabolic acidosis and proteasomes. Am J Physiol Cell Physiol 273:C1571–C1580Google Scholar
  11. 11.
    Kumaran C, Shivakumar K (2002) Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts. Am J Physiol Heart Circ Physiol 282:H1855–H1862PubMedGoogle Scholar
  12. 12.
    Brown RD, Ambler SK, Mitchell MD et al (2005) The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. Ann Rev Pharmacol Toxicol 45:657–687CrossRefGoogle Scholar
  13. 13.
    Kacimi R, Karliner JS, Koudssi F et al (1998) Expression and regulation of adhesion molecules in cardiac cells by cytokines. Circ Res 82:576–586PubMedGoogle Scholar
  14. 14.
    Walther M, Kaffenberger W, Van Beuningen D (1999) Influence of clinically used antioxidants on radiation-induced expression of intercellular cell adhesion molecule-1 on HUVEC. Int J Radiat Biol 75:1317–1325PubMedCrossRefGoogle Scholar
  15. 15.
    Munoz C, Castellanos MC, Alfranca A et al (1996) Transcriptional up-regulation of Intracellular Adhesion Molecule-1 in human endothelial cells by the antioxidant Pyrrolidine Dithiocarbamate involves the activation of Activating Protein-1. J Immunol 157:3587–3597PubMedGoogle Scholar
  16. 16.
    Radomska-Lesniewska DM, Sadowska AM, Van Overveld FJ et al (2006) Influence of N-acetylcysteine on ICAM-1 expression and IL-8 release from endothelial and epithelial cells. J Physiol Pharmacol 57:325–334PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Division of Cellular and Molecular CardiologySree Chitra Tirunal Institute for Medical Sciences and TechnologyTrivandrumIndia

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