Skip to main content
SpringerLink
Log in

NS398 protects cells from sodium nitroprusside-mediated cytotoxicity through enhancing HO-1 induction independent of COX-2 inhibition

  • Research Article
  • Drug Efficacy and Safety
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Heme oxygenase-1 (HO-1) plays a preventive role in oxidative stress. In contrast, COX-2 is involved in the pathogenesis of many inflammatory diseases, thus COX-2 inhibitor is believed to exert anti-inflammatory properties by blocking COX-2. Recently, however, salicylate the active metabolite of aspirin showed COX-independent anti-inflammatory effects through induction of HO-1. Thus, we hypothesized that HO-1 are induced as an adaptive response to sodium nitroprusside (SNP) and play a protective role against cytotoxicity. Moreover, we investigated the protective effect of NS398 known as a selective COX-2 inhibitor on SNP-mediated cytotoxicity, and whether the protective effect of NS398 is due to COX-2 inhibition or not. SNP induced cytotoxicity in a dose-dependent manner, which was enhanced by inhibition of HO-1, suggesting that HO-1 acts in an adaptive response to SNP. Interestingly, NS398 decreased SNP-mediated cytotoxicity whereas COX-2 siRNA did not. Furthermore, NS398 enhanced SNP-induced HO-1 induction even though NS398 alone failed to induce HO-1 protein expression. In addition, NS398 enhanced SNP-induced COX-2, even though NS398 effectively inhibited SNP-mediated PGE2 production. These results demonstrate that NS398 exerts cytoprotective effects by inducing HO-1 independent of COX-2 inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

COX-2:

cyclooxygenase-2

cAMP:

cyclic adenosine monophosphate

cGMP:

cyclic guanosine monophosphate

DFO:

deferoxamine

ERK:

extracellular regulated kinase

HO:

heme oxygenase

JNK:

c-jun N-terminal kinase

MAPK:

mitogen activating protein kinase

PGE2 :

prostaglandin E2

SNP:

sodium nitroprusside

References

  • Alcaraz, M. J., Habib, A., Créminon, C., Vicente, A. M., Lebret, M., Lévy-Toledano, S., and Maclouf, J., Heme oxygenase-1 induction by nitric oxide in RAW 264.7 macrophages is upregulated by a cyclo-oxygenase-2 inhibitor. Biochim. Biophys. Acta., 1526, 13–16 (2001)

    PubMed  CAS  Google Scholar 

  • Botros, F. T., Schwartzman, M. L., Stier, C. T. Jr., Goodman, A. I., and Abraham, N. G., Increase in heme oxygenase-1 levels ameliorates renovascular hypertension. Kidney Int., 68, 2745–2755 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Crofford, L. J., Wilde, R. L., Ristimaki, A. P., Sano, H., Remers, E. F., Epps, H. R., and Hla, T., Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids. J. Clin. Invest., 93, 1095–1101 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Durante, W., Christodoulides, N., Cheng, K., Peyton, K. J., Sunahara, R. K., and Schafer, A. I., cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle. Am. J. Physiol., 273, H317–H323 (1997).

    PubMed  CAS  Google Scholar 

  • Fu, J., Masferrer, J., Seibert, K., Raz, A., and Needleman, P., The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J. Biol. Chem., 265, 16737–16740 (1990).

    PubMed  CAS  Google Scholar 

  • Fürst, R., Blumenthal, S. B., Kiemer, A. K., Zahler, S., and Vollmar, A. M., Nuclear factor-kappa B-independent anti-inflammatory action of salicylate in human endothelial cells: induction of heme oxygenase-1 by the c-jun Nterminal kinase/activator protein-1 pathway. J. Pharmacol. Exp. Ther., 318, 389–394 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Halliwell, B. and Gutteridge, J. M. C., Free radicals in biology and medicine. Clarendon Press, Oxford, (1989).

    Google Scholar 

  • Herschman, H. R., Prostaglandin synthase 2. Biochim. Biophys. Acta., 1299, 125–140 (1996).

    PubMed  Google Scholar 

  • Hla, T., Ristimaki, A., Appleby, S. B., and Barriocanal, J. G., Cyclooxygenase gene expression in inflammation and angiogenesis. Ann. N.Y. Acad. Sci., 696, 197–204 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Jabbour, H. N., Kelly, R. W., and Boddy, S. C., Autocrine/paracrine regulation of apoptosis in epithelial cells by prostaglandin E2. Prostagland. Leukot. Essent. Fatty Acids, 67, 357–363 (2002).

    Article  CAS  Google Scholar 

  • Kim, H. J., Shin, W., Park, C. S., Kim, H. O., and Kim, T. Y., Differential Regulation of Cyclooxygenase-2 Expression by Phytosphingosine Derivatives, NAPS and TAPS, and its Role in the NAPS or TAPS-Mediated Apoptosis. J. Invest. Dermatol., 121, 1126–1134 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. J., Tsoy, I., Park, M. K., Lee, Y. S., Lee, J. H., Seo, H. G., and Chang, K. C., Iron released by sodium nitroprusside contributes to heme oxygenase-1 induction via the cAMP-protein kinase A-mitogen-activated protein kinase pathway in RAW 264.7 cells. Mol. Pharmacol., 69, 1633–1640 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Kim, S. and Ponka, P., Nitrogen monoxide-mediated control of ferritin synthesis: implications for macrophage iron homeostasis. Proc. Natl. Acad. Sci. U.S.A., 99, 12214–12219 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y. M., Bergonia, H., and Lancaster, J. R. Jr., Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett., 374, 228–232 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Kushida, T., Li Volti, G., Quan, S., Goodman, A., and Abraham, N. G.., Role of human heme oxygenase-1 in attenuating TNF-alpha-mediated inflammation injury in endothelial cells. J. Cell Biochem., 87, 377–385 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Lee, S. K., Park, D. Y., Lee, H. J., Lee, J., Choi, M. K., Jeon, B. H., Jun, C. D., Lee, S. K., and Kim, E. C., Functional interaction between nitric oxide-induced iron homeostasis and heme oxygenase-1 in immortalized and malignant oral keratinocytes. Cancer Lett., 249, 283–293 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Maines, M., The heme oxygenase system: a regulator of second messenger gases. Ann. Rev. Pharmacol. Toxicol., 37, 517–554 (1997).

    Article  CAS  Google Scholar 

  • Masferrer, J. L., Zweifel, B. S., Manning, P. T., Hauser, S. D., Leahy, K. M., Smith, W. G., Isakson, P. C., and Seibert, K., Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A., 91, 3228–3232 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Mikhael, M., Kim, S. F., Schranzhofer, M., Soe-Lin, S., Sheftel, A. D., Mullner, E. W., and Ponka, P., Iron regulatory protein-independent regulation of ferritin synthesis by nitrogen monoxide. FEBS J., 273, 3828–3836 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Morita, T., Mitsialis, S. A., KoiKe, H., Liu, Y., and Kourembanas, S., Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J. Biol. Chem., 272, 32804–32809 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Moore, B. A., Murase, N., Liu, F., Zuckerbraun, B. S., Bach, F. H., Choi, A. M., Nalesnik, M. A., Otterbein, L. E., and Bauer, A. J., Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility. Gut, 52, 1278–1285 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Otterbein, L. E., Overhaus, M., Sarady, J. K., Tsung, A., Kimizuka, K., Nalesnik, M. A., Kaizu, T., Uchiyama, T., Liu, F., Murase, N., Bauer, A. J., and Bach, F. H., Biliverdin protects the functional integrity of a transplanted syngeneic small bowel. Gastroenterology, 127, 595–606 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Polte, T., Abate, A., Dennery, P. A., and Schroder, H., Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler. Thromb. Vasc. Biol., 20, 1209–1215 (2000).

    PubMed  CAS  Google Scholar 

  • Poss, K. D. and Tonegawa, S., Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. U.S.A., 94, 10919–10924 (1997a).

    Article  PubMed  CAS  Google Scholar 

  • Poss, K. D. and Tonegawa, S., Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl. Acad. Sci. U.S.A., 94, 10925–10930 (1997b).

    Article  PubMed  CAS  Google Scholar 

  • Smith, W. L. and Dewitt, D. L., Prostaglandin endoperoxide H synthases-1 and -2. In: Dixon FJ (ed). Advances in Immunology Vol. 62. Orlando, FL: Academic Press, pp. 167–215 (1996).

    Chapter  Google Scholar 

  • Tegeder, I., Pfeilschifter, J., and Geisslinger, G., Cyclooxygenaseindependent actions of cyclooxygenase inhibitors. FASEB J., 15, 2057–2072 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Wadleigh, D. J. and Herschman, H. R., Transcriptional regulation of the cyclooxygenase-2 gene by diverse ligands in murine osteoblasts. Biochem. Biophys. Res. Commun., 264, 865–870 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Yachie, A., Niida, Y., Wada, T., Igarashi, N., Kaneda, H., Toma, T., Ohta, K., Kasahara, Y., and Koizumi, S., Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest., 103, 129–135 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Yet, S. F, Perrella, M. A., Layne, M. D., Hsieh, C. M., Maemura, K., Kobzik, L., Wiesel, P., Christou, H., Kourembanas, S., and Lee, M. E., Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J. Clin. Invest., 103, R23–29 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Yet, S. F., Pellacani, A., Patterson, C., Tan, L., Folta, S. C., Foster, L., Lee, W. S., Hsieh, C. M., and Perrella, M. A., Induction of heme oxygenase-1 expression in vascular smooth muscle cells. A link to endotoxic shock. J. Biol. Chem., 272, 4295–4301 (1997).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Korea

    Irina Tsoy Nizamutdinova, Jae Heun Lee, Han Geuk Seo, Ki Churl Chang & Hye Jung Kim

Authors
  1. Irina Tsoy Nizamutdinova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae Heun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han Geuk Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ki Churl Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hye Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ki Churl Chang or Hye Jung Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nizamutdinova, I.T., Lee, J.H., Seo, H.G. et al. NS398 protects cells from sodium nitroprusside-mediated cytotoxicity through enhancing HO-1 induction independent of COX-2 inhibition. Arch. Pharm. Res. 32, 99–107 (2009). https://doi.org/10.1007/s12272-009-1123-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-009-1123-3

Key words

Search

Navigation