Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-κB activation in Rat ventricular cardiomyocytes


The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1β and TNF-α can induce extracellular signal-regulated kinase (ERK), IKK, IκB degradation and NF-κB activation. Salicylate inhibited the IL-1β and TNF-α-induced COX-2 expressions, regulated the activation of ERK, IKK and IκB degradation, and the subsequent activation of NF-κB, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1β and TNF-α-induced COX-2 and PGE2 release. The antioxidant,N-acetyl-cys-teine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1β and TNF-α-treated cells. This antioxidant also inhibited the activation of ERK and NF-κB in neonatal rat cardiomyocytes. In addition, IL-1β and TNF-α stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IκB degradation and NF-κB activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IκB and NF-κB, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.

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


  1. Amann, R. and Peskar, B. A., Anti-inflammatory effects of aspirin and sodium salicylate.Eur. J. Pharmacol., 447(1), 1–9 (2002).

  2. Barnes, P. J. and Karin, M., Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.N. Engl. J. Med., 336, 1066–1071 (1997).

  3. Brian, J. E. Jr., Faraci, F. M., and Moore, S. A., COX-2-dependent delayed dilatation of cerebral arterioles in response to bradykinin.Am. J. Physiol. Heart. Circ. Physiol., 280(5), H2023–2029 (2001).

  4. Cromlish, W. A. and Kennedy, B. P., Selective inhibition of cyclooxygenase-1 and -2 using intact insect cell assays.Biochem. Pharmacol., 52(11), 1777–1785 (1996).

  5. Cronstein, B. N., Montesinos, M. C., and Weissmann, G., Sites of action for future therapy: an adenosine-dependent mechanism by which aspirin retains its anti-inflammatory activity in cyclooxygenase-2 and NF kappa B knockout mice.Osteoarthritis Cartilage., 7(4), 361–363 (1999).

  6. Frantz, B. and ONeill, E. A., The effect of sodium salicylate and aspirin on NF-kappa B.Science., 270(5244), 2017–2019 (1995).

  7. Grilli, M., Pizzi, M., Memo, M., and Spano, P., Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappa B activation.Science, 274(5291), 1383–1385 (1996).

  8. Haddad, J. J. and Land, S. C., Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis.Br. J. Pharmacol., 135(2), 520–536 (2002).

  9. Hiroyasu, I., Chieko, Y., Shuntaro, H., Yoshinori, T., and Tadashi, T., Transcriptional Regulation of Human Prostaglandin-endoperoxide Synthase-2 Gene by Lipopolysaccharide and Phorbol Ester in Vascular Endothelial Cells. Involvement of both Nuclear Factor for lnterleukin-6 Expression Site and Camp Response Element.J. Biol. Chem., 270 (42), 24965–24971 (1995).

  10. Chae, H. J., Chae, S. W., Chin, H. Y., Bang, B. G., Cho, S. B., Han, K. S., Kim, S. C., Tae, K. C., Lee, K. H., Kim, D. E., Im, M. K., Lee, S. J., Chang, J. Y., Lee, Y. M., Kim, H. M., Kim, H. H., Kim, Z. H., and Kim, H. R., The p38 Mitogen-activated protein kinase pathway regulates lnterleukin-6 synthesis in response to Tumor Necrosis Factor in osteoblasts.Bone, 28(1), 45–53 (2001).

  11. Jiang, C., Ting, A. T., and Seed, B., PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.Nature, 391(6662), 82–86 (1998).

  12. Jürgen, M. Lehmann, James, M. Lenhard, Beverly, B. Oliver, Gordon M. Ringold, and Steven, A., Kliewer Peroxisome Proliferator-activated Receptors α and β Are Activated by Indomethacin and Other Non-steroidal Anti-inflammatory Drugs.J. Biol. Chem., 272 (6), 3406–3410 (1997).

  13. Kei, Y., Toshiya, A., Natsuo, U., and Shozo, Y., Transcriptional Roles of Nuclear Factor B and Nuclear Factor-lnterleukin-6 in the Tumor Necrosis Factor-Dependent Induction of Cyclooxygenase-2 in MC3T3-E1 Cells.J. Biol. Chem., 270 (52), 31315–31320 (1995).

  14. Kim, H., Seo, J. Y., Roh, K. H., Lim, J. W., and Kim, K. H. Suppression of NF-kappaB activation and cytokine production by N-acetylcysteine in pancreatic acinar cells.Free Radic. Biol. Med., 29(7), 674–683 (2000).

  15. Kopp, E. and Ghosh, S., Inhibition of NF-kappa B by sodium salicylate and aspirin.Science, 265, 956–959 (1994).

  16. Matalka, M. S. and Deedwania, P. C., Pharmacotherapy in congestive heart failure: Do NSAIDs attenuate the therapeutic effect of ACE inhibitors in heart failure patients?Congest Heart Fail., 5(5), 228–234 (1999).

  17. Nakamura, T. and Sakamoto, K. Reactive oxygen species upregulates cyclooxygenase-2, p53, and Bax mRNA expression in bovine luteal cells.Biochem. Biophys. Res. Commun., 284(1), 203–210 (2001).

  18. Newton, R., Kuitert, L. M., Bergmann, M., Adcock, I. M., and Barnes, P. J., Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-1beta.Biochem. Biophys. Res. Commun., 237(1), 28–32 (1997).

  19. Paccani, S. R., Boncristiano, M., Ulivieri, C., DElios, M. M., Del Prete, G., and Baldari, C. T., Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction.J. Biol. Chem., 277(2), 1509–1513 (2002).

  20. Sano, M., Fukuda, K., Sato, T., Kawaguchi, H., Suematsu, M., Matsuda, S., Koyasu, S., Matsui, H., Yamauchi-Takihara, K., Harada, M., Saito, Y., and Ogawa, S., ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts.Circ. Res., 89(8), 661–669 (2001).

  21. Tegeder, I., Pfeilschifter, J., and Geisslinger, G., Cyclooxygenase-independent actions of cyclooxygenase inhibitors.FASEB J., 15(12), 2057–2072 (2001).

  22. Tomohiro, N. and Kazuichi, S., Reactive oxygen species up-regulates cyclooxygenase-2, p53 and Bax mRNA expression in bovine luteal cells.Biochem. Biophys. Res. Commun., 281, 203–210 (2001).

  23. Tuyt, L. M., Dokter, W. H., Birkrnkamp, K., Koopmans, S. B., Lummen, C., Kruijer, W., and Vellenga, E., Extracellular-regulated kinase 1/2, JunN-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes.J. Immunol., 162(8), 4893–4902 (1999).

  24. Vane, J. R., Mitchell, J. A., Appleton, I., Tomlinson, A., Bishop-Bailey, D., Croxtall, J., and Willoughby, D., Inducible Isoforms of Cyclooxygenase and Nitric-Oxide Synthase in Inflammation.Proc. Natl. Acad. Sci. USA., 91, 2046–2050 (1994).

  25. Walch, L. and Morris, P. L., Cyclooxygenase 2 pathway mediates IL-1beta regulation of IL-1alpha, -1beta, and IL-6 mRNA levels in Leydig cell progenitors.Endocrinology, 143(9), 3276–3283 (2000).

  26. Xiao-Ming, X., Leticia, S-G., Xian-Ming, C., Nevenka, M-A., Min, D., and Kenneth, K. W., Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate.Proc. Natl. Acad. Sci. USA., 96(9), 5292–5297 (1999).

  27. Yin, M. J., Yamamoto, Y., and Gaynor, R. B., The anti-inflammatory agents aspirin and salicylate inhibit the activity of l(kappa)B kinase-beta.Nature, 396(6706), 77–80 (1998).

  28. Dong, Z., Huang, C., Brown, R. E., and Ma, W.-Y., Inhibition of Activator Protein 1 Activity and Neoplastic Transformation by Aspirin.J. Biol. Chem., 272(15), 9962–9970 (1997).

Download references

Author information

Correspondence to Keun -Sang Kwon or Han -Jung Chae.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kwon, K.-., Chae, H.-. Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-κB activation in Rat ventricular cardiomyocytes. Arch Pharm Res 26, 545–553 (2003).

Download citation

Key words

  • Cyclooxygenase-2
  • Nuclear factor-kappaB
  • N-acetyl-L-cysteine
  • Reactive oxygen species
  • Interleukin-1
  • Tumor necrosis factor
  • Nas sodium salicylate