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Effect of sodium salicylate on COX-2 expression in neonatal rat cardiomyocytes

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Abstract

Salicylates, one of the oldest medicinal compounds known to humans, have been reported to show anti-inflammatory effects via cyclooxygenase (COX) inhibition. However, the pathophysiological role of COX-2 in the heart is conflicting, and the role of sodium salicylate in the regulation of cardiac inflammation has not yet been elucidated. We aimed to investigate the effect of salicylate on COX-2 expression and its associated prostaglandin production using cultured neonatal rat cardiomyocytes. The cells were incubated in the presence or absence of sodium salicylate (8 mM). Treatment with sodium salicylate significantly increased COX-2 expression at both mRNA and protein levels, induced prostaglandin D2 release, and increased TNF-α mRNA expression in cardiomyocytes. In addition, salicylate treatment induced cardiomyocyte hypertrophy. Taken together, we demonstrated that salicylate induced COX-2 expression, which in turn resulted in the regulation of expression of several inflammatory mediators in cardiomyocytes.

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References

  1. Rumore, M. M. & Kim, K. S. Potential role of salicylates in type 2 diabetes. Ann Pharmacother 44: 1207–1221 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Hennekens, C. H. & Dalen, J. E. Aspirin in the treatment and prevention of cardiovascular disease: past and current perspectives and future directions. Am J Med 126: 373–378 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Goldfine, A. B. et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 56: 714–723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pierce, G. L., Lesniewski, L. A., Lawson, B. R., Beske, S. D. & Seals, D. R. Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation 119: 1284–1292 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Russo-Marie, F., Paing, M. & Duval, D. Mechanism of glucocorticoid-induced inhibition of prostaglandin synthesis. Agents Actions Suppl:49–62 (1979).

    Google Scholar 

  7. Steinberg, G. R., Dandapani, M. & Hardie, D. G. AMPK: mediating the metabolic effects of salicylate-based drugs? Trends Endocrinol Metab 24: 481–487 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Preston, S. J., Arnold, M. H., Beller, E. M., Brooks, P. M. & Buchanan, W. W. Comparative analgesic and anti-inflammatory properties of sodium salicylate and acetylsalicylic acid (aspirin) in rheumatoid arthritis. Br J Clin Pharmacol 27: 607–611 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beynen, A. C., Buechler, K. F., van der Molen, A. J. & Geelen, M. J. Inhibition of hepatic lipogenesis by salicylate. Toxicology 24: 33–43 (1982).

    Article  CAS  PubMed  Google Scholar 

  10. Meex, R. C., Phielix, E., Moonen-Kornips, E., Schrauwen, P. & Hesselink, M. K. Stimulation of human whole-body energy expenditure by salsalate is fueled by higher lipid oxidation under fasting conditions and by higher oxidative glucose disposal under insulin-stimulated conditions. J Clin Endocrinol Metab 96: 1415–1423 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Tokudome, S. et al. Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase-derived PGD2 biosynthesis. J Clin Invest 119: 1477–1488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Streicher, J. M., Kamei, K., Ishikawa, T. O., Herschman, H. & Wang, Y. Compensatory hypertrophy induced by ventricular cardiomyocyte-specific COX-2 expression in mice. J Mol Cell Cardiol 49: 88–94 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chenevard, R. et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation 107: 405–409 (2003).

    Article  PubMed  Google Scholar 

  14. Mukherjee, D., Nissen, S. E. & Topol, E. J. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286: 954–959 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Bolli, R. et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 55: 506–519 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Inserte, J. et al. Constitutive COX-2 activity in cardiomyocytes confers permanent cardioprotection Constitutive COX-2 expression and cardioprotection. J Mol Cell Cardiol 46: 160–168 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Shinmura, K. et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A 97: 10197–10202 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tsatsanis, C., Androulidaki, A., Venihaki, M. & Margioris, A. N. Signalling networks regulating cyclooxygenase-2. Int J Biochem Cell Biol 38: 1654–1661 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Eguchi, Y. et al. Expression of lipocalin-type prostaglandin D synthase (beta-trace) in human heart and its accumulation in the coronary circulation of angina patients. Proc Natl Acad Sci U S A 94: 14689–14694 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Katsumata, Y. et al. Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension 63: 80–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Xiao, C. Y. et al. Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4. Circulation 109: 2462–2468 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Mitchell, J. A., Saunders, M., Barnes, P. J., Newton, R. & Belvisi, M. G. Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. Mol Pharmacol 51: 907–912 (1997).

    CAS  PubMed  Google Scholar 

  23. Xu, X. M. et al. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci U S A 96: 5292–5297 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chae, H. J., Chae, S. W., Reed, J. C. & Kim, H. R. Salicylate regulates COX-2 expression through ERK and subsequent NF-kappaB activation in osteoblasts. Immunopharmacol Immunotoxicol 26: 75–91 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Kwon, K. S. & Chae, H. J. Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-kappaB activation in rat ventricular cardiomyocytes. Arch Pharm Res 26: 545–553 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Levine, B., Kalman, J., Mayer, L., Fillit, H. M. & Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323: 236–241 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Meldrum, D. R. Tumor necrosis factor in the heart. Am J Physiol 274:R577–595 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Yokoyama, T. et al. Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation 95: 1247–1252 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109: 1594–1602 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Lecour, S. et al. Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol 34: 509–518 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Tanno, M. et al. Tumor necrosis factor-induced protection of the murine heart is independent of p38-MAPK activation. J Mol Cell Cardiol 35: 1523–1527 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Kurrelmeyer, K. M. et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci U S A 97: 5456–5461 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ichikawa, Y. et al. The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of ischemic preconditioning. Cardiovasc Res 62: 167–175 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Sack, M. Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heart disease. Pharmacol Ther 94: 123–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Shimizu, I. & Minamino, T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 97: 245–262 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, D. et al. Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function. Proc Natl Acad Sci U S A 106: 7548–7552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ock, S. et al. Receptor activator of nuclear factor-kappaB ligand is a novel inducer of myocardial inflammation. Cardiovasc Res 94: 105–114 (2012).

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea

    Sangmi Ock, Hyun Min Kim & Jaetaek Kim

  2. Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea

    Wang Soo Lee

  3. Korea Medical Institute, Seoul, Republic of Korea

    Jihyun Ahn

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  1. Sangmi Ock
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  2. Hyun Min Kim
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  3. Wang Soo Lee
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  4. Jihyun Ahn
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  5. Jaetaek Kim
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Correspondence to Jaetaek Kim.

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Ock, S., Kim, H.M., Lee, W.S. et al. Effect of sodium salicylate on COX-2 expression in neonatal rat cardiomyocytes. Mol. Cell. Toxicol. 14, 87–92 (2018). https://doi.org/10.1007/s13273-018-0011-7

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  • DOI: https://doi.org/10.1007/s13273-018-0011-7

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