Skip to main content
Search
Search
    Quick Search anywhere
    Quick search in Citations
Advanced Search
Skip main navigationClose Drawer MenuOpen Drawer Menu
Previous article
Next article
Original Communication

Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells

Published Online:March 07, 2019https://doi.org/10.1024/0300-9831/a000520

Abstract

Abstract. Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1β in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 μM) and ascorbic acid (15, 150, and 1,500 μM) at the same time that the dextrose was added reduced IL-1β, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1β, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1β, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1β levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

References

  • 1 Fuster, V., Badimon, L., Badomon, J.J., & Chesebro, J.H. (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med. 326, 310–318. First citation in articleCrossref Medline, Google Scholar

  • 2 Libby, P., Ridker, P.M., & Maseri, A. (2002) Inflammation and atherosclerosis. Circulation. 105, 1135–1143. First citation in articleCrossref Medline, Google Scholar

  • 3 Ross, R., & Glomset, J.A. (1976) The pathogenesis of atherosclerosis (first of two parts). N Engl J Med. 295, 369–377. First citation in articleCrossref Medline, Google Scholar

  • 4 Ross, R. (1999) Atherosclerosis-an inflammatory disease. N Eng J Med. 340, 115–126. First citation in articleCrossref Medline, Google Scholar

  • 5 Ridker, P.M., Hennekens, C.H., Roitman-Johnson, B., Stampfer, M.J., & Allen, J. (1998) Plasma concentration of soluble intercellular adhesion molecular molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 351, 88–92. First citation in articleCrossref Medline, Google Scholar

  • 6 Cybulsky, M.I., Iiyama, K., Li, H., Zhu, S., Chen, M., Iiyama, M., Davis, V., Gutierrez-Ramos, J.C., Connelly, P.W., & Milstone, D.S. (2001) A major role of VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 107, 1255–1262. First citation in articleCrossref Medline, Google Scholar

  • 7 Tedgui, A., & Mallat, Z. (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 86, 515–581. First citation in articleCrossref Medline, Google Scholar

  • 8 Surmi, B.K., & Hasty, A.H. (2010) The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue. Vas Pharmacol. 52, 27–36. First citation in articleCrossref Medline, Google Scholar

  • 9 Lee, I.M., Cook, N.R., Gaziano, J.M., Gordon, D., Ridker, P.M., Manson, J.E., Hennekens, C.H., & Buring, J.E. (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 294, 56–65. First citation in articleCrossref Medline, Google Scholar

  • 10 Sesso, H.D., Buring, J.E., Christen, W.G., Kurth, T., Belanger, C., MacFadyen, J., Bubes, V., Manson, J.E., Glynn, R.J., & Gaziano, J.M. (2008) Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 300, 2123–2133. First citation in articleCrossref Medline, Google Scholar

  • 11 Riccioni, G., D’Orazio, N., Salvatore, C., Franceschelli, S., Pesce, M., & Speranza, L. (2012) Carotenoids and vitamins C and E in the prevention of cardiovascular disease. Int J Vitamin Nutr Res. 82, 15–26. First citation in articleLink, Google Scholar

  • 12 Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., & Yasuhara, H. (1998) Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke. 29, 12–17. First citation in articleCrossref Medline, Google Scholar

  • 13 Sheikh-Ali, M., Sultan, S., Alamir, A.R., Haas, M.J., & Mooradian, A.D. (2010) Effects of antioxidants on glucose-induced oxidative stress and endoplasmic reticulum stress in endothelial cells. Diabetes Res Clin Pract. 87, 161–166. First citation in articleCrossref Medline, Google Scholar

  • 14 Mooradian, A.D., Onstead-Haas, L., & Haas, M.J. (2016) Asymmetrical cross-talk between the endoplasmic reticulum stress and oxidative stress caused by dextrose. Life Sci. 144, 37–48. First citation in articleCrossref Medline, Google Scholar

  • 15 Makhoul-Awach, S., Thomas, M., Onstead-Haas, L., Mooradian, A.D., & Haas, M.J. (2015) The glutathione mimic ebselen inhibits oxidative stress but not endoplasmic reticulum stress in endothelial cells. Life Sci. 134, 9–15. First citation in articleCrossref Medline, Google Scholar

  • 16 Xiao, L., Liu, Y., & Wang, N. (2014) New paradigms in inflammatory signaling in vascular endothelial cells. Am J Physiol Heart Circ Physiol. 306, H317–H325. First citation in articleCrossref Medline, Google Scholar

  • 17 Horani, M.H., Haas, M.J., & Mooradian, A.D. (2004) Rapid adaptive down regulation of oxidative burst induced by high dextrose in human umbilical vein endothelial cells. Diabetes Res Clin Pract. 66, 7–12. First citation in articleCrossref Medline, Google Scholar

  • 18 Kelleher, J., & Losowsky, M.S. (1970) The absorption of alpha-tocopherol in man. Br J Nutr. 24, 1033–1047. First citation in articleCrossref Medline, Google Scholar

  • 19 Mustacich, D.J., Shields, J., Horton, R.A., Brown, M.K., & Reed, D.J. (1998) Biliary secretion of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice. Arch Biochem Biophys Res Commun. 350, 183–192. First citation in articleCrossref, Google Scholar

  • 20 Liebler, D.C., Burr, J.A., Phillips, L., & Ham, A.J. (1996) Gas chromatography-mass spectrometry analysis of vitamin E and its oxidation products. Anal Biochem. 236, 27–34. First citation in articleCrossref Medline, Google Scholar

  • 21 Schultz, M., Leist, M., Petrzika, M., Gassmann, B., & Brigelius-Flohe, R. (1995) Novel urinary metabolite of alpha-tocopherol, 2, 5, 7, 8-tetramethyl-1(2’-carboxyethyl)-6-hydrochroman, as an indicator of an adequate vitamin E supply? Am J Clin Nutr. 62, 1527S–1534S. First citation in articleCrossref Medline, Google Scholar

  • 22 Pope, S.A., Clayton, P.T., & Muller, D.P. (2000) A new method for the analysis of urinary vitamin E metabolites and the tentative identification of a novel group of compounds. Arch Biochem Biophys. 381, 8–15. First citation in articleCrossref Medline, Google Scholar

  • 23 Dowd, P., & Zheng, Z.B. (1995) On the mechanism of the anticlotting actions of vitamin E quinone. Proc Natl Acad Sci USA. 92, 8171–8175. First citation in articleCrossref Medline, Google Scholar

  • 24 Neuzil, J., Witting, P.K., & Stocker, R. (1997) Alpha-tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low density lipoprotein lipids. Proc Natl Acad Sci USA. 94, 7885–7890. First citation in articleCrossref Medline, Google Scholar

  • 25 Grammas, P., Hamdheydari, L., Benaksas, E.J., Mou, S., Pye, Q.N., Wechter, W.J., Floyd, R.A., Stewart, C., & Hensley, K. (2004) Anti-inflammatory effects of tocopherol metabolites. Biochem Biophys Res Commun. 319, 1047–1052. First citation in articleCrossref Medline, Google Scholar

  • 26 Savini, I., Rossi, A., Pierro, C., Avigliano, L., & Catani, M.V. (2008) SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids. 34, 347–355. First citation in articleCrossref Medline, Google Scholar

  • 27 Brubacher, D., Moser, U., & Jordan, P. (2000) Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res. 70, 226–237. First citation in articleLink, Google Scholar

  • 28 Michels, A.J., & Frei, B. (2013) Myths, artifacts, and fatal flaws: identifying limitations and opportunities in vitamin C research. Nutrients. 5, 5161–5192. First citation in articleCrossref Medline, Google Scholar

  • 29 Michelss, A.J., Hagen, T.M., & Frei, B. (2013) Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Annu Rev Nutr. 33, 45–70. First citation in articleCrossref Medline, Google Scholar

  • 30 Muzakova, V., Kandar, R., Meloun, M., Skalicky, J., Kralovec, K., Zakova, P., & Vojtsek, P. (2010) Inverse correlation between plasma beta-carotene and interleukin-6 in patients with advanced coronary artery disease. Int J Vitam Nutr Res. 80, 369–377. First citation in articleLink, Google Scholar

  • 31 Bagheri Nesami, N., Mozaffari-Khosravi, H., Najarzadeh, A., & Salehifar, E. (2015) The Effect of Coenzyme Q10 Supplementation on Pro-Inflammatory Factors and Adiponectin in Mildly Hypertensive Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. Int J Vitam Nutr Res. 85, 156–164. First citation in articleLink, Google Scholar

  • 32 Greń, A. (2013) Effects of vitamin E, C and D supplementation on inflammation and oxidative stress in streptozotocin-induced diabetic mice. Int J Vitam Nutr Res. 83, 168–175. First citation in articleLink, Google Scholar

  • 33 Zanotti Simoes Dourado, G.K., de Abreu Ribeiro, L.C., Zeppone Carlos, I., & Borges César, T. (2013) Orange juice and hesperidin promote differential innate immune response in macrophages ex vivo. Int J Vitam Nutr Res. 83, 162–167. First citation in articleLink, Google Scholar

  • 34 Račková, L., Ergin, V., Burcu Bali, E., Kuniaková, M., & Karasu, Ç. (2014) Pomegranate Seed Oil Modulates Functions and Survival of BV-2 Microglial Cells in vitro. Int J Vitam Nutr Res. 84, 295–309. First citation in articleLink, Google Scholar

  • 35 Haddad, J.J., & Harb, H.L. (2005) L-γ-Glutamyl-L-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s)? Mol Immunol. 42, 987–1014. First citation in articleCrossref Medline, Google Scholar

  • 36 Schroder, K., & Tschopp, J. (2010) The inflammasomes. Cell. 140, 821–832. First citation in articleCrossref Medline, Google Scholar

  • 37 Maedler, K., Sergeev, P., Ris, F., Oberholzer, J., Joller-Jemelka, H.I., Spinas, G.A., Kaiser, N., Halban, P.A., & Donath, M.Y. (2002) Glucose-induced beta cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 110, 851–860. First citation in articleCrossref Medline, Google Scholar

  • 38 Boni-Schentzler, M., Thorne, J., Parnaud, G., Marselli, L., Ehses, J.A., Kerr-Conte, J., Pattou, F., Halban, P.A., Weir, G.C., & Donath, M.Y. (2008) Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J Clin Endocrinol Metab. 93, 4065–4074. First citation in articleCrossref Medline, Google Scholar

  • 39 McGeough, M.D., Pena, C.A., Mueller, J.L., Pociask, D.A., Broderick, L., Hoffman, H.M., & Brydges, S.D. (2012) IL-6 is a marker of inflammation with no direct role in inflammasome-mediated mouse models. J Immunol. 189, 2707–2711. First citation in articleCrossref Medline, Google Scholar

  • 40 Mortaz, E., Henricks, P.A., Kraneveld, A.D., Givi, M.E., Garssen, J., & Folkerts, G. (2011) Cigarette smoke induces the release of CXCL-8 from human bronchial epithelial cells via TLRs and induction of the inflammasome. Biochim Biophys Acta. 12, 1104–1110. First citation in articleCrossref, Google Scholar