Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 μmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.

Institute of Normal and Pathological Physiology and Centre of Excellence for Regulatory Role of Nitric Oxide in Civilization Diseases Slovak Academy of Sciences 813 71 Bratislava Slovakia

Institute of Physiology Academy of Sciences of the Czech Republic 142 20 Prague 4 Czech Republic; Centre of Cardiovascular Research 142 20 Prague 4 Czech Republic

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Liu H., Colavitti R., Rovira I. I., Finkel T. Redox-dependent transcriptional regulation. Circulation Research. 2005;97(10):967–974. doi: 10.1161/01.RES.0000188210.72062.10. PubMed DOI

Bar-Shai M., Carmeli E., Ljubuncic P., Reznick A. Z. Exercise and immobilization in aging animals: the involvement of oxidative stress and NF-κB activation. Free Radical Biology and Medicine. 2008;44(2):202–214. doi: 10.1016/j.freeradbiomed.2007.03.019. PubMed DOI

Kwak J.-H., Jung J.-K., Lee H. Nuclear factor-kappa B inhibitors; a patent review (2006–2010) Expert Opinion on Therapeutic Patents. 2011;21(12):1897–1910. doi: 10.1517/13543776.2011.638285. PubMed DOI

Grumbach I. M., Chen W., Mertens S. A., Harrison D. G. A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. Journal of Molecular and Cellular Cardiology. 2005;39(4):595–603. doi: 10.1016/j.yjmcc.2005.06.012. PubMed DOI

Morgan M. J., Liu Z.-G. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Research. 2011;21(1):103–115. doi: 10.1038/cr.2010.178. PubMed DOI PMC

Tranter M., Ren X., Forde T., et al. NF-ΚB driven cardioprotective gene programs; Hsp70.3 and cardioprotection after late ischemic preconditioning. Journal of Molecular and Cellular Cardiology. 2010;49(4):664–672. doi: 10.1016/j.yjmcc.2010.07.001. PubMed DOI PMC

Napetschnig J., Wu H. Molecular basis of NF-κB signaling. Annual Review of Biophysics. 2013;42(1):443–468. doi: 10.1146/annurev-biophys-083012-130338. PubMed DOI PMC

Sen C. K., Khanna S., Reznick A. Z., Roy S., Packer L. Glutathione regulation of tumor necrosis factor-α-induced NF-κB activation in skeletal muscle-derived L6 cells. Biochemical and Biophysical Research Communications. 1997;237(3):645–649. doi: 10.1006/bbrc.1997.7206. PubMed DOI

Chen F., Castranova V., Li Z., Karin M., Shi X. Inhibitor of nuclear factor kappa B kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. Cancer Research. 2003;63:7689–7693. PubMed

Vrána A., Kazdová L. The hereditary hypertriglyceridemic nonobese rat: an experimental model of human hypertriglyceridemia. Transplantation Proceedings. 1990;22(6):p. 2579. PubMed

Zicha J., Pecháňová O., Čačányiová S., et al. Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome? Physiological Research. 2006;55(supplement 1):S49–S63. PubMed

Kazdová L., Žák A., Vrána A. Increased lipoprotein oxidability and aortic lipid peroxidation in an experimental model of insulin resistance syndrome. Annals of the New York Academy of Sciences. 1997;827:521–525. doi: 10.1111/j.1749-6632.1997.tb51863.x. PubMed DOI

Shin H.-M., Kim M.-H., Kim B. H., et al. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-κB without affecting IκB degradation. FEBS Letters. 2004;571(1–3):50–54. doi: 10.1016/j.febslet.2004.06.056. PubMed DOI

Kogure K., Watson B. D., Busto R., Abe K. Potentiation of lipid peroxides by ischemia in rat brain. Neurochemical Research. 1982;7(4):437–454. doi: 10.1007/bf00965496. PubMed DOI

Ellman G. L. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 1959;82(1):70–77. doi: 10.1016/0003-9861(59)90090-6. PubMed DOI

Bredt D. S., Snyder S. H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(2):682–685. doi: 10.1073/pnas.87.2.682. PubMed DOI PMC

Pecháňová O., Bernátová I., Pelouch V., Šimko F. Protein remodelling of the heart in NO-deficient hypertension: the effect of captopril. Journal of Molecular and Cellular Cardiology. 1997;29(12):3365–3374. doi: 10.1006/jmcc.1997.0566. PubMed DOI

Pecháňová O., Zicha J., Kojšová S., Dobešová Z., Jendeková L., Kuneš J. Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension. Clinical Science. 2006;110(2):235–242. doi: 10.1042/cs20050227. PubMed DOI

Simko F., Luptak I., Matuskova J., et al. Heart remodeling in the hereditary hypertriglyceridemic rat: Effect of captopril and nitric oxide deficiency. Annals of the New York Academy of Sciences. 2002;967:454–462. PubMed

Kuneš J., Dobešová Z., Zicha J. Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia. Clinical Science. 2002;102(3):269–277. doi: 10.1042/CS20010214. PubMed DOI

Žourek M., Kyselová P., Mudra J., et al. The relationship between glycemia, insulin and oxidative stress in hereditary hypertriglyceridemic rat. Physiological Research. 2008;57(4):531–538. PubMed

Škottová N., Kazdová L., Oliyarnyk O., Večeřa R., Sobolová L., Ulrichová J. Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high-sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats. Pharmacological Research. 2004;50(2):123–130. doi: 10.1016/j.phrs.2003.12.013. PubMed DOI

Vranková S., Parohová J., Barta A., Janega P., Šimko F., Pecháňová O. Effect of nuclear factor kappa B inhibition on L-NAME-induced hypertension and cardiovascular remodelling. Journal of Hypertension. 2010;28(1):S45–S49. doi: 10.1097/01.hjh.0000388494.58707.0f. PubMed DOI

Lee M. H., Hyun D.-H., Jenner P., Halliwell B. Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production. Journal of Neurochemistry. 2001;78(1):32–41. doi: 10.1046/j.1471-4159.2001.00416.x. PubMed DOI

Ward N. C., Croft K. D. Hypertension and oxidative stress. Clinical and Experimental Pharmacology and Physiology. 2006;33(9):872–876. doi: 10.1111/j.1440-1681.2006.04457.x. PubMed DOI

Kojšová S., Jendeková L., Zicha J., Kuneš J., Andriantsitohaina R., Pecháňová O. The effect of different antioxidants on nitric oxide production in hypertensive rats. Physiological Research. 2006;55(supplement 1):S3–S16. PubMed

Wilcox C. S., Pearlman A. Chemistry and antihypertensive effects of tempol and other nitroxides. Pharmacological Reviews. 2008;60(4):418–469. doi: 10.1124/pr.108.000240. PubMed DOI PMC

Skibska B., Goraca A. The protective effect of lipoic acid on selected cardiovascular diseases caused by age-related oxidative stress. Oxidative Medicine and Cellular Longevity. 2015;2015:11. doi: 10.1155/2015/313021.313021 PubMed DOI PMC

Shaw P. X., Werstuck G., Chen Y. Oxidative stress and aging diseases. Oxidative Medicine and Cellular Longevity. 2014;2014:2. doi: 10.1155/2014/569146.569146 PubMed DOI PMC

Valko M., Leibfritz D., Moncol J., Cronin M. T. D., Mazur M., Telser J. Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology. 2007;39(1):44–84. doi: 10.1016/j.biocel.2006.07.001. PubMed DOI

Woodward M., Croft K. D., Mori T. A., et al. Association between both lipid and protein oxidation and the risk of fatal or non-fatal coronary heart disease in a human population. Clinical Science. 2009;116(1):53–60. doi: 10.1042/CS20070404. PubMed DOI

Dröge W., Schulze-Osthoff K., Mihm S., et al. Functions of glutathione and glutathione disulfide in immunology and immunopathology. The FASEB Journal. 1994;8(14):1131–1138. PubMed

Cho M.-L., Moon Y.-M., Heo Y.-J., et al. NF-κB inhibition leads to increased synthesis and secretion of MIF in human CD4+ T cells. Immunology Letters. 2009;123(1):21–30. doi: 10.1016/j.imlet.2009.01.010. PubMed DOI

Sasazuki T., Okazaki T., Tada K., et al. Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS. Molecular Immunology. 2004;41(5):547–551. doi: 10.1016/j.molimm.2004.03.030. PubMed DOI

Townsend D. M., Tew K. D., Tapiero H. The importance of glutathione in human disease. Biomedicine and Pharmacotherapy. 2003;57(3):145–155. doi: 10.1016/S0753-3322(03)00043-X. PubMed DOI PMC

Santos-Silva M. C., Freitas M. S. D., Assreuy J. Involvement of NF-κB and glutathione in cytotoxic effects of nitric oxide and taxol on human leukemia cells. Leukemia Research. 2006;30(2):145–152. doi: 10.1016/j.leukres.2005.06.021. PubMed DOI

Zhang S., Ong C.-N., Shen H.-M. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Letters. 2004;208(2):143–153. doi: 10.1016/j.canlet.2003.11.028. PubMed DOI

Orr J. G., Leel V., Cameron G. A., et al. Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells. Hepatology. 2004;40(1):232–242. doi: 10.1002/hep.20254. PubMed DOI