N‑acetylcysteine reduces oxidative stress, nuclear factor‑κB activity and cardiomyocyte apoptosis in heart failure

Wu,Xiao‑Yan; Luo,An‑Yu; Zhou,Yi‑Rong; Ren,Jiang‑Hua

doi:10.3892/mmr.2014.2292

N‑acetylcysteine reduces oxidative stress, nuclear factor‑κB activity and cardiomyocyte apoptosis in heart failure

Authors:
- Xiao‑Yan Wu
- An‑Yu Luo
- Yi‑Rong Zhou
- Jiang‑Hua Ren
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Affiliations: Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China, Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, P.R. China, Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, USA
Published online on: June 2, 2014 https://doi.org/10.3892/mmr.2014.2292
Pages: 615-624
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The roles of oxidative stress on nuclear factor (NF)‑κB activity and cardiomyocyte apoptosis during heart failure were examined using the antioxidant N‑acetylcysteine (NAC). Heart failure was established in Japanese white rabbits with intravenous injections of doxorubicin, with ten rabbits serving as a control group. Of the rabbits with heart failure, 12 were not treated (HF group) and 13 received NAC (NAC group). Cardiac function was assessed using echocardiography and hemodynamic analysis. Myocardial cell apoptosis, apoptosis‑related protein expression, NF‑κBp65 expression and activity, total anti‑oxidative capacity (tAOC), 8‑iso‑prostaglandin F2α (8‑iso‑PGF2α) expression and glutathione (GSH) expression levels were determined. In the HF group, reduced tAOC, GSH levels and Bcl‑2/Bax ratios as well as increased 8‑iso‑PGF2α levels and apoptosis were observed (all P<0.05), which were effects that were attenuated by the treatment with NAC. NF‑κBp65 and iNOS levels were significantly higher and the P‑IκB‑α levels were significantly lower in the HF group; expression of all three proteins returned to pre‑HF levels following treatment with NAC. Myocardial cell apoptosis was positively correlated with left ventricular end-diastolic pressure (LVEDP), NF‑κBp65 expression and 8‑iso‑PGF2α levels, but negatively correlated with the maximal and minimal rates of increase in left ventricular pressure (+dp/dtmax and ‑dp/dtmin, respectively) and the Bcl‑2/Bax ratio (all P<0.001). The 8‑iso‑PGF2α levels were positively correlated with LVEDP and negatively correlated with +dp/dtmax and ‑dp/dtmin (all P<0.001). The present study demonstrated that NAC increased the antioxidant capacity, decreased the NF‑κB activation and reduced myocardial cell apoptosis in an in vivo heart failure model.

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1	Lloyd-Jones D, Adams RJ, Brown TM, et al: Heart disease and stroke statistics - 2010 update: a report from the American Heart Association. Circulation. 121:e46–e215. 2010. View Article : Google Scholar : PubMed/NCBI
2	Roger VL, Go AS, Lloyd-Jones DM, et al: Heart disease and stroke statistics - 2012 update: a report from the American Heart Association. Circulation. 125:e2–e220. 2012. View Article : Google Scholar : PubMed/NCBI
3	Owan TE and Redfield MM: Epidemiology of diastolic heart failure. Progr Cardiovasc Dis. 47:320–332. 2005. View Article : Google Scholar : PubMed/NCBI
4	Ellis ER and Josephson ME: Heart failure and tachycardia-induced cardiomyopathy. Curr Heart Fail Rep. 10:296–306. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yancy CW: Heart failure in African Americans. Am J Cardiol. 96:3i–12i. 2005. View Article : Google Scholar : PubMed/NCBI
6	Thomas KL, Piccini JP, Liang L, et al: Racial differences in the prevalence and outcomes of atrial fibrillation among patients hospitalized with heart failure. J Am Heart Assoc. 2:e0002002013. View Article : Google Scholar : PubMed/NCBI
7	Neubauer S: The failing heart - an engine out of fuel. N Engl J Med. 356:1140–1151. 2007. View Article : Google Scholar : PubMed/NCBI
8	Giordano FJ: Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 115:500–508. 2005. View Article : Google Scholar : PubMed/NCBI
9	White M, Ducharme A, Ibrahim R, et al: Increased systemic inflammation and oxidative stress in patients with worsening congestive heart failure: improvement after short-term inotropic support. Clin Sci (Lond). 110:483–489. 2006. View Article : Google Scholar
10	Hare JM: Oxidative stress and apoptosis in heart failure progression. Circ Res. 89:198–200. 2001.PubMed/NCBI
11	Sawyer DB, Siwik DA, Xiao L, et al: Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 34:379–388. 2002. View Article : Google Scholar : PubMed/NCBI
12	Abbate A, Bussani R, Amin MS, Vetroec GW, et al: Acute myocardial infarction and heart failure: role of apoptosis. Int J Biochem Cell Biol. 38:1834–1840. 2006. View Article : Google Scholar : PubMed/NCBI
13	Wang RP, Yao Q, Xiao YB, et al: Toll-like receptor 4/nuclear factor-kappa B pathway is involved in myocardial injury in a rat chronic stress model. Stress. 14:567–575. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gordon JW, Shaw JA and Kirshenbaum LA: Multiple facets of NF-κB in the heart: to be or not to NF-κB. Circ Res. 108:1122–1132. 2011.
15	Frantz S, Hu K, Bayer B, et al: Absence of NF-kappaB subunit p50 improves heart failure after myocardial infarction. FASEB. 20:1918–1920. 2006. View Article : Google Scholar : PubMed/NCBI
16	Galang N, Sasaki H and Maulik N: Apoptotic cell death during ischemia/reperfusion and its attenuation by antioxidant therapy. Toxicology. 148:111–118. 2000. View Article : Google Scholar : PubMed/NCBI
17	Jones SM, Kirby MS, Harding SE, et al: Adriamycin cardiomyopathy in the rabbit: alterations in contractile proteins and myocyte function. Cardiovasc Res. 24:834–842. 1990. View Article : Google Scholar : PubMed/NCBI
18	Andre L, Fauconnier J, Reboul C, et al: Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure. Antioxid Redox Signal. 18:1009–1020. 2013. View Article : Google Scholar
19	van Dalen EC, Caron HN, Dickinson HO, et al: Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 15:CD0039172011.
20	Carvalho FS, Burgeiro A, Garcia R, et al: Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev. 34:106–135. 2014. View Article : Google Scholar : PubMed/NCBI
21	Dolinsky VW, Rogan KJ, Sung MM, et al: Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab. 305:E243–E253. 2013. View Article : Google Scholar : PubMed/NCBI
22	Langton D, Jover B, McGrath BP, et al: Cardiovascular responses to graded treadmill exercise during the development of doxorubicin induced heart failure in rabbits. Cardiovasc Res. 24:959–968. 1990. View Article : Google Scholar : PubMed/NCBI
23	Sarandol A, Sarandol E, Eker SS, et al: Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol. 22:67–73. 2007. View Article : Google Scholar
24	Erel O: A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 37:112–119. 2004. View Article : Google Scholar : PubMed/NCBI
25	Ye J, Ding M, Zhang X, et al: On the role of hydroxyl radical and the effect of tetrandrine on nuclear factor-κB activation by phorbol 12-myristate 13-acetate. Ann Clin Lab Sci. 30:65–71. 2000.
26	Kone BC, Schwöbel J, Turner P, et al: Role of NF-kappa B in the regulation of inducible nitric oxide synthase in an MTAL cell line. Am J Physiol. 269:F718–F729. 1995.PubMed/NCBI
27	Kubin AM, Skoumal R, Tavi P, et al: Role of reactive oxygen species in the regulation of cardiac contractility. J Mol Cell Cardiol. 50:884–893. 2011. View Article : Google Scholar : PubMed/NCBI
28	Finn NA and Kemp ML: Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells. Mol Biosyst. 8:650–662. 2012. View Article : Google Scholar : PubMed/NCBI
29	Sagristá ML, García AE, Africa De Madariaga M, et al: Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-L-cysteine and glutathione against free radical-induced lipid peroxidation. Free Radic Res. 36:329–340. 2002.PubMed/NCBI
30	The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th edition. Little, Brown & Co; Boston: pp. 253–256. 1994
31	You JS, Huang HF and Chang YL: Panax ginseng reduces adriamycin-induced heart failure in rats. Phytother Res. 19:1018–1022. 2005. View Article : Google Scholar : PubMed/NCBI
32	Dong JW, Zhu HF, Zhu WZ, et al: Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression. Cell Res. 13:385–391. 2003. View Article : Google Scholar : PubMed/NCBI
33	Sabbah HN, Sharov VG, Gupata RC, et al: Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure. J Am Coll Cardiol. 36:1698–1705. 2000. View Article : Google Scholar : PubMed/NCBI
34	Burke JR: Targeting I kappa B kinase for the treatment of inflammatory and other disorders. Curr Opin Drug Discov Devel. 6:720–728. 2003.PubMed/NCBI
35	Squadrito F, Deodato B, Squadrito G, et al: Gene transfer of IkappaBalpha limit infarct ischemia-reperfusion injury. Lab Invest. 83:1097–1104. 2003. View Article : Google Scholar : PubMed/NCBI
36	Altavilla D, Deodato B, Campo GM, et al: IRFI 042, a novel dual vitamin E-like antioxidant, inhibits activation of nuclear factor-kappaB and reduces the inflammatory response in myocardial ischemia-reperfusion injury. Cardiovasc Res. 47:515–528. 2000. View Article : Google Scholar
37	Monaco C and Paleolog E: Nuclear factor kappaB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res. 61:671–682. 2004. View Article : Google Scholar : PubMed/NCBI
38	Maier HJ, Schips TG, Wietelmann A, et al: Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure. Proc Natl Acad Sci USA. 109:11794–11799. 2012.
39	Hall G, Hasday JD and Rogers TB: Regulating the regulator: NF-kappaB signaling in heart. J Mol Cell Cardiol. 41:580–591. 2006. View Article : Google Scholar : PubMed/NCBI
40	Pye J, Ardeshirpour F, McCain A, et al: Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. Am J Physiol Heart Circ Physiol. 284:H919–H926. 2003.PubMed/NCBI
41	Gao Y, Lecker S, Post MJ, et al: Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide. J Clin Invest. 106:439–448. 2000. View Article : Google Scholar : PubMed/NCBI
42	Inserte J, Taimor G, Hofstaetter B, et al: Influence of simulated ischemia on apoptosis induction by oxidative stress in adult cardiomyocytes of rat. Am J Physiol Heart Circ Physiol. 278:H94–H99. 2000.PubMed/NCBI
43	Crespo MJ, Cruz N, Altieri PI, et al: Chronic treatment with N-acetylcysteine improves cardiac function but does not prevent progression of cardiomyopathy in Syrian cardiomyopathic hamsters. J Cardiovasc Pharmacol Ther. 16:197–204. 2011. View Article : Google Scholar
44	Haleagrahara N, Julian V and Chakravarthi S: N-acetylcysteine offers cardioprotection by decreasing cardiac lipid hydroperoxides and 8-isoprostane level in isoproterenol-induced cardiotoxicity in rats. Cardiovasc Toxicol. 11:373–381. 2011. View Article : Google Scholar
45	Basha RH and Priscilla DH: An in vivo and in vitro study on the protective effects of N-acetylcysteine on mitochondrial dysfunction in isoproterenol treated myocardial infarcted rats. Exp Toxicol Pathol. 65:7–14. 2013. View Article : Google Scholar : PubMed/NCBI
46	Adamy C, Le Corvoisier P, Candiani G, et al: Tumor necrosis factor alpha and glutathione interplay in chronic heart failure. Arch Mal Coeur Vaiss. 98:906–912. 2005.PubMed/NCBI
47	Chen F, Hadfield JM, Berzingi C, et al: N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress. J Appl Physiol. 1985. 115:514–524. 2013. View Article : Google Scholar : PubMed/NCBI
48	Wang T, Qiao S, Lei S, et al: N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats. PLoS One. 6:e239672011. View Article : Google Scholar
49	Dresdale AR, Barr LH, Bonow RO, et al: Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy. Am J Clin Oncol. 5:657–663. 1982. View Article : Google Scholar : PubMed/NCBI
50	Jo SH, Kim LS, Kim SA, et al: Evaluation of short-term use of N-acetylcysteine as a strategy for prevention of anthracycline-induced cardiomyopathy: EPOCH trial - a prospective randomized study. Korean Circ J. 43:174–181. 2013. View Article : Google Scholar : PubMed/NCBI