nach oben

Erschienen in:

01.01.2015 | Original Research Paper

Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea

verfasst von: Darlan Pase da Rosa, Luiz Felipe Forgiarini, Mariel Barbachan e Silva, Cíntia Zappe Fiori, Cristiano Feijó Andrade, Dênis Martinez, Norma Possa Marroni

Erschienen in: Inflammation Research | Ausgabe 1/2015

Einloggen, um Zugang zu erhalten

Abstract

Background

Sleep apnea causes intermittent hypoxia (IH). We aimed to investigate the proteins related to oxidative stress, inflammation and apoptosis in liver tissue subjected to IH as a simulation of sleep apnea in conjunction with the administration of either melatonin (MEL, 200 μL/kg) or N-acetylcysteine (NAC, 10 mg/kg).

Methods

Seventy-two adult male Balb-C mice were divided: simulation of IH (SIH), SIH + MEL, SIH + NAC, IH, IH + MEL and IH + NAC. The animals were subjected to simulations of sleep apnea for 8 h a day for 35 days. The data were analyzed with ANOVA and Tukey tests with the significance set at p < 0.05.

Results

In IH, there was a significant increase in oxidative stress and expression of HIF-1a. In addition, we observed increase in the activation levels of NF-kB. This increase may be responsible for the increased expression of TNF-alpha and iNOS as well as the significant increase of VEGF signaling and expression of caspase-3 and caspase-6, which suggests an increase in apoptosis. In the groups treated with antioxidants, the analysis showed that the enzyme activity and protein levels were similar to those of the non-simulated group.

Conclusions

Thus, we show that IH causes liver inflammation and apoptosis, which may be protected with either MEL or NAC.

Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112.PubMedCentralPubMedCrossRef

Zhou W, Li S, Wan N, Zhang Z, Guo R, Chen B. Effects of various degrees of oxidative stress induced by intermittent hypoxia in rat myocardial tissues. Respirology. 2012;17(5):821–9.PubMedCrossRef

Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev. 2003;7:35–51.PubMedCrossRef

Lavie L. Sleep-disordered breathing and cerebrovascular disease: a mechanistic approach. Neurol Clin. 2005;23:1059–75.PubMedCrossRef

Suzuki YJ, Jain V, Park AM, Day RM. Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases. Free Radic Biol Med. 2006;40:1683–92.PubMedCentralPubMedCrossRef

Lavie L. Oxidative stress—a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis. 2009;51:303–12.PubMedCrossRef

Aalto TK, Raivio KO. Nucleotide depletion due to reactive oxygen metabolites in endothelial cells: effects of antioxidants and 3-aminobenzamide. Pediatr Res. 1993;34:572–6.PubMedCrossRef

Szabo C, Zingarelli B, Salzman AL. Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res. 1996;78:1051–63.PubMedCrossRef

Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxicity. Science. 1994;263:687–9.PubMedCrossRef

10.

Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 2005;50:2338–43.PubMedCrossRef

11.

Tanne F, Gagnadoux F, Chazouilleres O, Fleury B, Wendum D, Lasnier E, Lebeau B, Poupon R, Serfaty L. Chronic liver injury during obstructive sleep apnea. Hepatology. 2005;41:1290–6.PubMedCrossRef

12.

Tatsumi K, Saibara T. Effects of obstructive sleep apnea syndrome on hepatic steatosis and nonalcoholic steatohepatitis. Hepatol Res. 2005;33:100–4.PubMedCrossRef

13.

Jouet P, Sabate JM, Maillard D, Msika S, Mechler C, Ledoux S, Harnois F, Coffin B. Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study. Obes Surg. 2007;17:478–85.PubMedCrossRef

14.

Kallwitz ER, Herdegen J, Madura J, Jakate S, Cotler SJ. Liver enzymes and histology in obese patients with obstructive sleep apnea. J Clin Gastroenterol. 2007;41:918–21.PubMedCrossRef

15.

Zamora-Valdes D, Mendez-Sanchez N. Experimental evidence of obstructive sleep apnea syndrome as a second hit accomplice in nonalcoholic steatohepatitis pathogenesis. Ann Hepatol. 2007;6:281–3.PubMed

16.

Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest. 2008;133:92–9.PubMedCrossRef

17.

Norman D, Bardwell WA, Arosemena F, Nelesen R, Mills PJ, Loredo JS, Lavine JE, Dimsdale JE. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep. 2008;31:121–6.PubMedCentralPubMed

18.

Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH. Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci (Lond). 2009;116:539–64.CrossRef

19.

Savransky V, Nanayakkara A, Vivero A, Li J, Bevans S, Smith PL, Torbenson MS, Polotsky VY. Chronic intermittent hypoxia predisposes to liver injury. Hepatology. 2007;45:1007–13.PubMedCrossRef

20.

Savransky V, Reinke C, Jun J, Bevans-Fonti S, Nanayakkara A, Li J, Myers AC, Torbenson MS, Polotsky VY. Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice. Exp Physiol. 2009;94:228–39.PubMedCentralPubMedCrossRef

21.

Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax. 2009;64:631–6.PubMed

22.

Htoo AK, Greenberg H, Tongia S, Chen G, Henderson T, Wilson D, Liu SF. Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation. Sleep Breath. 2006;10:43–50.PubMedCrossRef

23.

Greenberg H, Ye X, Wilson D, Htoo AK, Hendersen T, Liu SF. Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem Biophys Res Commun. 2006;343:591–6.PubMedCrossRef

24.

Selmi C, Montano N, Furlan R, Keen CL, Gershwin ME. Inflammation and oxidative stress in obstructive sleep apnea syndrome. Exp Biol Med (Maywood). 2007;232:1409–13.CrossRef

25.

Yamauchi M, Tamaki S, Tomoda K, Yoshikawa M, Fukuoka A, Makinodan K, Koyama N, Suzuki T, Kimura H. Evidence for activation of nuclear factor kappaB in obstructive sleep apnea. Sleep Breath. 2006;10:189–93.PubMedCrossRef

26.

Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394:485–90.PubMedCrossRef

27.

Ziment I. Acetylcysteine: a drug that is much more than a mucokinetic. Biomed Pharmacother. 1988;42:513–9.PubMed

28.

Rosa DP, Martinez D, Picada JN, Semedo JG, Marroni NP. Hepatic oxidative stress in an animal model of sleep apnoea: effects of different duration of exposure. Comp Hepatol. 2011;10:1.PubMedCentralPubMedCrossRef

29.

Savransky V, Bevans S, Nanayakkara A, Li J, Smith PL, Torbenson MS, Polotsky VY. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol. 2007;293:G871–7.PubMedCrossRef

30.

Halliwell B. Free radicals, reactive oxygen species and human disease: a critical evaluation with special reference to atherosclerosis. Br J Exp Pathol. 1989;70:737–57.PubMedCentralPubMed

31.

Martinez D, Fiori CZ, Baronio D, Carissimi A, Kaminski RS, Kim LJ, Rosa DP, Bos A. Brown adipose tissue: is it affected by intermittent hypoxia? Lipids Health Dis. 2010;9:121.PubMedCentralPubMedCrossRef

32.

Guven A, Yavuz O, Cam M, Ercan F, Bukan N, Comunoglu C, Gokce F. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats. Acta Histochem. 2006;108:85–93.PubMedCrossRef

33.

Vercelino R, Tieppo J, Dias AS, Marroni CA, Garcia E, Meurer L, Picada JN, Marroni NP. N-Acetylcysteine effects on genotoxic and oxidative stress parameters in cirrhotic rats with hepatopulmonary syndrome. Basic Clin Pharmacol Toxicol. 2008;102:370–6.PubMedCrossRef

34.

[Anon]. AVMA updates its euthanasia guidelines. Vet Rec. 2007;161:502–502.

35.

[Anon]. AVMA releases updated euthanasia guidelines. JAVMA. 2007, 231:827-827.

36.

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.PubMedCrossRef

37.

Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.PubMedCrossRef

38.

Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247:3170–5.PubMed

39.

Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–5.PubMedCrossRef

40.

Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA. 1979;76:4350–4.PubMedCentralPubMedCrossRef

41.

Park AM, Suzuki YJ. Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice. J Appl Physiol. 2007;102:1806–14.PubMedCrossRef

42.

Dutta A, Ray K, Singh VK, Vats P, Singh SN, Singh SB. l-carnitine supplementation attenuates intermittent hypoxia-induced oxidative stress and delays muscle fatigue in rats. Exp Physiol. 2008;93:1139–46.PubMedCrossRef

43.

Bertuglia S, Reiter RJ. Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia. J Pineal Res. 2009;46:307–13.PubMedCrossRef

44.

Lavie L, Hefetz A, Luboshitzky R, Lavie P. Plasma levels of nitric oxide and l-arginine in sleep apnea patients: effects of nCPAP treatment. J Mol Neurosci. 2003;21:57–63.PubMedCrossRef

45.

Sohn HY, Krotz F, Gloe T, Keller M, Theisen K, Klauss V, Pohl U. Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Cardiovasc Res. 2003;58:638–46.PubMedCrossRef

46.

Jordan W, Cohrs S, Degner D, Meier A, Rodenbeck A, Mayer G, Pilz J, Ruther E, Kornhuber J, Bleich S. Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome. J Neural Transm. 2006;113:239–54.PubMedCrossRef

47.

Phillips SA, Olson EB, Lombard JH, Morgan BJ. Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries. J Appl Physiol. 2006;100:1117–23.PubMedCrossRef

48.

Shpirer I, Copel L, Broide E, Elizur A. Continuous positive airway pressure improves sleep apnea associated fatty liver. Lung. 2010;188(4):301–7.PubMedCrossRef

49.

Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J. 2005;19:136–8.PubMed

50.

Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 1997;12:398–403.PubMedCrossRef

51.

Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.PubMedCrossRef

52.

Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284:16767–75.PubMedCentralPubMedCrossRef

53.

Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97–106.CrossRef

54.

Yuan G, Khan SA, Luo W, Nanduri J, Semenza GL, Prabhakar NR. Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol. 2011;226:2925–33.PubMedCrossRef

55.

Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011;53:1526–37.PubMedCentralPubMedCrossRef

56.

Blouin CC, Page EL, Soucy GM, Richard DE. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood. 2004;103:1124–30.PubMedCrossRef

57.

Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V. Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol. 2007;178:7516–9.PubMedCrossRef

58.

van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008;412:477–84.PubMedCentralPubMedCrossRef

59.

Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453:807–11.PubMedCentralPubMedCrossRef

60.

Beraza N, Malato Y, Vander Borght S, Liedtke C, Wasmuth HE, Dreano M, de Vos R, Roskams T, Trautwein C. Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut. 2008;57:655–63.PubMedCrossRef

61.

Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66.PubMedCrossRef

62.

Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.PubMedCrossRef

63.

Minet E, Michel G, Remacle J, Michiels C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int J Mol Med. 2000;5:253–9.PubMed

64.

Zhu H, Zeng L, Zhu D, Yuan Y. The role of TGF-beta 1 in mice hepatic fibrosis by Schistosomiasis Japonica. J Tongji Med Univ. 2000;20(320–321):329.

65.

Jeong WI, Do SH, Yun HS, Song BJ, Kim SJ, Kwak WJ, Yoo SE, Park HY, Jeong KS. Hypoxia potentiates transforming growth factor-beta expression of hepatocyte during the cirrhotic condition in rat liver. Liver Int. 2004;24:658–68.PubMedCrossRef

66.

Hampl V, Cornfield DN, Cowan NJ, Archer SL. Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells. Eur Respir J. 1995;8:515–22.PubMed

67.

Feelisch M, Fernandez BO, Bryan NS, Garcia-Saura MF, Bauer S, Whitlock DR, Ford PC, Janero DR, Rodriguez J, Ashrafian H. Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. J Biol Chem. 2008;283:33927–34.PubMedCentralPubMedCrossRef

68.

Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest. 2000;106:809–12.PubMedCentralPubMedCrossRef

69.

Moritz W, Meier F, Stroka DM, Giuliani M, Kugelmeier P, Nett PC, Lehmann R, Candinas D, Gassmann M, Weber M. Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha expression. FASEB J. 2002;16:745–7.PubMed

70.

Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, Niizeki H, Kawamura K, Hosokawa M, Asaka M. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001;61:6548–54.PubMed

71.

Greijer AE, van der Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol. 2004;57:1009–14.PubMedCentralPubMedCrossRef

Titel: Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea
verfasst von: Darlan Pase da Rosa
Luiz Felipe Forgiarini
Mariel Barbachan e Silva
Cíntia Zappe Fiori
Cristiano Feijó Andrade
Dênis Martinez
Norma Possa Marroni
Publikationsdatum: 01.01.2015
Verlag: Springer Basel
Erschienen in: Inflammation Research / Ausgabe 1/2015
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-014-0778-5

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea