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The relationship between glutathione levels in leukocytes and ocular clinical parameters in glaucoma


Autoři: Takeshi Yabana aff001;  Kota Sato aff001;  Yukihiro Shiga aff001;  Noriko Himori aff001;  Kazuko Omodaka aff001;  Toru Nakazawa aff001
Působiště autorů: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan aff001;  Collaborative Program for Ophthalmic Drug Discovery, Tohoku University Graduate School of Medicine, Sendai, Japan aff002;  Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, Japan aff003;  Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Japan aff004;  Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227078

Souhrn

Purpose

To investigate the effect of mitochondrial dysfunction on the autoregulation of blood flow, by measuring levels of glutathione, an indicator of mitochondrial dysfunction, in glaucoma patients.

Methods

Fifty-six OAG patients and 21 age-matched controls underwent a blood assay. Mitochondrial function was measured according to the levels of total glutathione (t-GSH), reduced GSH (GSH), and oxidized GSH (GSSG, glutathione disulfide) in peripheral blood mononuclear cells. Ocular blood flow in the optic nerve head was assessed with laser speckle flowgraphy parameters, including acceleration time index (ATI). We determined correlations between these measurements and other clinical parameters. Furthermore, we investigated the association between glutathione levels and glaucoma with a logistic regression analysis. Finally, we calculated the area under the receiver operating characteristic (ROC) curve in order to determine the power of redox index (the log GSH/GSSG ratio) to distinguish the groups.

Results

OAG patients demonstrated significantly higher GSSG levels and a lower redox index than the controls (p = 0.01, p = 0.01, respectively), but total GSH and reduced GSH levels were similar in the OAG subjects and controls (p = 0.80, p = 0.94, respectively). Additionally, redox index was significantly correlated with mean deviation (MD) of the visual field (r = 0.29, p = 0.03) and ATI (r = -0.30, p = 0.03). Multiple linear regression analysis showed that redox index contributed to MD (p = 0.02) and ATI (p = 0.04). The receiver operating characteristic curve (AUC) analysis suggested that redox index could differentiate between control eyes and eyes with glaucoma (AUC; 0.70: 95% interval; 0.57–0.84). The cutoff point for redox index to maximize its sensitivity and specificity was 2.0 (sensitivity: 91.1%, specificity: 42.9%).

Conclusions

These results suggest that redox index is lower in OAG patients than in controls. Thus, it is possible that mitochondrial dysfunction contributes to glaucoma pathogenesis by causing vascular alterations.

Klíčová slova:

Blood – Mitochondria – Glaucoma – Eyes – Lasers – Glutathione – Oxidation-reduction reactions – Retinal ganglion cells


Zdroje

1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. The British journal of ophthalmology. 2006;90(3):262–7. Epub 2006/02/21. doi: 10.1136/bjo.2005.081224 16488940; PubMed Central PMCID: PMC1856963.

2. Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Progress in retinal and eye research. 2002;21(4):359–93. Epub 2002/08/02. doi: 10.1016/s1350-9462(02)00008-3 12150988.

3. Wei Z, Li X, Li X, Liu Q, Cheng Y. Oxidative Stress in Parkinson's Disease: A Systematic Review and Meta-Analysis. Frontiers in molecular neuroscience. 2018;11:236. Epub 2018/07/22. doi: 10.3389/fnmol.2018.00236 30026688; PubMed Central PMCID: PMC6041404.

4. Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochimica et biophysica acta. 2014;1842(8):1219–31. Epub 2013/09/28. doi: 10.1016/j.bbadis.2013.09.010 24071439; PubMed Central PMCID: PMC3962811.

5. Mejia EM, Chau S, Sparagna GC, Sipione S, Hatch GM. Reduced Mitochondrial Function in Human Huntington Disease Lymphoblasts is Not Due to Alterations in Cardiolipin Metabolism or Mitochondrial Supercomplex Assembly. Lipids. 2016;51(5):561–9. Epub 2016/02/06. doi: 10.1007/s11745-015-4110-0 26846325.

6. Pansarasa O, Bordoni M, Drufuca L, Diamanti L, Sproviero D, Trotti R, et al. Lymphoblastoid cell lines as a model to understand amyotrophic lateral sclerosis disease mechanisms. Disease models & mechanisms. 2018;11(3). Epub 2018/02/09. doi: 10.1242/dmm.031625 29419416; PubMed Central PMCID: PMC5897724.

7. Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Investigative ophthalmology & visual science. 2006;47(6):2533–41. Epub 2006/05/26. doi: 10.1167/iovs.05-1639 16723467.

8. Tezel G. The role of glia, mitochondria, and the immune system in glaucoma. Investigative ophthalmology & visual science. 2009;50(3):1001–12. Epub 2009/02/27. doi: 10.1167/iovs.08-2717 19244206.

9. Lee S, Sheck L, Crowston JG, Van Bergen NJ, O'Neill EC, O'Hare F, et al. Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts. Investigative ophthalmology & visual science. 2012;53(4):2431–7. Epub 2012/03/20. doi: 10.1167/iovs.12-9596 22427588.

10. Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Current opinion in pharmacology. 2013;13(1):12–5. Epub 2012/10/17. doi: 10.1016/j.coph.2012.09.008 23069478.

11. Van Bergen NJ, Crowston JG, Craig JE, Burdon KP, Kearns LS, Sharma S, et al. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy. PloS one. 2015;10(10):e0140919. Epub 2015/10/27. doi: 10.1371/journal.pone.0140919 26496696; PubMed Central PMCID: PMC4619697.

12. Lascaratos G, Chau KY, Zhu H, Gkotsi D, King R, Gout I, et al. Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency. Neurobiology of disease. 2015;82:78–85. Epub 2015/06/10. doi: 10.1016/j.nbd.2015.05.012 26054436.

13. Zhao J, Wang S, Zhong W, Yang B, Sun L, Zheng Y. Oxidative stress in the trabecular meshwork (Review). International journal of molecular medicine. 2016;38(4):995–1002. Epub 2016/08/31. doi: 10.3892/ijmm.2016.2714 27572245.

14. Kamel K, Farrell M, O'Brien C. Mitochondrial dysfunction in ocular disease: Focus on glaucoma. Mitochondrion. 2017;35:44–53. Epub 2017/05/14. doi: 10.1016/j.mito.2017.05.004 28499981.

15. Barron MJ, Griffiths P, Turnbull DM, Bates D, Nichols P. The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head. The British journal of ophthalmology. 2004;88(2):286–90. Epub 2004/01/23. doi: 10.1136/bjo.2003.027664 14736793; PubMed Central PMCID: PMC1771975.

16. Ito YA, Di Polo A. Mitochondrial dynamics, transport, and quality control: A bottleneck for retinal ganglion cell viability in optic neuropathies. Mitochondrion. 2017;36:186–92. Epub 2017/09/04. doi: 10.1016/j.mito.2017.08.014 28866056.

17. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Molecular aspects of medicine. 2009;30(1–2):1–12. Epub 2008/09/18. doi: 10.1016/j.mam.2008.08.006 18796312; PubMed Central PMCID: PMC2696075.

18. Enns GM, Cowan TM. Glutathione as a Redox Biomarker in Mitochondrial Disease-Implications for Therapy. Journal of clinical medicine. 2017;6(5). Epub 2017/05/04. doi: 10.3390/jcm6050050 PubMed Central PMCID: PMC5447941. 28467362

19. Widlansky ME, Wang J, Shenouda SM, Hagen TM, Smith AR, Kizhakekuttu TJ, et al. Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes. Translational research: the journal of laboratory and clinical medicine. 2010;156(1):15–25. Epub 2010/07/14. doi: 10.1016/j.trsl.2010.04.001 20621033; PubMed Central PMCID: PMC2904361.

20. Clayton DA, Vinograd J. Complex mitochondrial DNA in leukemic and normal human myeloid cells. Proceedings of the National Academy of Sciences of the United States of America. 1969;62(4):1077–84. Epub 1969/04/01. doi: 10.1073/pnas.62.4.1077 5256408; PubMed Central PMCID: PMC223617.

21. Cecchi C, Latorraca S, Sorbi S, Iantomasi T, Favilli F, Vincenzini MT, et al. Gluthatione level is altered in lymphoblasts from patients with familial Alzheimer's disease. Neuroscience letters. 1999;275(2):152–4. Epub 1999/11/24. doi: 10.1016/s0304-3940(99)00751-x 10568522.

22. Leuner K, Schulz K, Schutt T, Pantel J, Prvulovic D, Rhein V, et al. Peripheral mitochondrial dysfunction in Alzheimer's disease: focus on lymphocytes. Molecular neurobiology. 2012;46(1):194–204. Epub 2012/07/24. doi: 10.1007/s12035-012-8300-y 22821186.

23. Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers. Redox biology. 2014;2:206–10. Epub 2014/02/05. doi: 10.1016/j.redox.2013.12.026 24494194; PubMed Central PMCID: PMC3909784.

24. Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, et al. Positive effects of nitric oxide on left ventricular function in humans. European heart journal. 2006;27(14):1699–705. Epub 2006/06/20. doi: 10.1093/eurheartj/ehl096 16782717.

25. Hernandez-Mijares A, Rocha M, Rovira-Llopis S, Banuls C, Bellod L, de Pablo C, et al. Human leukocyte/endothelial cell interactions and mitochondrial dysfunction in type 2 diabetic patients and their association with silent myocardial ischemia. Diabetes care. 2013;36(6):1695–702. Epub 2013/01/10. doi: 10.2337/dc12-1224 23300290; PubMed Central PMCID: PMC3661843.

26. Broniowska KA, Diers AR, Hogg N. S-nitrosoglutathione. Biochimica et biophysica acta. 2013;1830(5):3173–81. Epub 2013/02/19. doi: 10.1016/j.bbagen.2013.02.004 23416062; PubMed Central PMCID: PMC3679660.

27. Khan M, Dhammu TS, Dhaindsa TS, Khan H, Singh AK, Singh I. An NO/GSNO-based Neuroregeneration Strategy for Stroke Therapy. Journal of neurology and neuroscience. 2015;6(4). Epub 2015/01/01. 27668143; PubMed Central PMCID: PMC5034763.

28. Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(7):3070–4. Epub 1992/04/01. doi: 10.1073/pnas.89.7.3070 1348364; PubMed Central PMCID: PMC48805.

29. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2003;57(3–4):145–55. Epub 2003/06/24. doi: 10.1016/s0753-3322(03)00043-x 12818476.

30. Hoffmann MH, Griffiths H. The dual role of ROS in autoimmune and inflammatory diseases: evidence from preclinical models. Free radical biology & medicine. 2018. Epub 2018/03/20. doi: 10.1016/j.freeradbiomed.2018.03.016 29550327.

31. Galicia-Moreno M, Rosique-Oramas D, Medina-Avila Z, Alvarez-Torres T, Falcon D, Higuera-de la Tijera F, et al. Behavior of Oxidative Stress Markers in Alcoholic Liver Cirrhosis Patients. Oxidative medicine and cellular longevity. 2016;2016:9370565. Epub 2017/01/12. doi: 10.1155/2016/9370565 28074118; PubMed Central PMCID: PMC5198187.

32. Shiga Y, Asano T, Kunikata H, Nitta F, Sato H, Nakazawa T, et al. Relative flow volume, a novel blood flow index in the human retina derived from laser speckle flowgraphy. Investigative ophthalmology & visual science. 2014;55(6):3899–904. Epub 2014/05/31. doi: 10.1167/iovs.14-14116 24876283.

33. Sugiyama T, Araie M, Riva CE, Schmetterer L, Orgul S. Use of laser speckle flowgraphy in ocular blood flow research. Acta ophthalmologica. 2010;88(7):723–9. Epub 2009/09/04. doi: 10.1111/j.1755-3768.2009.01586.x 19725814.

34. Aizawa N, Nitta F, Kunikata H, Sugiyama T, Ikeda T, Araie M, et al. Laser speckle and hydrogen gas clearance measurements of optic nerve circulation in albino and pigmented rabbits with or without optic disc atrophy. Investigative ophthalmology & visual science. 2014;55(12):7991–6. Epub 2014/11/08. doi: 10.1167/iovs.14-15373 25377226.

35. Shiga Y, Omodaka K, Kunikata H, Ryu M, Yokoyama Y, Tsuda S, et al. Waveform analysis of ocular blood flow and the early detection of normal tension glaucoma. Investigative ophthalmology & visual science. 2013;54(12):7699–706. Epub 2013/10/17. doi: 10.1167/iovs.13-12930 24130177.

36. Monostori P, Wittmann G, Karg E, Turi S. Determination of glutathione and glutathione disulfide in biological samples: an in-depth review. Journal of chromatography B, Analytical technologies in the biomedical and life sciences. 2009;877(28):3331–46. Epub 2009/06/30. doi: 10.1016/j.jchromb.2009.06.016 19560987.

37. Asano Y, Himori N, Kunikata H, Yamazaki M, Shiga Y, Omodaka K, et al. Age- and sex-dependency of the association between systemic antioxidant potential and glaucomatous damage. Scientific reports. 2017;7(1):8032. Epub 2017/08/16. doi: 10.1038/s41598-017-08624-4 28808277; PubMed Central PMCID: PMC5556047.

38. Kearns PR, Pieters R, Rottier MM, Pearson AD, Hall AG. Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood. 2001;97(2):393–8. Epub 2001/01/12. doi: 10.1182/blood.v97.2.393 11154214.

39. Mulhern ML, Madson CJ, Danford A, Ikesugi K, Kador PF, Shinohara T. The unfolded protein response in lens epithelial cells from galactosemic rat lenses. Investigative ophthalmology & visual science. 2006;47(9):3951–9. Epub 2006/08/29. doi: 10.1167/iovs.06-0193 16936110.

40. Utsugi M, Dobashi K, Koga Y, Shimizu Y, Ishizuka T, Iizuka K, et al. Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN-gamma priming of IL-12 production. Journal of leukocyte biology. 2002;71(2):339–47. Epub 2002/01/31. 11818456.

41. Hamilos DL, Wedner HJ. The role of glutathione in lymphocyte activation. I. Comparison of inhibitory effects of buthionine sulfoximine and 2-cyclohexene-1-one by nuclear size transformation. Journal of immunology (Baltimore, Md: 1950). 1985;135(4):2740–7. Epub 1985/10/01. 4031498.

42. Izzotti A, Bagnis A, Sacca SC. The role of oxidative stress in glaucoma. Mutation research. 2006;612(2):105–14. Epub 2006/01/18. doi: 10.1016/j.mrrev.2005.11.001 16413223.

43. Mabuchi F, Tang S, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. The OPA1 gene polymorphism is associated with normal tension and high tension glaucoma. American journal of ophthalmology. 2007;143(1):125–30. Epub 2006/12/26. doi: 10.1016/j.ajo.2006.09.028 17188046.

44. Inoue-Yanagimachi M, Himori N, Sato K, Kokubun T, Asano T, Shiga Y, et al. Association between mitochondrial DNA damage and ocular blood flow in patients with glaucoma. The British journal of ophthalmology. 2018. Epub 2018/09/08. doi: 10.1136/bjophthalmol-2018-312356 30190366.

45. Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. European journal of biochemistry. 2000;267(16):4912–6. Epub 2000/08/10. doi: 10.1046/j.1432-1327.2000.01597.x 10931173.

46. Gherghel D, Griffiths HR, Hilton EJ, Cunliffe IA, Hosking SL. Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Investigative ophthalmology & visual science. 2005;46(3):877–83. Epub 2005/02/25. doi: 10.1167/iovs.04-0777 15728543.

47. Gherghel D, Mroczkowska S, Qin L. Reduction in blood glutathione levels occurs similarly in patients with primary-open angle or normal tension glaucoma. Investigative ophthalmology & visual science. 2013;54(5):3333–9. Epub 2013/04/20. doi: 10.1167/iovs.12-11256 23599328.

48. Aoyama K, Nakaki T. Impaired glutathione synthesis in neurodegeneration. International journal of molecular sciences. 2013;14(10):21021–44. Epub 2013/10/23. doi: 10.3390/ijms141021021 24145751; PubMed Central PMCID: PMC3821656.

49. Bakshi R, Zhang H, Logan R, Joshi I, Xu Y, Chen X, et al. Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release. Neurobiology of disease. 2015;82:574–9. Epub 2015/09/06. doi: 10.1016/j.nbd.2015.08.022 26341543; PubMed Central PMCID: PMC4641017.

50. Shoshani YZ, Harris A, Shoja MM, Rusia D, Siesky B, Arieli Y, et al. Endothelin and its suspected role in the pathogenesis and possible treatment of glaucoma. Current eye research. 2012;37(1):1–11. Epub 2011/10/28. doi: 10.3109/02713683.2011.622849 22029631.

51. Schmetterer L, Polak K. Role of nitric oxide in the control of ocular blood flow. Progress in retinal and eye research. 2001;20(6):823–47. Epub 2001/10/06. doi: 10.1016/s1350-9462(01)00014-3 11587919.

52. Prasanna G, Krishnamoorthy R, Clark AF, Wordinger RJ, Yorio T. Human optic nerve head astrocytes as a target for endothelin-1. Investigative ophthalmology & visual science. 2002;43(8):2704–13. Epub 2002/07/31. 12147606.

53. Zhang X, Cheng M, Chintala SK. Optic nerve ligation leads to astrocyte-associated matrix metalloproteinase-9 induction in the mouse retina. Neuroscience letters. 2004;356(2):140–4. Epub 2004/01/30. doi: 10.1016/j.neulet.2003.10.084 14746883.

54. Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Progress in retinal and eye research. 2000;19(3):297–321. Epub 2000/04/05. doi: 10.1016/s1350-9462(99)00017-8 10749379.

55. De Groef L, Van Hove I, Dekeyster E, Stalmans I, Moons L. MMPs in the neuroretina and optic nerve: modulators of glaucoma pathogenesis and repair? Investigative ophthalmology & visual science. 2014;55(3):1953–64. Epub 2014/04/01. doi: 10.1167/iovs.13-13630 24681977.

56. Grieshaber MC, Terhorst T, Flammer J. The pathogenesis of optic disc splinter haemorrhages: a new hypothesis. Acta ophthalmologica Scandinavica. 2006;84(1):62–8. Epub 2006/02/01. doi: 10.1111/j.1600-0420.2005.00590.x 16445441.

57. Omodaka K, Takahashi S, Matsumoto A, Maekawa S, Kikawa T, Himori N, et al. Clinical Factors Associated with Lamina Cribrosa Thickness in Patients with Glaucoma, as Measured with Swept Source Optical Coherence Tomography. PloS one. 2016;11(4):e0153707. Epub 2016/04/23. doi: 10.1371/journal.pone.0153707 27100404; PubMed Central PMCID: PMC4839731.

58. Taniguchi T, Shimazawa M, Sasaoka M, Shimazaki A, Hara H. Endothelin-1 impairs retrograde axonal transport and leads to axonal injury in rat optic nerve. Current neurovascular research. 2006;3(2):81–8. Epub 2006/05/25. doi: 10.2174/156720206776875867 16719791.

59. Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Archives of ophthalmology (Chicago, Ill: 1960). 1997;115(4):497–503. Epub 1997/04/01. doi: 10.1001/archopht.1997.01100150499009 9109759.

60. Luthra A, Gupta N, Kaufman PL, Weinreb RN, Yucel YH. Oxidative injury by peroxynitrite in neural and vascular tissue of the lateral geniculate nucleus in experimental glaucoma. Experimental eye research. 2005;80(1):43–9. Epub 2005/01/18. doi: 10.1016/j.exer.2004.08.016 15652525.

61. Mozaffarieh M, Flammer J. New insights in the pathogenesis and treatment of normal tension glaucoma. Current opinion in pharmacology. 2013;13(1):43–9. Epub 2012/10/25. doi: 10.1016/j.coph.2012.10.001 23092679.

62. Pingitore A, Lima GP, Mastorci F, Quinones A, Iervasi G, Vassalle C. Exercise and oxidative stress: potential effects of antioxidant dietary strategies in sports. Nutrition (Burbank, Los Angeles County, Calif). 2015;31(7–8):916–22. Epub 2015/06/11. doi: 10.1016/j.nut.2015.02.005 26059364.


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