Study of superoxide- and NO-dependent protective mechanisms of N-acetylcysteine and losartan in ratʼs aorta and liver under streptozoticin-induced type 1 diabetes mellitus

Authors

DOI:

https://doi.org/10.15587/2519-4852.2017.119490

Keywords:

streptozoticin, superoxide, aorta, liver, rats, N-acetylcysteine, losartan

Abstract

Aim. The aim of the research was to investigate superoxide- (SR) and NO-dependent mechanisms of action of N-acetylcysteine (NAC) and losartan (LOS) in aorta and liver of rats with type 1 diabetes mellitus (DMI).

Methods. Diabetic rats were treated with NAC (1.5g/kg), LOS (20mg/kg) or combination (NAC+LOS) for 4 weeks.

Results. The rate of SR generation by mitochondria of aorta in untreated diabetic animals was significantly higher than in control, while the level of NO was decreased. Production of SR and NO in the liver of diabetic rats were dramatically increased. The marker of oxidatively damaged DNA, 8-oxoG, was raised in urine of diabetic rats. All of pharmacological schemes showed significant decrease the rate of SR generation by mitochondria of aorta and liver; NO level was lowered in the liver tissue compared to DMI. Only NAC significantly restored NO level in aorta of diabetic rats. Intervention with NAC / LOS or NAC+LOS increased the level of 8-oxoG in compare to DM1.

Conclusion. In conclusion, treatment with NAC and LOS or combination is associated with protection of aorta and liver cells in diabetic animals against toxic action of SR, preventing mitochondrial dysfunction and further DNA damage, which point out the cardioprotective effects and overall metabolic improvement

Author Biographies

Inna Sytnyk, Bogomolets National Medical University T. Shevchenka blvd., 13, Kyiv, Ukraine, 01601

Postgraduate student

Department of Clinical Pharmacology and Clinical Pharmacy

Anatoliy Burlaka, R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of National Academy of Sciences of Ukraine Vasylkivska str., 45, Kyiv, Ukraine, 03022

Doctor of Biological Sciences, Senior Researcher

Laboratoryof metastatic microenvironment problems

Anastasia Vovk, R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of National Academy of Sciences of Ukraine Vasylkivska str., 45, Kyiv, Ukraine, 03022

PhD, Senior Engineer

Laboratoryof metastatic microenvironment problems 

Mykola Khaitovych, Bogomolets National Medical University T. Shevchenka blvd., 13, Kyiv, Ukraine, 01601

MD, Professor, Head of Department

Department of Clinical Pharmacology and Clinical Pharmacy

References

  1. Global report on diabetes (2016). Geneva: World Health Organization. Available at: http://www.who.int/diabetes/global-report/en/
  2. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants (2016). The Lancet, 387 (10027), 1513–1530. doi: 10.1016/s0140-6736(16)00618-8
  3. Giacco, F., Brownlee, M. (2010). Oxidative Stress and Diabetic Complications. Circulation Research, 107 (9), 1058–1070. doi: 10.1161/circresaha.110.223545
  4. Watanabe, K., Thandavarayan, R. A., Harima, M., Sari, F. R., Gurusamy, N., Veeraveedu, P. T. et. al. (2010). Role of Differential Signaling Pathways and Oxidative Stress in Diabetic Cardiomyopathy. Current Cardiology Reviews, 6 (4), 280–290. doi: 10.2174/157340310793566145
  5. Ansley, D. M., Wang, B. (2012). Oxidative stress and myocardial injury in the diabetic heart. The Journal of Pathology, 229 (2), 232–241. doi: 10.1002/path.4113
  6. Guo, R., Liu, B., Zhou, S., Zhang, B., Xu, Y. (2013). The Protective Effect of Fasudil on the Structure and Function of Cardiac Mitochondria from Rats with Type 2 Diabetes Induced by Streptozotocin with a High-Fat Diet Is Mediated by the Attenuation of Oxidative Stress. BioMed Research International, 2013, 1–9. doi: 10.1155/2013/430791
  7. Fulbright, J. M., Egas-Bejar, D. E., Huh, W. W., Chandra, J. (2015). Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy. Cancer Chemotherapy and Pharmacology, 76 (6), 1297–1307. doi: 10.1007/s00280-015-2879-4
  8. Wang, J., Wang, H., Hao, P., Xue, L., Wei, S., Zhang, Y., Chen, Y. (2011). Inhibition of aldehyde dehydrogenase 2 by oxidative stress is associated with cardiac dysfunction in diabetic rats. Molecular Medicine, 17 (3-4), 172–179. doi: 10.2119/molmed.2010.00114
  9. Dludla, P. V., Nkambule, B. B., Dias, S. C., Johnson, R. (2017). Cardioprotective potential of N-acetyl cysteine against hyperglycaemia-induced oxidative damage: a protocol for a systematic review. Systematic Reviews, 6 (1), 1–5. doi: 10.1186/s13643-017-0493-8
  10. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD (2013). European Heart Journal, 34 (39), 3035–3087. doi: 10.1093/eurheartj/eht108
  11. Axelsson, A., Iversen, K., Vejlstrup, N., Ho, C., Norsk, J., Langhoff, L. et. al. (2015). Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. The Lancet Diabetes & Endocrinology, 3 (2), 123–131. doi: 10.1016/s2213-8587(14)70241-4
  12. Ochiai, M., Brancalhao, E., Puig, R., Vieira, K., Cardoso, J., Oliveira-Jr, M., Barretto, A. (2014). Short-term add-on therapy with angiotensin receptor blocker for end-stage inotrope-dependent heart failure patients: B-type natriuretic peptide reduction in a randomized clinical trial. Clinics, 69 (5), 308–313. doi: 10.6061/clinics/2014(05)02
  13. Council Directive 2010/63/EU of 22 September 2010 on the protection of animals used for scientific purposes (2010). Official Journal of the European Communities, 276, 33–79.
  14. Brosius, F. (Ed.) (2003). Low-Dose Streptozotocin Induction Protocol (Mouse). The University of Michigan Medical Center, 3.
  15. Burlaka, A. P., Sidorik, E. P. (2006). Radical forms of oxygen and nitric oxide in tumourogenesis. Kyiv Naukova Dumka, 227.
  16. Burlaka, A. P., Ganusevich, I. І., Golotiuk, V. V., Vovk, A. V., Lukin, S. М. (2016). Superoxide- and NO-dependent mechanisms of antitumor and antimetastatic effect of L-arginine hydrochloride and coenzyme Q10. Experimental Oncology, 38 (1), 31–35.
  17. Liu, Q., Wang, S., Cai, L. (2014). Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage. Journal of Diabetes Investigation, 5 (6), 623–634. doi: 10.1111/jdi.12250
  18. Raza, H., Prabu, S. K., John, A., Avadhani, N. G. (2011). Impaired Mitochondrial Respiratory Functions and Oxidative Stress in Streptozotocin-Induced Diabetic Rats. International Journal of Molecular Sciences, 12 (12), 3133–3147. doi: 10.3390/ijms12053133
  19. Wang, S., Wang, C., Yan, F., Wang, T., He, Y., Li, H. et. al. (2017). N-Acetylcysteine Attenuates Diabetic Myocardial Ischemia Reperfusion Injury through Inhibiting Excessive Autophagy. Mediators of Inflammation, 2017, 1–10. doi: 10.1155/2017/9257291
  20. Sivitz, W. I., Yorek, M. A. (2010). Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities. Antioxidants & Redox Signaling, 12 (4), 537–577. doi: 10.1089/ars.2009.2531
  21. Liu, C., Lu, X.-Z., Shen, M.-Z., Xing, C.-Y., Ma, J., Duan, Y.-Y., Yuan, L.-J. (2015). N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition. BMC Cardiovascular Disorders, 15 (1), 84. doi: 10.1186/s12872-015-0076-3
  22. Su, W., Zhang, Y., Zhang, Q., Xu, J., Zhan, L., Zhu, Q. et. al. (2016). N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats. Cardiovascular Diabetology, 15 (1), 1–46. doi: 10.1186/s12933-016-0460-z
  23. Sleem, M., Taye, A., El-Moselhy, M. A., Mangoura, S. A. (2014). Combination therapy with losartan and l-carnitine protects against endothelial dysfunction of streptozotocin-induced diabetic rats. European Journal of Pharmacology, 744, 10–17. doi: 10.1016/j.ejphar.2014.09.032
  24. Dianat, M., Hamzavi, G. R., Badavi, M., Samarbafzadeh, A. (2014). Effects of Losartan and Vanillic Acid Co-Administration on Ischemia-Reperfusion-Induced Oxidative Stress in Isolated Rat Heart. Iranian Red Crescent Medical Journal, 16 (7). doi: 10.5812/ircmj.16664
  25. Kamper, M., Tsimpoukidi, O., Chatzigeorgiou, A., Lymberi, M., Kamper, E. F. (2010). The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats. Translational Research, 156 (1), 26–36. doi: 10.1016/j.trsl.2010.05.004
  26. Sytnyk, I. M., Khaitovych, M. V., Chernovol, P. A. (2016). Antioxidant activity of angiotensin II inhibitors and metabotropic cardioprotectors under the conditions in vitro and in silico. Pharmacology and Drug Toxicology, 48 (2), 80–85.
  27. Wang, T., Qiao, S., Lei, S., Liu, Y., Ng, K. F. J., Xu, A. et. al. (2011). N-Acetylcysteine and Allopurinol Synergistically Enhance Cardiac Adiponectin Content and Reduce Myocardial Reperfusion Injury in Diabetic Rats. PLoS ONE, 6 (8), e23967. doi: 10.1371/journal.pone.0023967
  28. Mao, X., Wang, T., Liu, Y., Irwin, M. G., Ou, J., Liao, X. et. al. (2013). N-Acetylcysteine and Allopurinol Confer Synergy in Attenuating Myocardial Ischemia Injury via Restoring HIF-1α/HO-1 Signaling in Diabetic Rats. PLoS ONE, 8 (7), e68949. doi: 10.1371/journal.pone.0068949
  29. Kumar, S., Prasad, S., Sitasawad, S. L. (2013). Multiple Antioxidants Improve Cardiac Complications and Inhibit Cardiac Cell Death in Streptozotocin-Induced Diabetic Rats. PLoS ONE, 8 (7), e67009. doi: 10.1371/journal.pone.0067009
  30. Falach-Malik, A., Rozenfeld, H., Chetboun, M. et. al. (2016). N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice. American Journal of Translational Research, 9 (8), 3744–3756.
  31. Chughlay, M. F., Kramer, N., Spearman, C. W., Werfalli, M., Cohen, K. (2016). N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review. British Journal of Clinical Pharmacology, 81 (6), 1021–1029. doi: 10.1111/bcp.12880
  32. Li, Y.-S., Song, M.-F., Kasai, H., Kawai, K. (2013). 8-Hydroxyguanine in Urine and Serum as an Oxidative Stress Marker: Effects of Diabetes and Aging. Journal of UOEH, 35 (2), 119–127. doi: 10.7888/juoeh.35.119
  33. Kumar, P., Swain, M. M., Pal, A. (2016). Hyperglycemia-induced inflammation caused down-regulation of 8-oxoG-DNA glycosylase levels in murine macrophages is mediated by oxidative-nitrosative stress-dependent pathways. The International Journal of Biochemistry & Cell Biology, 73, 82–98. doi: 10.1016/j.biocel.2016.02.006
  34. Simone, S., Gorin, Y., Velagapudi, C., Abboud, H. E., Habib, S. L. (2008). Mechanism of Oxidative DNA Damage in Diabetes. Diabetes, 57 (10), 2626–2636. doi: 10.2337/db07-1579
  35. Kumar, P., Rao, G. N., Pal, B. B., Pal, A. (2014). Hyperglycemia-induced oxidative stress induces apoptosis by inhibiting PI3-kinase/Akt and ERK1/2 MAPK mediated signaling pathway causing downregulation of 8-oxoG-DNA glycosylase levels in glial cells. The International Journal of Biochemistry & Cell Biology, 53, 302–319. doi: 10.1016/j.biocel.2014.05.038
  36. Lodovici, M., Bigagli, E., Tarantini, F., Di Serio, C., Raimondi, L. (2015). Losartan reduces oxidative damage to renal DNA and conserves plasma antioxidant capacity in diabetic rats. Experimental Biology and Medicine, 240 (11), 1500–1504. doi: 10.1177/1535370215570826
  37. Cooke, M. S., Henderson, P. T., Evans, M. D. (2009). Oxidative Stress-Induced Carcinogenesis and Its Prevention Guest Editor: Shinya Toyokuni Sources of Extracellular, Oxidatively-Modified DNA Lesions: Implications for Their Measurement in Urine. Journal of Clinical Biochemistry and Nutrition, 45 (3), 255–270. doi: 10.3164/jcbn.sr09-41

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2017-12-31

How to Cite

Sytnyk, I., Burlaka, A., Vovk, A., & Khaitovych, M. (2017). Study of superoxide- and NO-dependent protective mechanisms of N-acetylcysteine and losartan in ratʼs aorta and liver under streptozoticin-induced type 1 diabetes mellitus. ScienceRise: Pharmaceutical Science, (6 (10), 25–31. https://doi.org/10.15587/2519-4852.2017.119490

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Pharmaceutical Science