Anti-Inflammatory and Anti-Fibrotic Effects of Ursodeoxycholic Acid in Streptozocin-Induced Diabetic Rats

INTRODUCTION: Diabetic cardiomyopathy is a consequence of free fatty acid oxidation, dysfunction in mitochondria, oxidative stress and diffuse myocardial fibrosis. We aimed to investigate the anti-inflammatory and anti-fibrotic effect of ursodeoxycholic acid in streptozocin-induced diabetic rat model. METHODS: Male Sprague Dawley albino mature rats were divided into 3 groups: Group 1 (n=10) control group; group 2 (n=10) diabetic rats group; group 3 (n=10): diabetic rats treated with ursodeoxycholic acid group. Diabetes mellitus model was established after injection of intraperitoneal streptozocin. Histopathological and biochemical examinations were done after 4 weeks from heart tissues. Immunoexpression levels of fibronectin and TGF-β were obtained. Malondialdehyde levels were used to determine lipid peroxidation and pentraxin-3 levels were used to determine inflammation. Myocardial damage was also determined with troponin-T and pro-BNP levels. RESULTS: Cardiac muscle cell thickness (hypertrophy), TGFβ levels, fibronectin immunoexpression malondialdehyde, pentraxin-3, troponin-T and pro-BNP levels were increased significantly in groups 2 and 3 when compared to control group. Administration of ursodeoxycholic acid significantly reduced inflammation and fibrosis in group 3 compared to group 2. DISCUSSION AND CONCLUSION: In this experimental study, we demonstrated the anti-inflammatory and anti-fibrotic effects of UDCA on diabetic rats and it can be a good drug candidate for DM patients

Ursodeoksikolik Asidin Streptozosin ile Diyabet Oluşturulmuş Farelerde Kardiyomyopatideki Antiinflamatuar ve Anti-Fibrotik Etkileri

GİRİŞ ve AMAÇ: Diabetik kardiyomyopati, serbest yağ aside oksidasyonu, mitokondrial disfonksiyon, oksidatif stress ve diffuz miyokardiyal fibrozise seconder olarak gelişmektedir. Bu deneysel çalışmada, ursodeoksikolik asidin streptozocin ile tetiklenmiş diabetik fare modelinde anti-inflamatuar ve antifibrotik etkilerini araştırmayı hedefledik. YÖNTEM ve GEREÇLER: Sprague Dawley albino 30 erişkin fare 3 gruba ayrıldı: Grup-1: kontrol grubu (n=10); Grup-2 (n=10) diabetik fare grubu; Grup-3 (n=10) ursodeoksikolik asit verilen diabetic fare grubu. Histopatolojik ve biyokimyasal değerlendirmeler 4 hafta sonra kalp dokusundan yapıldı. Fibronektin ve TGF-β immunekspresyonu, TGF-β, malondialdehid, pentraxin-3, pro-BNP ve troponin-T düzeyleri ölçüldü. BULGULAR: Fibronektin immunekspresyonu, TGF-β, pentraxin-3, troponin-t, pro-BNP ve malondialdehid düzeyleri diabetik farelerde control grubuna göre anlamlı olarak artmış saptandı. Ursodeoksikolik asidin inflamasyon belirteçlerini ve fibroz düzeyini anlamlı olarak azalttığı izlendi TARTIŞMA ve SONUÇ: Bu deneysel çalışmada, ursodeoksikolik asidin diabetik farelerde anti-inflammatuar ve anti-fibrotik etkilerini gösterdik. Diabetik hastalarda ursodeoksikolik asidin ilaç olarak kullanımı klinik olarak fayda gösterebilir.

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1. International Diabetes Federation. Global Burden: Prevalence and Projections, 2015 and 2040. International Diabetes Federation; 2017. http://www.diabetesatlas.org/across-the-globe.html

2. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care 2004; 27: 1879–84.

3. Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 2008; 121: 748-57.

4. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardio¬vasc Res 2011; 92: 10-8.

5. Aragno M, Mastrocola R, Medana C, Catalano MG, Vercellinatto I, Danni O, et al. Oxidative stressdependent impairment of cardiac-specific tran¬scription factors in experimental diabetes. Endocrinology 2006; 147: 5967-74.

6. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014; 57: 660–71.

7. Makino I, Tanaka H. From a choleretic to an immunomodulator: historical review of ursodeoxycholic acid as a medicament. Journal of gastroenterology and hepatology 1998; 13: 659–64.

8. Rodrigues CM, Fan G, Wong PY, Kren BT and Steer CJ. Ursodeoxycholic acid may inhibit deoxycholic acidinduced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med 1998; 4: 165- 78.

9. Lukivskaya O, Patsenker E and Buko VU. Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: link with oxidative stress. Life Sci 2007; 80: 2397-402.

10. Mahmoud AAA, Elshazly SM. Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats. PLoS ONE 2014; 9: e106993.

11. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopa¬thy: pathophysiology and clinical features. Heart Fail Rev 2013; 18: 149-66.

12. Lee W, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med 2017; 32: 404-21.

13. Tschope C, Walther T, Escher F, Spillmann F, Du J, Altman C, et al. Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J. 2005; 19: 2057–9.

14. Westermann D, van Linthout S, Dhayat S, Dhayat N, Escher F, Bücker-Gartner C, et al. Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes. 2007; 56: 1834–41.

15. Pathil A, Warth A, Chamulitrat W, Stremmel W. Comparison of different bile acid-phospholipid conjugates in acute hepatitis. Eur J Clin Invest. 2012; 42: 130-8.

16. Pathil A, Mueller J, Warth A, Chamulitrat W, Stremmel W. Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease. Hepatology 2012; 55: 1369-78.

17. Chen K, Mehta JL, Li D, Joseph L, Joseph J. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II. Circ Res 2004; 95: 1167–73.

18. Pathil A, Mueller J, Ludwig JM, Wang J, Warth A, Chamulitrat W, et al. Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGFbeta1/Smad2/3 signalling. Br J Pharmacol. 2014; 171: 5113-26.

19. Ko J, Mills T, Huang J, Chen NY, Mertens TCJ, Collum SD, et al. Transforming growth factor beta 1 alters the 3’UTR of mRNA to promote lung fibrosis. J Biol Chem. 2019; 294: 15781-94.

20. Galsgaard J, Persson F, Hansen TW, Jorsal A, Tarnow L, Parving HH, et al. Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy. Kidney Int 2017; 92: 1242-8.

21. Huelsmann M, Neuhold S, Strunk G, Moertl D, Berger R, Prager R, et al. NT-proBNP has a high negative predictive value to rule-out short-term cardiovascular events in patients with diabetes mellitus. Eur Heart J 2008; 29: 2259-64.

22. Jay D, Hitomi H, Griendling KK. Oxidative stress and diabetic cardivascular complications. Free Radic Biol Med. 2006; 40: 183-92.

23. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010; 107: 1058-70.

24. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardio¬vasc Res 2011; 92: 10-8.

25. Kanter M, Akpolat M, Aktas C. Protective effects of the volatile oil of Nigella sativa seedsonβcell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study. J MolHist 2009; 40: 379–85.

26. Cordis GA, Das DK, Riedel W. Highperformance liquid chromatographic peak identification of 2,4-dinitrophenylhydrazine derivatives of lipid peroxidation aldehydes by photodiode array detection. J Chromatogr A 1998; 798: 117-23.

27. Ljubuncic P, Tanne Z, Bomzon A. Ursodeoxycholic acid suppresses extent of lipid peroxidation in diseased liver in experimental cholestatic liver disease. Dig Dis Sci 2009; 45: 1921– 8.

28. Gorelik J, Shevchuk AI, Diakonov I, de Swiet M, Lab M, Korchev Y, et al. Dexamethasone and ursodeoxycholic acid protect against the arrhythmogenic effect of taurocholate in an in vitro study or rat cardiomyocytes. BJOG Int J Obstet Gynaecol 2003; 110: 424-9.

29. Hanafi NI, Mohamed AS, Md Noor J, Abdul Hamid Hasani N, Siran T, Osman NJ, et al. Ursodeoxycholic acid upregulates ERK and Akt in the protection of cardiomyoctes against hypoxia. Genet Mol Res GMR 2016; 15.

30. Bahrle S, Szabo G, Stiehl A, Theilmann L, Tj D, Zimmermann R, et al. Adjuvant treatment with ursodeoxycholic acid may reduce the incidence of acute cardiac allograft rejection. J Heart Lung Transplant 1998; 17: 592-8.

31. von Haehling S, Schefold JC, Jankowska EA, Springer J, Vazir A, Kalra PR, et al. Ursodeoxycholic acid in patients with chronic heart failure: a double blind, randomized, placebo-controlled crossover trial. J Am Coll Cardiol 2012; 59: 585-92.
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  • ISSN: 2147-0758
  • Başlangıç: 2012
  • Yayıncı: -
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