Thalidomide attenuates the hyporesponsiveness of isolated atria to chronotropic stimulation in BDL rats: The involvement of TNF-α, IL-6 inhibition, and SOCS1 activation

Document Type : Original Article

Authors

1 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Laboratory of Sciences, Faculty of Paramedical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

3 Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Pathology, School of Medicine, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

5 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Cirrhotic cardiomyopathy is a complication of uncured cirrhosis which is associated with hyporesponsiveness of the heart to sympathetic stimulation. The enhancement of portal pressure, nitric oxide (NO) level, pro-inflammatory mediators and down-regulation of Suppressor of Cytokine Signaling 1 (SOCS1) are involved in this situations. The present study seeks to examine the beneficial effect of thalidomide on cirrhotic cardiomyopathy.
Materials and Methods: The male rats were grouped as: Sham/saline, Sham/Thalidomide, Bile Duct Ligation (BDL)/saline and BDL/Thalidomide. BDL model of cirrhosis was used. In the treatment groups, thalidomide (200 mg/kg/day) was administrated by intragastrial gavage for 28 consecutive days, the chronotropic response was assessed in isolated atria by isoproterenol stimulation. Serum levels of NO, IL-6 and TNF-α hepatic level were evaluated. The intrasplenic pulp pressure (ISPP) as the portal pressure and histopathologic assessment were assessed. Real time RT-PCR was used for the evaluation of SOCS1 gene expression.
Results: Our results showed that thalidomide administration could significantly increase the atrial chronotropic response in BDL animals. The increased level of portal pressure decreased by thalidomide in BDL animals. Thalidomide could ameliorate the histopathological conditions of BDL rats. Furthermore, the chronic treatment by this drug diminished the elevated levels of NO, TNF-α and IL-6 in BDL animals. On the other hand, hepatic SOCS1 expression was up-regulated by thalidomide treatment in this group.
Conclusion: Thalidomide improves the chronotropic hyporesponsiveness of isolated atria in BDL. This effect is probably mediated by the inhibiting NO, TNF-α and IL-6 production, reducing portal pressure and increasing the expression of SOCS1.

Keywords

Main Subjects


1. Fernandez-Martinez E, Perez-Alvarez V, Tsutsumi V, Shibayama M, Muriel P. Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat. Exp Toxicol Pathol 2006;58:49-58.
2. Bernardi M. Cirrhotic cardiomyopathy. Clin Liver Dis 2013;2:99-101.
3. Møller S, Henriksen J H. Cirrhotic cardiomyopathy. J Hepatol 2010;53:179-190.
4. Choi I, Kang H S, Yang Y, Pyun K H. IL-6 induces hepatic inflammation and collagen synthesis in vivo. Clin Exp Immunol 1994;95:530-535.
5. Sudo K, Yamada Y, Moriwaki H, Saito K, Seishima M. Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice. Cytokine 2005;29:236-244.
6. Hu L S, George J, Wang J H. Current concepts on the role of nitric oxide in portal hypertension. World J Gastroenterol 2013;19:1707-1717.
7. Kilbourn R G, Gross S S, Jubran A, Adams J, Griffith O W, Levi R, et al. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 1990;87:3629-3632.
8. Alexander W S, Starr R, Fenner J E, Scott C L, Handman E, Sprigg N S, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999;98:597-608.
9. Hong F, Jaruga B, Kim W H, Radaeva S, El-Assal O N, Tian Z, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest 2002;110:1503-1513.
10. Naka T, Tsutsui H, Fujimoto M, Kawazoe Y, Kohzaki H, Morita Y, et al. SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo. Immunity 2001;14:535-545.
11. Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y, et al. SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. J Exp Med 2004;199:1701-1707.
12. Brunton L, Chabner B A, Knollman B. IGoodman & Gilman’s the Pharmacological Basis of Therapeutics. 12 th Edition; 2011.
13. Shanbhag PS, Viswanath V, Torsekar R. Thalidomide: current status. Indian J Dermatol Venereol Leprol 2006;72:75.
14. Chong L-W, Hsu Y-C, Chiu Y-T, Yang K-C, Huang Y-T. Anti-fibrotic effects of thalidomide on hepatic stellate cells and dimethylnitrosamine-intoxicated rats. J Biomed Sc 2006;13:403-418.
15. Yang Y Y, Lee K C, Huang Y T, Lee F Y, Chau G Y, Loong C C, et al. Inhibition of hepatic tumour necrosis factor‐α attenuates the anandamide‐induced vasoconstrictive response in cirrhotic rat livers. Liver Int 2009;29:678-685.
16. Bashiri H, Hosseini-Chegeni H, Alsadat Sharifi K, Sahebgharani M, Salari A-A. Activation of TRPV1 receptors affects memory function and hippocampal TRPV1 and CREB mRNA expression in a rat model of biliary cirrhosis. Neurol Res 2018;40:938-947.
17. Ebrahimkhani M R, Sadeghipour H, Dehghani M, Kiani S, Payabvash S, Riazi K, et al. Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis. Life Sci 2005;76:2497-2512.
18. Ackerman Z, Karmeli F, Amir G, Rachmilewitz D. Renal vasoactive mediator generation in portal hypertensive and bile duct ligated rats. J Hepatol 1996;24:478-486.
19. Raoofian R, Noori-Daloii M R, Saee-Rad S, Modarresi M H, Ghaffari S H, Mojarrad M, et al. Differential expression of human homeodomain TGIFLX in brain tumor cell lines. Acta Med Iran 2013;834-841.
20. Bagnyukova T V, Tryndyak V P, Muskhelishvili L, Ross S A, Beland F A, Pogribny I P. Epigenetic down-regulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats. Cell Cycle 2008;7:3202-3210.
21. Lopez‐Talavera J C, Cadelina G, Olchowski J, Merrill W, Groszmann R J. Thalidomide inhibits tumor necrosis factor α, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal‐hypertensive rats. Hepatology 1996;23:1616-1621.
22. Franks M E, Macpherson G R, Figg W D. Thalidomide. The Lancet 2004;363:1802-1811.
23. Napoli J, Prentice D, Niinami C, Bishop G A, Desmond P, McCaughan G W. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor β in a bile duct ligated rat model of cirrhosis. Hepatology 1997;26:624-633.
24. Wnendt S, Finkam M, Winter W, Ossig J, Raabe G, Zwingenberger K. Enantioselective inhibition of TNF‐α release by thalidomide and thalidomide‐analogues. Chirality 1996;8:390-396.
25. Das S, Santra A, Lahiri S, Mazumder D G. Implications of oxidative stress and hepatic cytokine (TNF-α and IL-6) response in the pathogenesis of hepatic collagenesis in chronic arsenic toxicity. Toxicol Appl Pharmacol 2005;204:18-26.
26. Reeves H L, Friedman S L. Activation of hepatic stellate cells—a key issue in liver fibrosis. Front Biosci 2002;7:808-826.
27. Mani A R, Ippolito S, Ollosson R, Moore K P. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 2006;43:847-856.
28. Wiest R, Groszmann R J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002;35:478-491.
29. Yokoyama Y, Xu H, Kresge N, Keller S, Sarmadi A H, Baveja R, et al. Role of thromboxane A2 in early BDL-induced portal hypertension. Am J Physiol Gastrointest Liver Physiol 2003;284:G453-G460.
30. Torisu T, Nakaya M, Watanabe S, Hashimoto M, Yoshida H, Chinen T, et al. Suppressor of cytokine signaling 1 protects mice against concanavalin A–induced hepatitis by inhibiting apoptosis. Hepatology 2008;47:1644-1654.
31. Ammerpohl O, Pratschke J, Schafmayer C, Haake A, Faber W, von Kampen O, et al. Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma. Liver Int 2012;130:1319-1328.
32. Okochi O, Hibi K, Sakai M, Inoue S, Takeda S, Kaneko T, et al. Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Clin Cancer Res 2003;9:5295-5298.
33. Yeh T-S, Ho Y-P, Huang S-F, Yeh J-N, Jan Y-Y, Chen M-F. Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats. J Hepatol 2004;41:606-612.
34. Görgün G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010;116:3227-3237.
35. Jazaeri F, Tavangar S M, Ghazi‐Khansari M, Khorramizadeh M R, Mani A R, Dehpour A R. Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats. Liver Int 2013;33:368-374.