Etanerecept ameliorate inflammatory responses and apoptosis induces by myocardial ischemia/reperfusion in male mice

[Open Access]           Full Text-PDF

American Journal of BioMedicine  Volume 2, Issue 6, pages 732-744, June 2014

Najah R. Hadi, Fadhil G. Al-Amran, Maitham G Yousif,  Saif M. Hassan


Ischemia/reperfusion of cardiac tissues may lead to a prominent damage of the cardiomyocyte through either necrosis or apoptosis. In this study, we investigated the effects of Etanercept in myocardial ischemia/reperfusion injury. Acute myocardial injury was induced by ligation of the left anterior descending coronary artery (LAD) for 30 minutes followed by 120 minutes reperfusion in white albino adult male. At the end of reperfusion, cardiac tissue TNF-α, IL-1β, IL-6, caspase-3 and Bcl-2, as well as plasma cardiac troponin I (cTn-I) were measured. It has been found that Etanercept treated group showed significant reduction in TNF-α, IL-1β, IL-6, caspase-3, Bcl-2 and cTn-I with respect to the control groups (P˂0.01). Histopathology study revealed that the treatment with Etanercept significantly improved cardiac injury as compared with control groups (P˂0.05). Further, the total severity scores showed 16.7 % of the group had no damage, while 50% had mild cardiac injury and only 33.3% with moderate cardiac injury in Etanercept treated group. We demonstrated that Etanercept reduces inflammatory reaction, cardiomyocyte apoptosis and myocardial damage induced by ischemia/reperfusion injury.

Keywords: Etanercept; Caspase-3; Ischemia/reperfusion; LAD; Myocardial injury


1. Zhang H, Park Y, Wu J, Chen Xp, Lee S, Yang J, Dellsperger KC, Zhang C. Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond). 2009;116(3):219-30. [PubMed]

2. Gottlieb RA. Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther 2011;16(3-4):233-8. [PubMed]

3. Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. The American journal of cardiology 2010;106(3):360-368. [PubMed]

4. Ha SJ, Kim W.  Mechanism of Ischemia and Reperfusion Injury to the Heart: From the Viewpoint of Nitric Oxide and Mitochondria. Chonnam Medical Journal 2010;46(3):129-139.

5. Souza DG, Coutinho SF, Silveira MR, Cara DC, Teixeira MM. Effects of a BLT receptor antagonist on local and remote reperfusion injuries after transient ischemia of the superior mesenteric artery in rats. European journal of pharmacology 2000;403(1):121-128. [PubMed]

6. Borutaite V. Brown GC. Mitochondria in apoptosis of ischemic heart. FEBS letters 2003;541(1):1-5. [PubMed]

7. Rathi SS, Xu YJ, Dhalla NS. Mechanism of cardioprotective action of TNF-α in the isolated rat heart. Experimental & Clinical Cardiology 2002; 7(2/3):146. [PubMed]

8. Balakumar P, Singh M. Anti-tumour necrosis factor-alpha therapy in heart failure: future directions. Basic Clin Pharmacol Toxicol. 2006; 99(6):391-7. [PubMed]

9. Feldmann M, Maini RN, TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nature medicine 2003;9(10):1245-1250. [PubMed]

10. Spencer-Green G, Etanercept (Enbrel): update on therapeutic use. Annals of the rheumatic diseases 2000; 59(suppl 1):i46-i49.

11. Wu Y, Yin X, Wijaya C, Huang MH, McConnell BK. Acute myocardial infarction in rats. Journal of visualized experiments: JoVE 2011;(48). [PubMed]

12. Liu A, Fang H, Yang Y, Sun J, Fan H, Liu S, Dirsch O, Dahmen U. The Fibrin-Derived Peptide Bβ15-42 Attenuates Liver Damage in a Rat Model of Liver Ischemia/Reperfusion Injury. Shock, 2013;39(4):397-403. [PubMed]

13. Kolk MV, Meyberg D, Deuse T, Tang-Quan KR, Robbins RC, Reichenspurner H, Schrepfer S. LAD-ligation: a murine model of myocardial infarction. J Vis Exp 2009;(32):1438. [PubMed]

14. Ding, J.-W., et al., Activated protein C protects myocardium via activation of anti-apoptotic pathways of survival in ischemia-reperfused rat heart. Journal of Korean medical science 2010; 25(11):1609-1615. [PubMed]

15. Wayman NS, Ellis BL,Thiemermann C, Simvastatin reduces infarct size in a model of acute myocardial ischemia and reperfusion in the rat. Medical Science Monitor, 2003; 9(5):BR155-BR159. [PubMed]

16. Zingarelli B,  Salzman AL, Szabó C. Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circulation Research 1998; 83(1):85-94.

17. Maekawa N, Wada H, Kanda T, Niwa T, Yamada Y, Saito K, Fujiwara H, Sekikawa K, Seishima M. Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J Am Coll Cardiol. 2002 ;39(7):1229-35. [PubMed]

18. Esposito E, Mazzon E, Muià C, Meli R, Sessa E, Cuzzocrea S. Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-α. Journal of leukocyte biology 2007;81(4):1032-1043. [PubMed]

19. Saini HK, Xu YJ, Zhang M, Liu PP, Kirshenbaum LA, Dhalla NS. Role of tumour necrosis factor-alpha and other cytokines in ischemia-reperfusion-induced injury in the heart. Exp Clin Cardiol. 2005;10(4):213-22. [PubMed]

20. Granado M, Fernández N, Monge L, Figueras JC, Carreño-Tarragona G, Amor S, García-Villalón AL. Effects of coronary ischemia-reperfusion in a rat model of early overnutrition. Role of Angiotensin receptors. PloS one, 2013. 8(2): p. e54984. [PubMed]

21. Zingarelli B, Salzman AL, Szabo C. Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 1998; 83(1):85-94. [PubMed]

22. Rohilla A, Rohilla S, Kushnoor A. Myocardial postconditioning: next step to cardioprotection. Arch Pharm Res. 2011;34(9):1409-15. [PubMed]

23. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. American Journal of Transplantation 2006; 6(4):652-658. [PubMed]

24. Kan H, Finkel MS. Inflammatory mediators and reversible myocardial dysfunction. Journal of cellular physiology 2003; 195(1): 1-11. [PubMed]

25. Xu Y, Arenas IA, Armstrong SJ, Plahta WC, Xu H, Davidge ST. Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-α. Cardiovascular research 2006;69(4):836-844. [PubMed]

26. Choi DE, Jeong JY, Lim BJ, Na KR, Shin YT, Lee KW. Pretreatment with the tumor necrosis factor-a blocker etanercept attenuated ischemia-reperfusion renal injury. Transplant Proc 2009;41:3590-3596. [PubMed]

27. Gu Q, Yang XP, Bonde P, DiPaula A, Fox-Talbot K, Becker LC. Inhibition of TNF-[alpha] Reduces Myocardial Injury and Proinflammatory Pathways Following Ischemia-Reperfusion in the Dog. Journal of cardiovascular pharmacology 2006; 48(6): 320-328. [PubMed]

28. Chen Y, et al. Effect of Etanerceptan on inflammatory cytokines in rats with ischemia-reperfusion injury. Journal of Hainan Medical University 2011;10: 001.

29. Genovese T, Mazzon E, Crisafulli C, Di Paola R, Muià C, Bramanti P, Cuzzocrea S. Immunomodulatory effects of etanercept in an experimental model of spinal cord injury. J Pharmacol Exp Ther 2006;316(3):1006-16. [PubMed]

30. Di Paola R1, Mazzon E, Muià C, Crisafulli C, Terrana D, Greco S, Britti D, Santori D, Oteri G, et al. Effects of etanercept, a tumour necrosis factor-alpha antagonist, in an experimental model of periodontitis in rats. Br J Pharmacol. 2007;150(3):286-97. [PubMed]

31. White LE, Santora RJ, Cui Y, Moore FA, Hassoun HT. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury. Am J Physiol Lung Cell Mol Physiol. 2012; 303(5):L449-59. [PubMed]

32. Gao C, Liu Y, Yang Q, Liu J, Liu P, Wang H, Guo Y, et al. Upregulation of adiponectin is involved in the cardioprotective effect of etanercept in myocardial ischemia/reperfusion (MI/R) mice. Heart 2011;2011;97:A30. [Abstract/Full-Text]

33. Chiang CH. Effects of anti-tumor necrosis factor-alpha and anti-intercellular adhesion molecule-1 antibodies on ischemia/reperfusion lung injury. Chin J Physiol. 2006;49(5):266-74. [PubMed]

Print Friendly, PDF & Email