Protective effect of tacrolimus on myocardial ischemia/reperfusion injury in rats Tacrolimus in reperfusion Takrolimusun sıçanlarda miyokardiyal iskemi / reperfüzyon hasarı üzerindeki koruyucu etkisi Reperfüzyonda takrolimus

Abstract

Aim: Acute myocardial infarction is a major cause of morbidity and mortality worldwide. Although thrombolytic therapy and primary percutaneous coronary intervention are the therapeutic approaches to reduce the myocardial ischemic injury and limit the infarct size by providing reperfusion, process can itself induce cardiomyocyte death known as myocardial reperfusion injury. In addition to effects on immunsuppression for organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia/reperfusion (I/R) injury. In this study, we aimed to evaluate the effects of tacrolimus on myocardial I/R injury in rats. Material and Methods: Adult male Wistar albino rats (n=18; mean weight, 252±20 g; age, 46-54 days) were included to this study. Rats were randomly assigned into three groups: Group 1 (sham, n=4), Group 2 (I/R+saline, control, n=7), Group 3 (tacrolimus+I/R, n=7). Tacrolimus (0.1 mg/kg) was administered as an intravenous infusion in the first 15 min of reperfusion after 45 min ischemia period. Results: Although there were no change in area at risk, infarct size was markedly reduced in tacrolimus group when compared to control group (p<0.05). Histopathological parameters (myofibrillar edema, myocytolysis, focal hemorrhage and polymorphonuclear leukocyte infiltration) were markedly increased in I/R control group, and significantly reduced by tacrolimus treatment (p<0.05). However, there were no marked changes in biochemical analysis. Conclusion: This study demonstrated that tacrolimus showed cardioprotective effects in myocardial I/R injury in rats.

Keywords

• tacrolimus
• occlusion
• infarct size
• myocardial

Takrolimusun sıçanlarda miyokardiyal iskemi / reperfüzyon hasarı üzerindeki koruyucu etkisi

Abstract

Amaç: Akut miyokard enfarktüsü, dünya çapında önemli bir morbidite ve mortalite nedenidir. Trombolitik tedavi ve birincil perkütan koroner müdahale, miyokardiyal iskemik hasarı azaltmak ve reperfüzyon sağlayarak enfarktüs boyutunu sınırlamak için terapötik yaklaşımlar olsa da, sürecin kendisi miyokardiyal reperfüzyon hasarı olarak bilinen kardiyomiyosit ölümüne neden olabilir. Organ transplantasyonu için immün baskılama üzerindeki etkilerine ek olarak, takrolimus, iskemi / reperfüzyon (İ / R) hasarında iyileşme ile sonuçlanan çeşitli etkilere sahiptir. Bu çalışmada, takrolimusun sıçanlarda miyokardiyal İ / R hasarı üzerindeki etkilerini değerlendirmeyi amaçladık. Gereç ve Yöntemler: Erişkin erkek Wistar albino sıçanlar (n = 18; ortalama ağırlık, 252 ± 20 g; yaş, 46-54 gün) bu çalışmaya dahil edildi. Sıçanlar rastgele üç gruba ayrıldı: Grup 1 (şam, n = 4), Grup 2 (İ / R + salin, kontrol, n = 7), Grup 3 (takrolimus + İ / R, n = 7). Takrolimus (0,1 mg / kg) 45 dakikalık iskemi süresinden sonra reperfüzyonun ilk 15 dakikasında intravenöz infüzyon olarak uygulandı. Bulgular: Risk altındaki alanda değişiklik olmamasına rağmen, kontrol grubuna göre takrolimus grubunda infarkt boyutu belirgin şekilde azaldı (p <0,05). Histopatolojik parametreler (miyofibriler ödem, miyositoliz, fokal kanama ve polimorfonükleer lökosit infiltrasyonu) İ / R kontrol grubunda belirgin şekilde artmış ve takrolimus tedavisi ile önemli ölçüde azalmıştır (p <0,05). Bununla birlikte, biyokimyasal analizde belirgin bir değişiklik olmadı. Sonuçlar: Bu çalışma, takrolimusun sıçanlarda miyokardiyal İ / R hasarında kardiyoprotektif etkilere sahip olduğunu göstermiştir.

Keywords

• takrolimus
• oklüzyon
• reperfüzyon
• infarkt boyutu

References

1. 1) Li X, Bilali A, Qiao R, Paerhati T, Yang Y. Association of the PPAR-gamma/PI3K/Akt pathway with the cardioprotective effects of tacrolimus in myocardial ischemic/reperfusion injury. Molec Med Rep 2018; 17: 6759-67.
2. 2) Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: Targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 2004; 61: 448-60.
3. 3) Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121-35.
4. 4) Kim HC, Hwang EA, Han SY, Park SB, Kim HT, Cho WH. Primary immunsuppression with tacrolimus in kidney transpalntation: Three-year follow-up in a single center. Transplant Proc 2004; 36: 2082-83.
5. 5) Pratschke S, Bilzer M, Grützner U et al. Tacrolimus preconditioning of rat liver allografts impacts glutathione homeostasis and early reperfusion injury. J Surg Res 2012; 176: 309-16.
6. 6) Polsker GL, Foster RH. Tacrolimus: A further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 2000; 59: 323-89.
7. 7) Kobayashi M, Saitoh H, Kobayashi M, Tadano K, Takahashi Y, Hirano T. Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther 2004; 309:1029-35.
8. 8) Demiryürek S, Kara AF, Celik A, Tarakçioğlu M, Bağci C, Demiryürek AT. Effects of Y-27632, a selective Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats. BiochemPharmacol 2005; 69: 49-58.

9. 9) Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123: 92-100.
10. 10) Oyama JI, Blais C, Liu X et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4- deficient mice. Circulation 2004; 109: 784-89.
11. 11) Shi X, Tao G, Tian G. Sappanone A protects against myocardial ischemia reperfusion injury by modulation of Nrf2. Drug Des Devel Ther 2020; 14: 61-71.
12. 12) Ibanez B, Heusch G, Ovize M, Werf FV. Evolving therapies for myocardial ischemia/reperfusion injury. JACC 2015; 65: 1454-71.
13. 13) Arunachalam M, SoodS. Pharmacological evaluation of tacrolimus (FK506) on ischemia reperfusion induced vasculatic neuropathic pain in rats. J Brachial Plex Peripher Nerve Inj 2010; 5: 64-74.
14. 14) Krishnadason B, Naidu B, Rosengart M et al. Decreased lung ischemia-reperfusion injury in rats after preoperative administartion of cyclosporine and tacrolimus. CSP 2002; 123: 756-67.
15. 15) Ustundag UV, Sahin S, Ak K, Keskin I, Alturfan EE. The effects of tacrolimus on the activity and expression of tissue factor in the rat ovary with ischemia-reperfusion induced injury. Reproductive Biology 2015; 15: 139-45.
16. 16) Stringa P, Romania D, Lausada N et al. Ischemic preconditioning and tacrolimus pretreatment as strategies to attenuate intestinal ischemia-reperfusion injury in mice. Transplantation Proceedings 2013; 45: 2480-85.
17. 17) Huser N, Doll D, Altomonte J et al. Graft preconditioning with low-dose tacrolimus (FK506) and nitric oxide inhibitor aminoguanidine (AGH) reduces ischemia/reperfusion injury after liver transplantation in the rat. Arch Pharm Res 2009; 32: 215-20.
18. 18) Takeichi T, Uemoto S, Minamiguchi S et al. Effect of ONO-4057 and tacrolimus on ischemia-reperfusion injury of the liver. World J Gastroenterol 2009; 15: 5712-15.
19. 19) Bayer J, Das NA, Baisden CE, Rai M et al. Effect of inhaled tacrolimus on ischemia reperfusion injury in rat transplantation model. J Thorac Cardiovasc Surg 2013; 146: 1213-19.
20. 20) Sahin S, Ozakpinar OB, Ak K et al. The protective effects of tacrolimus on rat uteri exposed to ischemia-reperfusion injury: a biochemical and histopathologic evaluation. Fertil Steril 2014; 101: 1176- 82.
21. 21) Sheu JJ, Sump PH, Leu S et al. Innate immun response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity. J Biomed Sci 2013; 20: 82-104.
22. 22) Yang CC, Sung PH, Chiang JY et al. Combined tacrolimus and melatonin effectively protected kidney against acute ischemia-reperfusion injury. The FASET Journal 2021; 35: 21661.
23. 23) Nishinaka Y, Sugiyama S, Yokota M, Saito H, Ozawa T. Protective effect of FK506 on ischemia-reperfusion-induced myocardial damage in canine heart. J Cardiovasc Pharma 1993; 21: 448-54.
24. 24) Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2004; 109: 784-89.
25. 25) Chua S, Leu S, Sheu JJ et al. Intra-coronary administartion of tacrolimus markedly attenuates infarct size and preserves heart function in porcine myocardial infarction. J Inflamm 2012; 9: 17-28.
26. 26) Feng X, Li J, Liu J et al. Protective effect of FK506 on myocardial ischemia-reperfusion injury by suppression of CaN and ASK1 signaling circuitry. Cardiovasc Toxicol 2011; 11: 18-27.
27. 27) Vafadri R, Kraaijeveld R, Weimer W, Raan CC. Tacrolimus inhibits NF-KB activation in peripheral human T-cells. PloS One 2013; 8: 60784.
28. 28) Squadrito F, Altavilla D, Squadrito G, Saitta A, Deodato B, Arlotta M. Tacrolimus limits polymorphonuclear leucocyte accumulation and protects against myocardial ischemia-reperfusion. J Mol Cell Cardiol 2000; 32: 429-40.
29. 29) Mohebbi N, Mihailova M, Wagner CA. The calcineurin inhibtor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins. Am J Physiol Renal Physiol 2009; 297: 499-50.