Telmisartan protects from myocardial ischemia/reperfusion injury via down regulation of the inflammatory response and apoptosis

Najah R. Hadi; Fadhil G. Al-Amran; Maitham G. Yousif; Suaad  T. Zamil

AJBM  Volume 2, Issue 4, pages 448–462, April 2014             Full Text-PDF


Myocardial Ischemia-Reperfusion (I/R) injury refers to myocardial, vascular or electrophysiological dysfunction of heart induced by the restoration of blood flow to previously ischemic tissue. In this study, we investigated the effects of Telmisartan in I/R injury and apoptosis. Mice are subjected to 30 min ischemia followed by 120 min reperfusion through ligation of descending coronary artery (LAD). Mice treated with Telmisartan (0.5mg/kg, via IP injection) significantly attenuated I/R-induced increases of myocardial TNF-α, IL-1β, IL-6 and markedly increased myocardial Bcl-2 protein expression. Furthermore, Telmisartan significant protective effect against myocardial I/R injury. These results demonstrated that Telmisartan reduces inflammatory reaction associated with I/R injury induced by LAD ligation in addition to its reduction for cardiac injury and apoptosis  induced by ischemia reperfusion.

Keywords: Telmisartan;  I/R; cTn-I; Pro-inflammatory cytokines;  Apoptosis


1. Singhal AK,  Symons JD, Boudina S, Jaishy B, Shiu YE. Role of endothelial cells in myocardial ischemia-reperfusion injury. Vascular disease prevention 2010;7:1-14.[Abstract/Full-Text]

 2. Deng C, Sun Z, Tong G, Yi W, Ma L, Zhao B, Cheng L, Zhang J, Cao F, Yi D.                     αLipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injurythrough activation of PI3K/Akt/Nrf2 pathway. PLoS One 2013; 8(3): e58371. [Abstract/Full-Text]

3. Jugdutt BI. Apoptosis after reperfused myocardial infarction: Role of angiotensin II. Exp Clin Cardiol 2014; 9(4):219-228. [Abstract/Full-Text]

4. Yousif  NG, Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC Cardiovasc Disord 2011; 11: 62. [Abstract/Full-Text]

5. Takai S, Kirimura K, Jin D, Muramatsu M, Yoshikawa K, Mino Y, Miyazaki M. Significance of angiotensin II receptor blocker lipophilicities and their protective effect against vascular remodeling. Hypertens Res 2005; 28(7):593-600. [PubMed]

6. Kaschina E, Schrader F, Sommerfeld M, Kemnitz UR, Grzesiak A, Krikov M, Unger T.Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation. J Hypertens 2008; 26(12):2361-73. [PubMed]

7. Amr A. Fouad, Habib A. Qureshi, Ali Ibrahim Al-Sultan, Mohamed T. Yacoubi, Walid N. Al-Melhim. Nephroprotective Effect of Telmisartan in Rats with Ischemia/Reperfusion Renal Injury. Pharmacology 2010; 85:158-167. [Abstract/Full-Text]                  

8. Kumtepe Y, Odabasoglu F, Karaca M, Polat B, Halici MB, Keles ON, Altunkaynak Z, Gocer F. Protective effects of telmisartan on ischemia/reperfusion injury of rat ovary: biochemical and histopathologicevaluation.Fertil Steril 2010;193(4):1299-307. [PubMed]

9. Wiedemann D, Schneeberger S, Friedl P, Zacharowski K, Wick N, Boesch F, Margreiter R, Laufer G, Petzelbauer P, Semsroth S.The fibrin-derived peptide Bbeta(15-42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model.Transplantation 2010;15;89(7):824-9.[PubMed]

10. Ding JW, Tong XH, Yang J, Liu ZQ, Zhang Y, Yang J, Li S, Li L. Activated protein C protects myocardium via activation of anti-apoptotic pathways of survival in ischemia-reperfused rat heart. J Korean Med Sci 2010; 25:1609-15. [PubMed]                      

11. 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 2010; 3;39(7):1229-35. [PubMed]  

12. Bancroft JD, Stevens A. Theory and practice of histological techniques. Churchill Livingstone. Melbourne 1982; 2:125.                                                         

13. Zhang M, Xu YJ ,Saini HK, Turan B, Liu PP, Dhalla NS. Pentoxifylline attenuate cardiac dysfunction and reduces TNF alfa level in ischemia-reperfused heart. Am J Physiol Heart Circ Physiol 2005; 289: 832-9. [PubMed]  

14. Arslan F, Smeets MB, O'Neill LA, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 2010; 5;121(1):80-90. [PubMed]  

15. Deng H, Guo H, Qian X. Clinical significance of fibrinolytic system defectiveness in exercise induced myocardial ischemia and its mechanism. Chung Hua Nei Ko Tsa Chih 1995; 34: 305–308.  [PubMed]                                                                              

16. Yang B, Li D, Phillips M, Mehta P, Mehta JL. Myocardial angiotensin II receptor expression and ischemia-reperfusion injury. Vasc Med 1998;3:21–130. [Abstract/Full-Text] 

17. Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the bcl-2-to Bax protein ratio in the cell. J Clin Invest 1998;101: 1326–1342. [Abstract/Full-Text] 

18. Yamagishi S, Takeuchi M. Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property. Med Hypotheses 2005; 64:476–478.  [Abstract/Full-Text]                                                                                                                                

19. Sukumaran V, Watanabe K, Veeraveedu PT, Ma M, Gurusamy N, Rajavel V, Suzuki K, Yamaguchi K, Kodama M, Aizawa Y.Telmisartan ameliorates experimental autoimmune myocarditis associated with inhibition of inflammation and oxidative stress. Eur J Pharmacol 2011;10;652(1-3):126-35. [Abstract/Full-Text]                                          

20. Takagi H, Mizuno Y, Yamamoto H, Goto SN, Umemoto T. Effects of telmisartan therapy on interleukin-6 and tumor necrosis factor-alpha levels: a meta-analysis ofrandomized controlled trials. Hypertens Res 2013; 36(4):368-73. [PubMed]  

21. Zeng XC, Li XS, Wen H. (2013)Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury byactivation of peroxisome proliferator-activated receptor gamma. BMC Cardiovasc Disord 2013;5;13(1):39. [Abstract/Full-Text] 

22. Muller DN, Dechend R, Mervaala EM, Park JK, Schmidt F, Fiebeler A, Theuer J, Breu V, Ganten D, Haller H. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 2000;35(1 Pt 2):193-201. [PubMed]  

23. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis: countervailing influences of nitric oxide and angiotensin II. Circ Res 1996;9:748–756.                                              

24. Li  D, Tomson K, Yang B, Mehta P, Croker BP, Mehta JL. Modulation of constitutive nitric oxide synthase, bcl-2 and Fas expression in cultured human coronary endothelialcells exposed to anoxiareoxygenation and angiotensin II: role of AT1 receptor activation. Cardiovasc Res 1999; 41(1):109-15. [PubMed]                                     

25. Goyal S, Arora S, Bhatt TK, Das P, Sharma A, Kumari S, Arya DS. Modulation of PPAR-gamma by telmisartan protects the heart against myocardial infarction in experimental diabetes. Chem Biol Interact 2010; 185(3):271–280. [PubMed]

26. Jung KH , Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI, KimJM, KimM, RohJK. Blockade of AT1 receptor reduces apoptosis, inflammation,and oxidative stress in normotensive rats withintracerebral hemorrhage. J Pharmacol Exp Ther 2007; 322(3):1051-8. [Abstract/Full-Text] 

27. Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, Suzuki K, Kodama M, Watanabe K. Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmunemyocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis. Int J Biol Sci 2011; 7(8):1077-92. [PubMed]

28.Tang JR, Yan XN, Zhou CQ. Effects of telmisartan on endoplasmic reticulum stress induced cardiomyocyte apoptosis in abdominal aortic banded rats. Zhonghua Xin Xue Guan Bing Za Zhi.  2008; 36(9):838-42. 

29. Grünenfelder J, Miniati DN, Murata S, Falk V, Hoyt EG, Kown M, Koransky   ML, Robbins RC. Upregulation of Bcl-2 through caspase-3 inhibition ameliorates ischemia/reperfusion injury in rat cardiacallografts. Circulationm 2001;18;104(12 Suppl 1): I202-6. [PubMed]

30. Rinaldi B Rinaldi B, Di Filippo C, Capuano A, Donniacuo M, Sodano L, Ferraraccio F, Rossi F, D'Amico M. Adiponectin elevation by telmisartan ameliorates ischaemic myocardium in Zucker diabetic fatty rats with metabolic syndrome. Diabetes Obes Metab 2012;14(4):320-8. [PubMed]

31. EW Austin, NG Yousif, L Ao, D A, Fullerton, X Meng. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American journal of BioMedicine 2013;1(2):33-47. [Article-AJBM]

32. Fogari R, Mugellini A, Zoppi A, Preti P, Destro M, Lazzari P, Derosa G. Effect of telmisartan and ramipril on atrial fibrillation recurrence and severity in hypertensive patients with metabolic syndrome and recurrent symptomatic paroxysmal and persistent atrial fibrillation. J Cardiovasc Pharmacol Ther 2012; 17(1):34-43.[Abstract/Full-Text] 

33. Iqbal M, Dubey K, Anwer T, Ashish A, Pillai KK. Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats. Pharmacol Rep 2008;60(3):382-90. [Abstract/Full-Text] 

34. Yousif NG,  Ao L, Li J,  Aly A, Austin E,Fullerton DA, Meng X. Myocardial tissue TLR4 plays a major role in mediating myocardial injury following cold ischemia and reperfusion through up-regulation of MCP-1. Journal of Surgical Research 2011; 165(2):181. [Abstract/Full-Text]

Print Friendly, PDF & Email