Valsartan preconditioning protects against myocardial ischemia–reperfusion injury through TLR4/NF-κB signaling pathway

  • Jian Yang
  • Hong Jiang
  • Jun Yang
  • Jia-Wang Ding
  • Li-Hua Chen
  • Song Li
  • Xiao-Dong Zhang
Article

Abstract

Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-κB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-κB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-κB signaling pathway.

Keywords

Valsartan Reperfusion injury Inflammation Toll-like receptors Nuclear factor kappa-B 

Notes

Acknowledgment

We thank Jia-jun Wang from the Department of Immunology, Medical Science College of China Three Gorges University for his technical support and helpful suggestions on this study.

References

  1. 1.
    Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI) (1986) Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1:397–402Google Scholar
  2. 2.
    ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988) Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17, 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349–360Google Scholar
  3. 3.
    Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ et al (2000) Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283:2941–2947. doi: 10.1001/jama.283.22.2941 CrossRefPubMedGoogle Scholar
  4. 4.
    Ribichini F, Wijns W (2002) Acute myocardial infarction: reperfusion treatment. Heart 88:298–305. doi: 10.1136/heart.88.3.298 CrossRefPubMedGoogle Scholar
  5. 5.
    Hansen PR (1995) Myocardial reperfusion injury: experimental evidence and clinical relevance. Eur Heart J 16:734–740PubMedGoogle Scholar
  6. 6.
    Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL (1998) Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 97:2259–2267PubMedGoogle Scholar
  7. 7.
    Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53:31–47. doi: 10.1016/S0008-6363(01)00434-5 CrossRefPubMedGoogle Scholar
  8. 8.
    Serhan CN, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B et al (2003) Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol 171:6856–6865PubMedGoogle Scholar
  9. 9.
    Serhan CN (2005) Novel omega-3-derived local mediators in anti-inflammation and resolution. Pharmacol Ther 105:7–21. doi: 10.1016/j.pharmthera.2004.09.002 CrossRefPubMedGoogle Scholar
  10. 10.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 388:394–397. doi: 10.1038/41131 CrossRefPubMedGoogle Scholar
  11. 11.
    Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface toll-like receptors. Semin Immunol 19:3–10. doi: 10.1016/j.smim.2006.12.002 CrossRefPubMedGoogle Scholar
  12. 12.
    Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680. doi: 10.1038/90609 CrossRefPubMedGoogle Scholar
  13. 13.
    Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. J Infect Dis 183:1617–1624. doi: 10.1086/320712 CrossRefPubMedGoogle Scholar
  14. 14.
    Oyama J, Blais C Jr, Liu X, Pu M, Kobzik L, Kelly RA et al (2004) Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109:784–789. doi: 10.1161/01.CIR.0000112575.66565.84 CrossRefPubMedGoogle Scholar
  15. 15.
    Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL et al (2004) Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128:170–179. doi: 10.1016/j.jtcvs.2003.11.036 CrossRefPubMedGoogle Scholar
  16. 16.
    Yang J, Yang J, Ding JW, Chen LH, Wang YL, Li S et al (2008) Sequential expression of TLR4 and its effects on the myocardium of rats with myocardial ischemia-reperfusion injury. Inflammation 31:304–312. doi: 10.1007/s10753-008-9079-x CrossRefPubMedGoogle Scholar
  17. 17.
    Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U et al (2002) Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003. doi: 10.1016/S0140-6736(02)08089-3 CrossRefPubMedGoogle Scholar
  18. 18.
    Brunner HR, Gavras H (2002) Angiotensin blockade for hypertension: a promise fulfilled. Lancet 359:990–992. doi: 10.1016/S0140-6736(02)08062-5 CrossRefPubMedGoogle Scholar
  19. 19.
    Zannad F, Fay R (2007) Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies. Fundam Clin Pharmacol 21:181–190. doi: 10.1111/j.1472-8206.2007.00464.x CrossRefPubMedGoogle Scholar
  20. 20.
    Navalkar S, Parthasarathy S, Santanam N, Khan BV (2001) Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 37:440–444. doi: 10.1016/S0735-1097(00)01138-4 CrossRefPubMedGoogle Scholar
  21. 21.
    Cianchetti S, Del Fiorentino A, Colognato R, Di Stefano R, Franzoni F, Pedrinelli R (2008) Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis 198:22–28. doi: 10.1016/j.atherosclerosis.2007.09.013 CrossRefPubMedGoogle Scholar
  22. 22.
    Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME et al (2004) Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis. Circulation 109:1536–1542. doi: 10.1161/01.CIR.0000124061.78478.94 CrossRefPubMedGoogle Scholar
  23. 23.
    Sironi L, Gelosa P, Guerrini U, Banfi C, Crippa V, Brioschi M et al (2004) Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall. J Pharmacol Exp Ther 311:989–995. doi: 10.1124/jpet.104.072066 CrossRefPubMedGoogle Scholar
  24. 24.
    Varagic J, Frohlich ED, Susic D, Ahn J, Matavelli L, López B et al (2008) AT1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure. Am J Physiol Heart Circ Physiol 294:H853–H858. doi: 10.1152/ajpheart.00737.2007 CrossRefPubMedGoogle Scholar
  25. 25.
    Chan YC, Leung PS (2007) Angiotensin II type 1 receptor-dependent nuclear factor-kappaB activation-mediated proinflammatory actions in a rat model of obstructive acute pancreatitis. J Pharmacol Exp Ther 323:10–18. doi: 10.1124/jpet.107.124891 CrossRefPubMedGoogle Scholar
  26. 26.
    Maulik N, Engelman RM, Rousou JA, Flack JEIII, Deaton D, Das DK (1999) Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation 100:II369–II375PubMedGoogle Scholar
  27. 27.
    Marino JH, Cook P, Miller KS (2003) Accurate and statistically verified quantification of relative mRNA abundances using SYBR Green I and real-time RT-PCR. J Immunol Methods 283:291–306. doi: 10.1016/S0022-1759(03)00103-0 CrossRefPubMedGoogle Scholar
  28. 28.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034Google Scholar
  29. 29.
    Altavilla D, Saitta A, Guarini S, Galeano M, Squadrito G, Cucinotta D et al (2001) Oxidative stress causes nuclear factor-kappaB activation in acute hypovolemic hemorrhagic shock. Free Radic Biol Med 30:1055–1066. doi: 10.1016/S0891-5849(01)00492-0 CrossRefPubMedGoogle Scholar
  30. 30.
    Zheng YQ, Wei W (2005) Total glucosides of paeony suppresses adjuvant arthritis in rats and intervenes cytokine-signaling between different types of synoviocytes. Int Immunopharmacol 5:1560–1573. doi: 10.1016/j.intimp.2005.03.010 CrossRefPubMedGoogle Scholar
  31. 31.
    Zeuke S, Ulmer AJ, Kusumoto S, Katus HA, Heine H (2002) TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS. Cardiovasc Res 56:126–134. doi: 10.1016/S0008-6363(02)00512-6 CrossRefPubMedGoogle Scholar
  32. 32.
    Nemoto S, Vallejo JG, Knuefermann P, Misra A, Defreitas G, Carabello BA et al (2002) Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol 282:H2316–H2323PubMedGoogle Scholar
  33. 33.
    Beg AA (2002) Endogenous ligands of toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23:509–512. doi: 10.1016/S1471-4906(02)02317-7 CrossRefPubMedGoogle Scholar
  34. 34.
    Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N et al (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690. doi: 10.1161/hc0602.103617 CrossRefPubMedGoogle Scholar
  35. 35.
    Altavilla D, Deodato B, Campo GM, Arlotta M, Miano M, Squadrito G et al (2000) IRFI 042, a novel dual vitamin E-like antioxidant, inhibits activation of nuclear factor-kappaB and reduces the inflammatory response in myocardial ischemia-reperfusion injury. Cardiovasc Res 47:515–528. doi: 10.1016/S0008-6363(00)00124-3 CrossRefPubMedGoogle Scholar
  36. 36.
    Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ et al (2006) Inhibition of toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114:I270–I274. doi: 10.1161/CIRCULATIONAHA.105.000901 CrossRefPubMedGoogle Scholar
  37. 37.
    Ridker PM, Danielson E, Rifai N, Glynn RJ, Val-MARC Investigators (2006) Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial. Hypertension 48:73–79. doi: 10.1161/01.HYP.0000226046.58883.32 CrossRefPubMedGoogle Scholar
  38. 38.
    Mueller EA, Griffin WS, Wildenthal K (1977) Isoproterenol-induced cardiomyopathy: changes in cardiac enzymes and protection by methylprednisolone. J Mol Cell Cardiol 9:565–578. doi: 10.1016/S0022-2828(77)80371-4 CrossRefPubMedGoogle Scholar
  39. 39.
    van Kats JP, Duncker DJ, Haitsma DB, Schuijt MP, Niebuur R, Stubenitsky R et al (2000) Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II. Circulation 102:1556–1563PubMedGoogle Scholar
  40. 40.
    Silvestre JS, Heymes C, Oubénaïssa A, Robert V, Aupetit-Faisant B, Carayon A et al (1999) Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 99:2694–2701PubMedGoogle Scholar
  41. 41.
    Dai Q, Xu M, Yao M, Sun B (2007) Angiotensin AT1 receptor antagonists exert anti-inflammatory effects in spontaneously hypertensive rats. Br J Pharmacol 152:1042–1048. doi: 10.1038/sj.bjp.0707454 CrossRefPubMedGoogle Scholar
  42. 42.
    Seeger H, Mueck AO, Lippert TH (2000) Effects of valsartan and 17 beta-estradiol on the oxidation of low-density lipoprotein in vitro. Coron Artery Dis 11:347–349. doi: 10.1097/00019501-200006000-00008 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Jian Yang
    • 1
  • Hong Jiang
    • 1
  • Jun Yang
    • 2
  • Jia-Wang Ding
    • 3
  • Li-Hua Chen
    • 2
  • Song Li
    • 3
  • Xiao-Dong Zhang
    • 2
  1. 1.Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanChina
  2. 2.Department of Cardiology, The First College of Clinical Medical SciencesChina Three Gorges UniversityYichangChina
  3. 3.Department of CardiologyYichang Central People’s HospitalYichangChina

Personalised recommendations