Abstract
To determine whether the cardioprotection effect of fluvastatin mediates by toll-like receptor 4 (TLR4) signaling pathway, fifty Sprague–Dawley rats were randomly divided into five groups: sham operation group, ischemia/reperfusion (I/R) group, fluvastatin groups (high-dosage, medium-dosage, low-dosage, n = 10 in each group). Except sham operation group, the rest four groups of rats were artificially afflicted with coronary occlusion for 30 min, then reperfusion 2 h. Light microscope and transmission electronic microscope were used to observe structural changes of myocardium. RT–PCR was used to measure TLR4 mRNA expression level, TLR4 protein expression was detected by immunohistochemistry. Western blot was used to measure myocardial NF-κB protein level; ELISA was used to measure the level of TNF-α in myocardium. The results demonstrated that fluvastatin treatment markedly decreased ischemic injury caused by ischemia/reperfusion, and inhibited the expression levels of TLR4, TNF-α and NF-κB, all of which up-regulated by ischemia/reperfusion. Taken together, our results suggest that proper dosage of fluvastatin may have protective effect on the ischemic injury mediated by ischemia/reperfusion in the hearts, which might be associated with inhibition of TLR4 signaling pathway and inflammatory response during ischemia/reperfusion.





Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Blancke F, Claeys MJ, Jorens P, Vermeiren G, Bosmans J, Wuyts FL, Vrints CJ (2005) Systemic inflammation and reperfusion injury in patients with acute myocardial infarction. Mediat Inflamm 2005:385–389
Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Potter BJ, Zhang C (2008) Role of TNF-alpha-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. Am J Physiol Heart Circ Physiol 295:H2242–H2249
Oyama J, Blais C Jr, Liu X, Pu M, Kobzik L, Kelly RA, Bourcier T (2004) Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109:784–789
Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL, Yada M, Pohlman TH, Verrier ED (2004) Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128:170–179
Cha J, Wang Z, Ao L, Zou N, Dinarello CA, Banerjee A, Fullerton DA, Meng X (2008) Cytokines link toll-like receptor 4 signaling to cardiac dysfunction after global myocardial ischemia. Ann Thorac Surg 85:1678–1685
Matsuki A, Igawa A, Nozawa T, Nakadate T, Igarashi N, Nonomura M, Inoue H (2006) Early administration of fluvastatin, but not at the onset of ischemia or reperfusion, attenuates myocardial ischemia–reperfusion injury through the nitric oxide pathway rather than its antioxidant property. Circ J 70:1643–1649
Tiefenbacher CP, Kapitza J, Dietz V, Lee CH, Niroomand F (2003) Reduction of myocardial infarct size by fluvastatin. Am J Physiol Heart Circ Physiol 285:H59–H64
Hodgkinson CP, Ye S (2008) Statins inhibit toll-like receptor 4-mediated lipopolysaccharide signaling and cytokine expression. Pharmacogenet Genomics 18:803–813
Zhao ZH, Shan J, Xiang MX, Xu G, Fu GS, Bao XF (2005) Influence of fluvastatin on left ventricular remodeling after myocardial infarction in rats. Zhejiang Da Xue Xue Bao Yi Xue Ban 34:447–453, 464
Chimenti S, Carlo E, Masson S, Bai A, Latini R (2004) Myocardial infarction: animal models. Methods Mol Med 98:217–226
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
Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, Miyake K (2008) Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun 368:94–99
Gohda J, Matsumura T, Inoue J (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 173:2913–2917
Yang J, Yang J, Ding JW, Chen LH, Wang YL, Li S, Wu H (2008) Sequential expression of TLR4 and its effects on the myocardium of rats with myocardial ischemia-reperfusion injury. Inflammation 31:304–312
Methe H, Kim JO, Kofler S, Nabauer M, Weis M (2005) Statins decrease toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 25:1439–1445
Niessner A, Steiner S, Speidl WS, Pleiner J, Seidinger D, Maurer G, Goronzy JJ, Weyand CM, Kopp CW, Huber K, Wolzt M, Wojta J (2006) Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis 189:408–413
Földes G, von Haehling S, Okonko DO, Jankowska EA, Poole-Wilson PA, Anker SD (2008) Fluvastatin reduces increased blood monocyte toll-like receptor 4 expression in whole blood from patients with chronic heart failure. Int J Cardiol 124:80–85
Brown M, McGuinness M, Wright T, Ren X, Wang Y, Boivin GP, Hahn H, Feldman AM, Jones WK (2005) Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. Am J Physiol Heart Circ Physiol 289:H466–H476
Liao XX, Li X, Ma ZF, Wang LC, Du ZM, Dong YG, Ma H (2008) Role of nuclear factor-KappaB in endothelial injury in acute myocardial infarction. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 20:413–415
Moss NC, Tang RH, Willis M, Stansfield WE, Baldwin AS, Selzman CH (2008) Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection. J Thorac Cardiovasc Surg 136:1274–1279
Gu Q, Yang XP, Bonde P, DiPaula A, Fox-Talbot K, Becker LC (2006) Inhibition of TNF-alpha reduces myocardial injury and proinflammatory pathways following ischemia-reperfusion in the dog. J Cardiovasc Pharmacol 48:320–328
Author information
Authors and Affiliations
Corresponding author
Additional information
Jun Yang, Jian Yang contributed equally to this work.
Rights and permissions
About this article
Cite this article
Yang, J., Zhang, XD., Yang, J. et al. The cardioprotective effect of fluvastatin on ischemic injury via down-regulation of toll-like receptor 4. Mol Biol Rep 38, 3037–3044 (2011). https://doi.org/10.1007/s11033-010-9970-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-010-9970-z


