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Int J Sports Med 2014; 35(04): 344-350
DOI: 10.1055/s-0033-1349075
Clinical Sciences
© Georg Thieme Verlag KG Stuttgart · New York

Effect of Aerobic Exercise on miRNA-TLR4 Signaling in Atherosclerosis

X.-D. Wu
1   Anesthesiology, Fujian Provincial Clinical Medical College, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
,
K. Zeng
2   Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
,
W.-L. Liu
3   Rehabilitation, Fujian University of Traditional Chinese Medicine, Fuzhou, China
,
Y.-G. Gao
2   Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
,
C.-S. Gong
1   Anesthesiology, Fujian Provincial Clinical Medical College, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
,
C.-X. Zhang
4   Physical Education, Institute of Human Movement Sciences Research, Hunan Normal University, Changsha, China
,
Y.-Q. Chen
1   Anesthesiology, Fujian Provincial Clinical Medical College, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
› Author Affiliations
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Publication History



accepted after revision 29 April 2013

Publication Date:
10 September 2013 (online)

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Abstract

Toll-like receptor 4 (TLR4)-tumor necrosis factor receptor 6 (TRAF6) signaling is activated in atherosclerosis (AS), inducing inflammatory mediators. Because miR-146a, a TLR4 microRNA (miRNA), can regulate TLR4 signaling during inflammatory responses, this study investigated the effects of aerobic exercise on TLR4-targeted miRNAs in AS. Apolipoprotein E-null mice fed a high-fat diet for 12 weeks were separated into 3 groups: (i) no treatment (AS), (ii) statin treatment (AD), or (iii) aerobic exercise (AE). Plaques and foam cells were observed in the untreated control and statin groups, respectively, but not in the AE group. Reduced angiotensin II (Ang II) and endothelin 1 (ET1) levels were observed in the AE group. Both treatment groups significantly altered the expression of inflammatory cytokine expression and reduced vascular TLR4 levels. Increased miR-146a and miR-126 and reduced miR-155 levels were observed in both treatment groups (all, P<0.001). miR-146a interacted with the 3′ untranslated region of the TRAF6 gene, reducing its expression. Thus, aerobic exercise and statins may induce miR-146a expression, thereby reducing vascular TRAF and TLR4 signaling and vascular inflammatory injury in AS. Further analysis of this pathway may provide insight into the protective effects of aerobic exercise on vascular disease as well as new therapeutic targets.

Key words

atherosclerosis - inflammation - TLR4 - miRNA
 

  • References

  • 1 Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang F, Wang TJ, Chan SY. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol 2011; 589: 3983-3994
    CrossrefPubMedSearch in Google Scholar
  • 2 Beuvink I, Kolb FA, Budach W, Garnier A, Lange J, Natt F, Dengler U, Hall J, Filipowicz W, Weiler J. A novel microarray approach reveals new tissue-specific signatures of known and predicted mammalian microRNAs. Nucleic Acids Res 2007; 35: e52
    CrossrefPubMedSearch in Google Scholar
  • 3 Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem 2004; 279: 48487-48490
    CrossrefPubMedSearch in Google Scholar
  • 4 Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986; 232: 34-47
    CrossrefPubMedSearch in Google Scholar
  • 5 Coen PM, Flynn MG, Markofski MM, Pence BD, Hannemann RE. Adding exercise to rosuvastatin treatment: influence on C-reactive protein, monocyte toll-like receptor 4 expression, and inflammatory monocyte (CD14+CD16+) population. Metabolism 2010; 59: 1775-1783
    CrossrefPubMedSearch in Google Scholar
  • 6 den Dekker WK, Cheng C, Pasterkamp G, Duckers HJ. Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis 2010; 209: 314-320
    CrossrefPubMedSearch in Google Scholar
  • 7 Derbigny WA, Shobe LR, Kamran JC, Toomey KS, Ofner S. Identifying a role for Toll-like receptor 3 in the innate immune response to Chlamydia muridarum infection in murine oviduct epithelial cells. Infect Immun 2012; 80: 254-265
    CrossrefPubMedSearch in Google Scholar
  • 8 Fernandes-Silva MM, Carvalho VO, Guimarães GV, Bacal F, Bocchi EA. Physical exercise and microRNAs: new frontiers in heart failure. Arq Bras Cardiol 2012; 98: 459-466
    CrossrefPubMedSearch in Google Scholar
  • 9 Fernando P, Bonen A, Hoffman-Goetz L. Predicting submaximal oxygen consumption during treadmill running in mice. Can J Physiol Pharmacol 1993; 71: 854-857
    CrossrefPubMedSearch in Google Scholar
  • 10 Fukao K, Shimada K, Naito H, Sumiyoshi K, Inoue N, Iesaki T, Kume A, Kiyanagi T, Hiki M, Hirose K, Matsumori R, Ohsaka H, Takahashi Y, Toyoda S, Itoh S, Miyazaki T, Tada N, Daida H. Voluntary exercise ameliorates the progression of atherosclerotic lesion formation via anti-inflammatory effects in apolipoprotein E-deficient mice. J Atheroscler Thromb 2010; 17: 1226-1236
    CrossrefPubMedSearch in Google Scholar
  • 11 Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA 2008; 105: 1516-1521
    CrossrefPubMedSearch in Google Scholar
  • 12 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522-531
    CrossrefPubMedSearch in Google Scholar
  • 14 Higashimori M, Tatro JB, Moore KJ, Mendelsohn ME, Galper JB, Beasley D. Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2011; 31: 50-57
    CrossrefPubMedSearch in Google Scholar
  • 15 Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H, Dean DB, Zhang C. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation. Circ Res 2007; 100: 1579-1588
    CrossrefPubMedSearch in Google Scholar
  • 16 John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human MicroRNA targets. PLoS Biol 2004; 2: e363
    CrossrefPubMedSearch in Google Scholar
  • 17 Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505
    CrossrefPubMedSearch in Google Scholar
  • 18 Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell 2003; 115: 787-798
    CrossrefPubMedSearch in Google Scholar
  • 19 Li H, Sun B. Toll-like receptor 4 in atherosclerosis. J Cell Mol Med 2007; 11: 88-95
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu N, Olson EN. MicroRNA regulatory networks in cardiovascular development. Dev Cell 2010; 18: 510-525
    CrossrefPubMedSearch in Google Scholar
  • 21 Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A, Seijkens T, Engel D, Cleutjens J, Keller AM, Naik SH, Boon L, Oufella HA, Mallat Z, Ahonen CL, Noelle RJ, de Winther MP, Daemen MJ, Biessen EA, Weber C. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med 2010; 207: 391-404
    CrossrefPubMedSearch in Google Scholar
  • 22 Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M, Feldman DS, Schmittgen TD, Elton TS. The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding. J Biol Chem 2007; 282: 24262-24269
    CrossrefPubMedSearch in Google Scholar
  • 23 Mitani H, Takimoto M, Bandoh T, Kimura M. Increases of vascular endothelin-converting enzyme activity and endothelin-1 level on atherosclerotic lesions in hyperlipidemic rabbits. Eur J Pharmacol 2000; 387: 313-319
    CrossrefPubMedSearch in Google Scholar
  • 24 Naiki Y, Sorrentino R, Wong MH, Michelsen KS, Shimada K, Chen S, Yilmaz A, Slepenkin A, Schröder NW, Crother TR, Bulut Y, Doherty TM, Bradley M, Shaposhnik Z, Peterson EM, Tontonoz P, Shah PK, Arditi M. TLR/MyD88 and liver X receptor α signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis. J Immunol 2008; 181: 7176-7185
    CrossrefPubMedSearch in Google Scholar
  • 25 O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA 2007; 104: 1604-1609
    CrossrefPubMedSearch in Google Scholar
  • 26 Renlund DG, Taylor DO. Cardiac transplantation. In: Topol EJ. (ed.). Textbook of cardiovascular medicine. 2nd edn. Philadelphia: Lippincott, Williams & Wilkins; 2002: 1915-1934
    Search in Google Scholar
  • 27 Schmidt M, Raghavan B, Müller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 2010; 11: 814-819
    CrossrefPubMedSearch in Google Scholar
  • 28 Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 2002; 8: 1211-1217
    CrossrefPubMedSearch in Google Scholar
  • 29 Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-κB dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103: 12481-12486
    CrossrefPubMedSearch in Google Scholar
  • 30 Yang K, He YS, Wang XQ, Lu L, Chen QJ, Liu J, Sun Z, Shen WF. MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. FEBS Lett 2011; 585: 854-860
    CrossrefPubMedSearch in Google Scholar
  • 31 Yoshimura E, Kumahara H, Tobina T, Ayabe M, Matono S, Anzai K, Higaki Y, Kiyonaga A, Tanaka H. A 12-week aerobic exercise program without energy restriction improves intrahepatic fat, liver function and atherosclerosis-related factors. Obesity Res Clin Pract 2011; 5: e249-e257
    PubMedSearch in Google Scholar
  • 32 Zouridakis EG, Schwartzman R, Garcia-Moll X, Cox ID, Fredericks S, Holt DW, Kaski JC. Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression. Eur Heart J 2001; 22: 1578-1584
    CrossrefPubMedSearch in Google Scholar
  • 33 Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-661
    CrossrefPubMedSearch in Google Scholar