Skip to main content

Advertisement

Springer Nature Link
Log in

Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Mononuclear cell infiltration in valvular tissue is one of the characteristics in calcific aortic valve disease. The inflammatory responses of aortic valve interstitial cells (AVICs) play an important role in valvular inflammation. However, it remains unclear what may evoke AVIC inflammatory responses. Accumulation of biglycan has been found in diseased aortic valve leaflets. Soluble biglycan can function as a danger-associated molecular pattern to induce the production of proinflammatory mediators in cultured macrophages. We tested the hypothesis that soluble biglycan induces AVIC production of proinflammatory mediators involved in mononuclear cell infiltration through Toll-like receptor (TLR)-dependent signaling pathways.

Methods

Human AVICs isolated from normal aortic valve leaflets were treated with specific siRNA and neutralizing antibody against TLR2 or TLR4 before biglycan stimulation. The production of ICAM-1 and MCP-1 was assessed. To determine the signaling pathway involved, phosphorylation of ERK1/2 and p38 MAPK was analyzed, and specific inhibitors of ERK1/2 and p38 MAPK were applied.

Results

Soluble biglycan induced ICAM-1 expression and MCP-1 release in human AVICs, but had no effect on IL-6 release. TLR4 blockade and knockdown reduced ICAM-1 and MCP-1 production induced by biglycan, while knockdown and neutralization of TLR2 resulted in greater suppression of the inflammatory responses. Biglycan induced the phosphorylation of ERK1/2 and p38 MAPK, but ICAM-1 and MCP-1 production was reduced only by inhibition of the ERK1/2 pathway. Further, inhibition of ERK1/2 attenuated NF-κB activation following biglycan treatment.

Conclusions

Soluble biglycan induces the expression of ICAM-1 and MCP-1 in human AVICs through TLR2 and TLR4 and requires activation of the ERK1/2 pathway. AVIC inflammatory responses induced by soluble biglycan may contribute to the mechanism of chronic inflammation associated with calcific aortic valve disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

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

  1. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316–26.

    Article  PubMed  Google Scholar 

  2. Parolari A, Loardi C, Mussoni L, Cavallotti L, Camera M, Biglioli P, et al. Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention. Eur J Cardiothorac Surg. 2009;35(3):493–504.

    Article  PubMed  Google Scholar 

  3. Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004;95(9):858–66.

    Article  CAS  PubMed  Google Scholar 

  4. Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH. The cardiac valve interstitial cell. Int J Biochem Cell Biol. 2003;35(2):113–8.

    CAS  PubMed  Google Scholar 

  5. Schober A. Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol. 2008;28(11):1950–9.

    Article  CAS  PubMed  Google Scholar 

  6. New SE, Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 2011;108(11):1381–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(11):2292–301.

    Article  CAS  PubMed  Google Scholar 

  8. Song Y, Fullerton DA, Mauchley D, Su X, Ao L, Yang X, et al. Microfilaments facilitate TLR4-Mediated ICAM-1 expression in human aortic valve interstitial cells. J Surg Res. 2009;166:52–8.

    Article  PubMed  Google Scholar 

  9. Zeng Q, Jin C, Ao L, Cleveland JC Jr, Song R, Xu D, et al. Cross-talk between the toll-like receptor 4 and notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves. Circulation. 2012;126(11 Suppl 1):S222–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Schaefer L, Iozzo RV. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction. J Biol Chem. 2008;283(31):21305–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Moreth K, Brodbeck R, Babelova A, Gretz N, Spieker T, Zeng-Brouwers J, et al. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J Clin Invest. 2010;120(12):4251–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Popovic ZV, Wang S, Papatriantafyllou M, Kaya Z, Porubsky S, Meisner M, et al. The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis. J Immunol. 2011;187(12):6217–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Schaefer L, Iozzo RV. Small leucine-rich proteoglycans, at the crossroad of cancer growth and inflammation. Curr Opin Genet Dev. 2012;22(1):56–7.

    Article  CAS  PubMed  Google Scholar 

  14. Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest. 2005;115(8):2223–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Moreth K, Iozzo RV, Schaefer L. Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation. Cell Cycle. 2012;11(11):2084–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Meng X, Ao L, Song Y, Babu A, Yang X, Wang M, et al. Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis. Am J Physiol Cell Physiol. 2008;294(1):C29–35.

    CAS  PubMed  Google Scholar 

  17. Derbali H, Bosse Y, Cote N, Pibarot P, Audet A, Pepin A, et al. Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2. Am J Pathol. 2010;176(6):2638–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Stephens EH, Saltarrelli JG, Baggett LS, Nandi I, Kuo JJ, Davis AR, et al. Differential proteoglycan and hyaluronan distribution in calcified aortic valves. Cardiovasc Pathol. 2010;20(6):334–42.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Messier RH Jr, Bass BL, Aly HM, Jones JL, Domkowski PW, Wallace RB, et al. Dual structural and functional phenotypes of the porcine aortic valve interstitial population: characteristics of the leaflet myofibroblast. J Surg Res. 1994;57(1):1–21.

    Article  PubMed  Google Scholar 

  20. Moresco EM, LaVine D, Beutler B. Toll-like receptors. Curr Biol. 2011;21(13):R488–93.

    Article  CAS  PubMed  Google Scholar 

  21. Zeng Q, Song R, Ao L, Weyant MJ, Lee J, Xu D, et al. Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-kappaB activation. Arterioscler Thromb Vasc Biol. 2013;33(7):1580–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Yang X, Fullerton DA, Su X, Ao L, Cleveland JC, Meng X. Pro-osteogenic phenotype of human aortic valve interstitial cells is associated with higher levels of Toll-like receptors 2 and 4 and enhanced expression of bone morphogenetic protein 2. J Am Coll Cardiol. 2009;53:491–500.

    Article  CAS  PubMed  Google Scholar 

  23. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Cardiovascular Health Study, et al. Clinical factors associated with calcific aortic valve disease. J Am Coll Cardiol. 1997;29(3):630–4.

    Article  CAS  PubMed  Google Scholar 

  24. Song R, Zeng Q, Ao L, Yu JA, Cleveland JC, Zhao KS, et al. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via toll-like receptor-2. Arterioscler Thromb Vasc Biol. 2012;32:2711–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009;284(36):24035–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Schaefer L, Macakova K, Raslik I, Micegova M, Grone HJ, Schonherr E, et al. Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction. Am J Pathol. 2002;160(3):1181–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. de Kluijver J, Schrumpf JA, Evertse CE, Sont JK, Roughley PJ, Rabe KF, et al. Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma. Clin Exp Allergy. 2005;35(10):1361–9.

    Article  PubMed  Google Scholar 

  28. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994;90(2):844–53.

    Article  CAS  PubMed  Google Scholar 

  29. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH. Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation. 2006;114(1 Suppl):I547–52.

    PubMed  Google Scholar 

  30. Kaden JJ, Kilic R, Sarikoc A, Hagl S, Lang S, Hoffmann U, et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med. 2005;16(5):869–72.

    CAS  PubMed  Google Scholar 

  31. Oak S, Mandrekar P, Catalano D, Kodys K, Szabo G. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. J Immunol. 2006;176(12):7628–35.

    Article  CAS  PubMed  Google Scholar 

  32. Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol. 2007;82(2):237–43.

    Article  CAS  PubMed  Google Scholar 

  33. Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res. 2012;53(9):2002–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A, et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol. 2004;172(8):4733–43.

    Article  CAS  PubMed  Google Scholar 

  35. Medvedev AE, Kopydlowski KM, Vogel SN. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J Immunol. 2000;164:5564–74.

    Article  CAS  PubMed  Google Scholar 

  36. Lehmann S, Walther T, Kempfert J, Rastan A, Garbade J, Dhein S, et al. Mechanical strain and the aortic valve: influence on fibroblasts, extracellular matrix, and potential stenosis. Ann Thorac Surg. 2009;88(5):1476–83.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by National Institutes of Heart, Lung and Blood Grant HL106582.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Colorado Denver, 12700 E 19th Avenue, Box C-320, Aurora, CO, 80045, USA

    Rui Song, Lihua Ao, Daniel Zheng, Neil Venardos, David A. Fullerton & Xianzhong Meng

  2. Department of Pathophysiology, Southern Medical University, Guangzhou, China

    Rui Song & Ke-seng Zhao

Authors
  1. Rui Song
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Lihua Ao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Ke-seng Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Daniel Zheng
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Neil Venardos
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. David A. Fullerton
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Xianzhong Meng
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Xianzhong Meng.

Additional information

Responsible Editor: Bernhard Gibbs.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, R., Ao, L., Zhao, Ks. et al. Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway. Inflamm. Res. 63, 703–710 (2014). https://doi.org/10.1007/s00011-014-0743-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-014-0743-3

Keywords

Profiles

  1. Rui Song View author profile