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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

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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.

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Acknowledgments

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

Conflict of interest

None.

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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
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  2. Lihua Ao
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  3. Ke-seng Zhao
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  4. Daniel Zheng
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  5. Neil Venardos
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  6. David A. Fullerton
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  7. Xianzhong Meng
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Correspondence to Xianzhong Meng.

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Responsible Editor: Bernhard Gibbs.

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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

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

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