國家衛生研究院 NHRI:Item 3990099045/10043

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Title:	Toll-like receptor 2 promotes vascular calcification via the chondrogenic transdifferentiation of vascular smooth muscle cells
Authors:	Lee, GL;Kuo, CC
Contributors:	Institute of Cellular and Systems Medicine
Abstract:	Objective: vascular smooth muscle cell (VSMC) transformation to osteoblast/ chondrocyte Phenotype is an initiative event for arterial calcification, which is highly correlated with cardiovascular disease morbidity and mortality. Toll-like receptors (TLRs) play key roles in the development of vascular diseases, but their regulation in vascular calcification remains unclear. Methods and results: Calcification assays by Alizarin red S staining revealed that TLR2 agonists promoted VSMC calcification. TLR2 deficiency or inhibition of TLR2 signaling with anti-TLR2 antibody suppressed TLR2 agonist-induced VSMC calcification and IL-6 production. Neutralizing anti-IL-6 antibodies impaired TLR2-mediated VSMC calcification, while addition of IL-6 recombinant protein promoted VSMC calcification. Additionally, ApoE-/- mice fed high-fat diet (HFD) exhibited vascular calcium accumulation and serum IL-6 elevation, which were ameliorated in Tlr2-/-ApoE-/- mice. Further studies demonstrated that TLR2 agonist time-dependently increased chondrogenic transdifferentiation transcription factors SOX9 and osterix but suppressed osteo/chondrogenic transdifferentiation transcription factor Runx2 and osteoprotegerin (OPG) in wild-type but not in Tlr2 -/- VSMCs. Furthermore, TLR2-induced transdifferentiation of wild-type VSMCs into chondrogenic cells was suppressed by both of neutralizing anti-IL6 antibodies and OPG recombinant protein. Conclusions: Our results suggest that upon ligand binding, TLR2 promotes chondrogenic transdifferentiation of VSMC via modulating expression of IL-6 and OPG production, SOX9 and osterix. The chondrogenic VSMCs in turn contributes to vascular calcification during the pathogenesis of atherosclerosis.
Date:	2016-08
Relation:	European Journal of Immunology. 2016 Aug;46(Suppl. 1):371.
Link to:	http://dx.doi.org/10.1002/eji.201670200
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0014-2980&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000383610400745
Appears in Collections:	[Cheng-Chin Kuo] Conference Papers/Meeting Abstract

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