國家衛生研究院 NHRI:Item 3990099045/12203
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    题名: TLR2 promotes vsmc calcification via the concerted actions of OPG suppression and IL-6-mediated rankl induction
    作者: Lee, GL;Yeh, CC;Wu, JY;Lin, HC;Wang, YF;Kuo, YY;Hsieh, YTH;Hsu, YJ;Kuo, CC
    贡献者: Institute of Cellular and Systems Medicine
    摘要: Background and Aims: Considering the role of inflammation in atherosclerotic progression, including atherosclerosis and atherosclerotic calcification and functional TLR2 promoting inflammation in VSMCs, we postulated that TLR2-mediated inflammation participates in mediating atherosclerotic calcification and VSMC calcification. Methods: we used ApoE-/-Tlr2-/- mice and TLR2 deficient VSMCs to investigate the role ofTLR2 in vascular calcification and VSMC calcification. Results: We found that TLR2 deficiency prohibits atherosclerotic plaque formation in short-term (8 weeks) HFD feeding, but does not prevent the formation of atherosclerotic plaques in long-term HFD-fed mice (20 weeks).However, TLR2 deficiency prohibited HFD-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and osteoprotegerin (OPG) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Further, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL-6-mediated receptor activator of nuclear factor kappa-B ligand (RANKL) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6mediated RANKL induction is signaled by p38 and ERK1/2 pathways, whereas the OPG is suppressed via NF-kB dependent signaling mediated by ERK1/2. Conclusions: TLR2 promotes VSMC chondrogenic differentiation and consequent calcification via the concerted actions of IL-6-mediated RANKL induction and OPG suppression. The IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 pathways, whereas OPG suppression is via NFkB-dependent signaling mediated by ERK1/2. These findings provide mechanistic insights into the key role of TLR2 in atherosclerotic calcification as demonstrated by the reduction of calcification with chondrogenic metaplasia within atherosclerotic lesions in ApoE-/-Tlr2-/- mice.
    日期: 2019-08
    關聯: Atherosclerosis. 2019 Aug;287:E27.
    Link to: http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.078
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0021-9150&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000482110800077
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