國家衛生研究院 NHRI:Item 3990099045/10167
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    題名: Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow
    作者: Wang, L;Luo, JY;Li, BC;Tian, XY;Chen, LJ;Huang, Y;Liu, J;Deng, D;Lau, CW;Wan, S;Ai, D;Mak, KKL;Tong, KK;Kwan, KM;Wang, NP;Chiu, JJ;Zhu, Y;Huang, Y
    貢獻者: Institute of Cellular and Systems Medicine
    摘要: The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1), effectors of the Hippo pathway, have been identified as mediators for mechanical stimuli. However, the role of YAP/TAZ in haemodynamics-induced mechanotransduction and pathogenesis of atherosclerosis remains unclear. Here we show that endothelial YAP/TAZ activity is regulated by different patterns of blood flow, and YAP/TAZ inhibition suppresses inflammation and retards atherogenesis. Atheroprone-disturbed flow increases whereas atheroprotective unidirectional shear stress inhibits YAP/TAZ activity. Unidirectional shear stress activates integrin and promotes integrin-Galpha13 interaction, leading to RhoA inhibition and YAP phosphorylation and suppression. YAP/TAZ inhibition suppresses JNK signalling and downregulates pro-inflammatory genes expression, thereby reducing monocyte attachment and infiltration. In vivo endothelial-specific YAP overexpression exacerbates, while CRISPR/Cas9-mediated Yap knockdown in endothelium retards, plaque formation in ApoE-/- mice. We also show several existing anti-atherosclerotic agents such as statins inhibit YAP/TAZ transactivation. On the other hand, simvastatin fails to suppress constitutively active YAP/TAZ-induced pro-inflammatory gene expression in endothelial cells, indicating that YAP/TAZ inhibition could contribute to the anti-inflammatory effect of simvastatin. Furthermore, activation of integrin by oral administration of MnCl2 reduces plaque formation. Taken together, our results indicate that integrin-Galpha13-RhoA-YAP pathway holds promise as a novel drug target against atherosclerosis.
    日期: 2016-12-22
    關聯: Nature. 2016 Dec 22;540:579-582.
    Link to: http://dx.doi.org/10.1038/nature20602
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0028-0836&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000391190500051
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85008231121
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