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http://ir.nhri.org.tw/handle/3990099045/10167
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| Title: | Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow |
| Authors: | 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 |
| Contributors: | Institute of Cellular and Systems Medicine |
| Abstract: | 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. |
| Date: | 2016-12-22 |
| Relation: | 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 |
| Appears in Collections: | [裘正健] 期刊論文
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| PUB27926730.pdf | | 8041Kb | Adobe PDF | 494 | View/Open |
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