期刊
NATURE
卷 540, 期 7634, 页码 579-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature20602
关键词
-
资金
- Hong Kong Research Grants Council [CUHK2/CRF/12G]
- Natural Science Foundation of China [91339117, 81130002, 31430045]
- RGC [T12-402/13-N, C7055-14G, CUHK14105814]
- Croucher Foundation
- CUHK Vice Chancellor's Discretionary Fund
- Lui Che Woo Foundation
- Ministry of Science and Technology, Taiwan [MOST104-2321-B-400-017, MOST104-2320-B-400-002-MY3]
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(1). 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-G alpha(13) 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-G alpha(13)-RhoA-YAP pathway holds promise as a novel drug target against atherosclerosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据