Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow

Yu Huang, Li Wang, Jiang Yun Luo, Bochuan Li, Xiao Yu Tian, Li Jing Chen, Yuhong Huang, Jian Liu, Dan Deng, Chi Wai Lau, Song Wan, DIng Ai, King Lun Kingston Mak, Ka Kui Tong, Kin Ming Kwan, Nanping Wang, Jeng Jiann Chiu, Yi Zhu

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132 Citations (Scopus)

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-Gα 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 MnCl 2 reduces plaque formation. Taken together, our results indicate that integrin-Gα 13-RhoA-YAP pathway holds promise as a novel drug target against atherosclerosis.

Original languageEnglish
Pages (from-to)579-582
Number of pages4
JournalNature
Volume540
Issue number7634
DOIs
Publication statusPublished - Dec 22 2016
Externally publishedYes

ASJC Scopus subject areas

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    Huang, Y., Wang, L., Luo, J. Y., Li, B., Tian, X. Y., Chen, L. J., Huang, Y., Liu, J., Deng, D., Lau, C. W., Wan, S., Ai, DI., Mak, K. L. K., Tong, K. K., Kwan, K. M., Wang, N., Chiu, J. J., & Zhu, Y. (2016). Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature, 540(7634), 579-582. https://doi.org/10.1038/nature20602