Journal Article

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

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

2016

Overview

YAP and TAZ, effectors of the Hippo pathway, sense mechanical forces generated by blood flow and play a role in atherosclerosis pathogenesis. Signalling an anti-atherosclerotic effect YAP and TAZ, effectors of the Hippo signalling pathway, have previously been reported to be sensors for mechanical stimuli. Now Yu Huang and colleagues show that these molecules sense mechanical forces generated by blood flow and play a role in atherosclerosis pathogenesis. Atherosclerotic plaques form in regions of disturbed blood flow. The authors show that disturbed flow increases YAP/TAZ activity and increases expression of proinflammatory genes, whereas steady unidirectional shear flow inhibits YAP/TAZ activity through integrin activation. The authors show that in mice, endothelial cell-specific knockdown of YAP retards atherosclerotic plaque formation. This work points to the integrin–Gα 13 –RhoA–YAP pathway as a possible target against atherosclerosis. 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–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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/1338/2100 / 692/699/75/593/2100 / Atherosclerosis / Coronary vessels / Development and progression / Gene expression / Health aspects / Hemodynamics / Humanities and Social Sciences / Integrins / Kinases / letter / Medical research / Medicine, Experimental / multidisciplinary / Phosphorylation / Rodents / Science / Shear stress / Signal transduction / Statins / Studies