Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow - PubMed (original) (raw)

. 2016 Dec 22;540(7634):579-582.

doi: 10.1038/nature20602. Epub 2016 Dec 7.

Jiang-Yun Luo 1 2, Bochuan Li 3 4, Xiao Yu Tian 1 2, Li-Jing Chen 5, Yuhong Huang 1 2, Jian Liu 1, Dan Deng 1, Chi Wai Lau 1, Song Wan 6, Ding Ai 3 4, King-Lun Kingston Mak 2, Ka Kui Tong 7, Kin Ming Kwan 7, Nanping Wang 8, Jeng-Jiann Chiu 5, Yi Zhu 3 4, Yu Huang 1 2

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

Li Wang et al. Nature. 2016.

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-Gα13 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-Gα13-RhoA-YAP pathway holds promise as a novel drug target against atherosclerosis.

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