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

Abstract

YAP and TAZ, effectors of the Hippo pathway, sense mechanical forces generated by blood flow and play a role in atherosclerosis pathogenesis. 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–Gα13–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 stimuli1. 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.

Cite this article

Wang, L., Luo, JY., Li, B. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016). https://doi.org/10.1038/nature20602

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