Integrin YAP/TAZ JNK cascade mediates atheroprotective effect of unidirectional shear flow
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 Ga13 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 Ga13 RhoA YAP pathway holds promise as a novel drug target against atherosclerosis.
Nature