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

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

Superparamagnetic Iron Oxide Nanoparticle-Mediated Forces Enhance the Migration of Schwann Cells Across the Astrocyte-Schwann Cell Boundary In vitro

“…Integrin has been demonstrated to mediate mechanotransduction in various types of cells, including neurons, fibroblasts, epithelial cells, cardiomyocytes, and tendon stem/progenitor cells (Ye et al, 2010; Zhang et al, 2011; Moore et al, 2012; Fiore et al, 2015; Israeli-Rosenberg et al, 2015; Sun X. et al, 2016; Sun Z. et al, 2016; Wang et al, 2016). Recent studies have also shown that integrin plays a vital role in cell migration; the migration of SCs on astrocytes was shown to be clearly integrin-dependent (Nodari et al, 2007; Afshari et al, 2010).…”

Modulation of microenvironment for controlling the fate of periodontal ligament cells: the role of Rho/ROCK signaling and cytoskeletal dynamics

“…Recent studies shed light on the striking roles of transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), which are the downstream effectors of the Hippo pathway (Pan 2010), in mechanotransduction. YAP/TAZ activity requires Rho and tension of the actin cytoskeleton, but is independent of the Hippo cascade (Dupont et al 2011;Wang et al 2016). Our understanding of the entire process of mechanotransduction is yet preliminary, and further in vivo investigation is needed.…”

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

“…YAP is a mechanical sensor whose cellular localization changes in response to various environmental stimuli including cell-cell interaction and alterations of cytoskeletal dynamics (34,35). We assessed whether YAP cellular localization affected CDC42 activity.…”