c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

Li, Bochuan; He, Jinlong; Lv, Huizhen; Liu, Yajin; Lv, Xue; Zhang, Chenghu; Zhu, Yi; Ai, Ding

doi:10.1172/jci122440

Cited by 110 publications

(112 citation statements)

References 42 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…The athero-protective unidirectional shear flow results in a decrease in the activity of YAP in EC mediated through the integrin/RhoA axis [34]. Most recently, oscillatory shear stress has been shown to lead to YAP activation mediated through the integrin alpha 5beta1 [35]. In embryogenesis, ARHG AP18 is an effector of YAP [21].…”

Section: Discussionmentioning

confidence: 99%

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

et al. 2020

View full text Add to dashboard Cite

Background: Vascular endothelial cell alignment in the direction of flow is an adaptive response that protects against aortic diseases such as atherosclerosis. The RhoGTPases are known to regulate this alignment. We have shown previously that ARHGAP18 in endothelial cells is a negative regulator of RhoC and its expression is essential in flow-mediated alignment. Depletion of ARHGAP18 inhibits alignment and results in the induction of a proinflammatory phenotype. In embryogenesis, ARHGAP18 was identified as a downstream effector of the Yesassociated protein, YAP, which regulates cell shape and size. Methods: We have used siRNA technology to deplete either ARHGAP18 or YAP in human endothelial cells. The in vitro studies were performed under athero-protective, laminar flow conditions. The analysis of YAP activity was also investigated, using high performance confocal imaging, in our ARHGAP18 knockout mutant mice.Results: We show here that loss of ARHGAP18, although decreasing the expression of YAP results in its nuclear localisation consistent with activation. We further show that depletion of YAP itself results in its activation as defined by an in increase in its nuclear localisation and an increase in the YAP target gene, CyR61. Depletion of YAP, similar to that observed for ARHGAP18 depletion, results in loss of endothelial cell alignment under high shear stress mediated flow and also in the activation of NFkB, as determined by p65 nuclear localisation. In contrast, ARHGAP18 overexpression results in upregulation of YAP, its phosphorylation, and a decrease in the YAP target gene Cyr61, consistent with YAP inactivation. Finally, in ARHGAP18 deleted mice, in regions where there is a loss of endothelial cell alignment, a situation associated with a priming of the cells to a pro-inflammatory phenotype, YAP shows nuclear localisation. Conclusion:Our results show that YAP is downstream of ARHGAP18 in mature endothelial cells and that this pathway is involved in the athero-protective alignment of endothelial cells under laminar shear stress. ARHGAP18 depletion leads to a disruption of the junctions as seen by loss of VE-Cadherin localisation to these regions and a concomitant localisation of YAP to the nucleus.

show abstract

Section: Discussionmentioning

confidence: 99%

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

et al. 2020

View full text Add to dashboard Cite

show abstract

“…DF leads to the continuous activation and nuclear translocation of YAP in ECs, which is dependent on integrin α5β1 activation. The activation of integrin α5β1 induces the phosphorylation of YAP at Tyr357 via c-Abl tyrosine kinase, which usually colocalizes with integrin α5 and is activated in cells treated with fibronectin or fluid shear stress 15 . Bosutinib, a tyrosine kinase inhibitor, greatly inhibits the phosphorylation of YAP at Tyr357 and the generation of atherosclerosis in ApoE −/− mice 15 .…”

Section: Introductionmentioning

confidence: 99%

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Yuan

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Atherosclerosis is a multifactorial disease of the vasculature, and shear stress is a crucial regulator of its process. Disturbed flow promotes atherosclerotic effects, while laminar flow has a protective action on the endothelium. Hippo/YAP is a major cascade that senses various mechanical cues and mediates the expression of pro-inflammatory genes. However, the mechanism modulating the transcription factor YAP in response to different patterns of blood flow remains unclear. In this study, we provide evidence that shear stress modulates YAP activity via autophagy in endothelial cells. Laminar flow promoted the expression of the autophagic markers BECLIN 1 and LC3II/LC3I. Autophagy blockade using a chemical inhibitor repressed YAP degradation under laminar flow. Conversely, the induction of autophagy under disturbed flow partially antagonized the nuclear import and transcriptional activation of YAP. In parallel, laminar flow led to the increased expression of SIRT1 protein, a NAD +-dependent deacetylase. Further investigation showed that SIRT1-mediated YAP deacetylation. The forced expression of SIRT1 under disturbed flow effectively attenuated YAP activation and nuclear accumulation, thereby downregulating the expression of proinflammatory genes. In atheroprone vessels of mice receiving rapamycin to induce autophagy, the enhanced expression of SIRT1 was observed together with YAP repression. Altogether, these results show that endothelial autophagy and SIRT1 expression induced by laminar flow contribute to the inhibition of Hippo/YAP signaling and interrupt atherosclerotic plaque formation.

show abstract

“…e mechanotransduction of a grafted vein involves the response to shear stress, cyclic stress, and normal stress. Bondareva reported that oscillatory shear stress (OSS) stimulation for 6 hours could activate the EGR1 and YAP/ TAZ complex in human endothelial cells, based on ChIP-seq and luciferase assays [26]. Moreover, Moonen et al suggested that disturb laminar shear stress (LSS) could aggravate endothelial-to-mesenchymal transition (EndMT), targeting MEK5 signaling, eventually leading to neointimal hyperplasia [27].…”

Section: Discussionmentioning

confidence: 99%

Reconstruction of a lncRNA-Associated ceRNA Network in Endothelial Cells under Circumferential Stress

Huang

Winata

Zhang

et al. 2020

Cardiology Research and Practice

View full text Add to dashboard Cite

Background. Numerous studies have highlighted that long noncoding RNA (lncRNA) can indirectly regulate the expression of mRNAs by binding to microRNA (miRNA). LncRNA-associated ceRNA networks play a vital role in the initiation and progression of several pathological mechanisms. However, the lncRNA-miRNA-mRNA ceRNA network in endothelial cells under cyclic stretch is seldom studied. Methods. The miRNA, mRNA, and lncRNA expression profiles of 6 human umbilical vein endothelial cells (HUVECs) under circumferential stress were obtained by next-generation sequencing (NGS). We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the R software package GDCRNATools. Cytoscape was adopted to construct a lncRNA-miRNA-mRNA ceRNA network. In addition, through GO and KEGG pathway annotations, we analyzed gene functions and their related pathways. We also adopted ELISA and TUNEL to investigate the effect of si-NEAT1 on endothelial inflammation and apoptosis. Results. We recognized a total of 32978 lncRNAs, 1046 miRNAs, and 31958 mRNAs in 6 samples; among them, 155 different expressed lncRNAs, 74 different expressed miRNAs, and 960 different mRNAs were adopted. Based on the established theory, the ceRNA network was composed of 13 lncRNAs, 44 miRNAs, and 115 mRNAs. We constructed and visualized a lncRNA-miRNA-mRNA network, and the top 20 nodes are identified after calculating their degrees. The nodes with most degrees in three kinds of RNAs are hsa-miR-4739, NEAT1, and MAP3K2. Functional analysis showed that different biological processes enriched in biological regulation, response to stimulus and cell communication. Pathway analysis was mainly enriched in longevity regulating, cell cycle, mTOR, and FoxO signaling pathway. Circumferential stress can significantly downregulate NEAT1, and after transducing si-NEAT1 for 24 h, inflammatory cytokine IL-6 and MCP-1 were significantly increased; furthermore, fewer TUNEL-positive cells were found in the si-NEAT1 treated group. Conclusions. The establishing of a ceRNA network can help further understand the mechanism of vein graft failure. Our data demonstrated that NEAT1 may be a core factor among the mechanical stress factors and that cyclic stress can significantly reduce expression of NEAT1, give rise to inflammation in the early stage of endothelial dysfunction, and promote EC apoptosis, which may play an essential role in vein graft failure.

show abstract

c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

Cited by 110 publications

References 42 publications

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Reconstruction of a lncRNA-Associated ceRNA Network in Endothelial Cells under Circumferential Stress

Contact Info

Product

Resources

About