YAP accelerates vascular senescence via blocking autophagic flux and activating mTOR

Pan, Xiaobo; Wu, Baichang; Fan, Xianglin; Xu, Guanghui; Ou, Caiwen; Chen, Minsheng

doi:10.1111/jcmm.15902

Cited by 36 publications

(27 citation statements)

References 40 publications

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“…[14,15] In aged-vascular tissue, YAP is highly expressed, and inhibition and knockdown of YAP reduce senescence, whereas overexpression of YAP enhances senescence in both vascular endothelial cells and vascular tissues. [16] Additionally, YAP is known as a "mechano-sensor" because of its ability to recognize mechanical microenvironments. [17] For instance, cultured cells can sense the stiffness of cell-adhesive gels: stiff gels that mimic aged tissues promote nuclear YAP localization, whereas soft gels that mimic young tissues promote cytoplasmic YAP localization.…”

Section: Introductionmentioning

confidence: 99%

Delayed Senescence of Human Vascular Endothelial Cells by Molecular Mobility of Supramolecular Biointerfaces

Arisaka

Masuda

Yoda

et al. 2021

Macromolecular Bioscience

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Yes-associated protein (YAP), a transcriptional coactivator of the Hippo signaling pathway, has been widely implicated in vascular aging and diseases. For preventing vascular endothelial cell senescence, the design and development of biomaterials to regulate YAP activity are required. This study prepares polyrotaxane-coated surfaces with molecular mobility and clarifies the role of the mobility on vascular endothelial cell senescence through Hippo-YAP signaling. The polyrotaxane surface with high mobility induces cytoplasmic YAP localization in endothelial cells, whereas the surface with low mobility induces nuclear YAP localization. After serial cultivation of endothelial cells using polyrotaxane surfaces with different mobilities for 35 d, the endothelial cells aged on the polyrotaxane surface with high mobility exhibit higher proliferative potential, smaller spreading size, and lower activity of senescence-associated 𝜷-galactosidase than those aged on the surface with low mobility. These findings suggest that cellular senescence can be delayed by modulating the molecular mobility on polyrotaxane surfaces.

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Section: Introductionmentioning

confidence: 99%

Delayed Senescence of Human Vascular Endothelial Cells by Molecular Mobility of Supramolecular Biointerfaces

Arisaka

Masuda

Yoda

et al. 2021

Macromolecular Bioscience

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“…By far, whether PLAU causes cellular senescence has not been reported in the existing studies. YAP upregulates the expression of PLAU [ 39 ], and YAP promotes senescence in both endothelial cells and smooth muscle cells [ 40 ], suggesting that PLAU may serve as a downstream molecule, contributing to YAP-induced vascular cell senescence. However, in another study on glioma cells, glioblastoma cells, and astrocytes, it was shown that YAP prevents senescence induced by several factors [ 41 , 42 ], and in cancer cells, PLAU accelerates proliferation [ 39 , 43 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

Wan

Liu

et al. 2022

IJMS

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Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.

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“…The figure was obtained using PathFindR from the R package [Colour figure can be viewed at wileyonlinelibrary.com] activity reduces senescence while its overexpression enhances senescence in both vascular endothelial cells and vascular tissues. 48 Moreover, modulation of YAP localization (i.e., cytoplasmic or nuclear) was shown to delay senescence of vascular endothelial cells through subcellular YAP localization. 49 Further studies will be needed to clarify the mechanisms by which the Hippo signaling pathway affects endothelial homeostasis.…”

Section: Discussionmentioning

confidence: 99%

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome

et al. 2022

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Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features.Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating Nur Canpolat and Dingxiao Liu contributed equally to this work.

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YAP accelerates vascular senescence via blocking autophagic flux and activating mTOR

Cited by 36 publications

References 40 publications

Delayed Senescence of Human Vascular Endothelial Cells by Molecular Mobility of Supramolecular Biointerfaces

Delayed Senescence of Human Vascular Endothelial Cells by Molecular Mobility of Supramolecular Biointerfaces

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome

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