YAP/TAZ affects the development of pulmonary fibrosis by regulating multiple signaling pathways

Zhu, Ting; Ma, Zhifeng; Jia, Xiaomin; Wu, Yifan; Fu, Linhai; Li, Zhupeng; Zhang, Chu; Yu, Guanzhen

doi:10.1007/s11010-020-03866-9

Cited by 14 publications

(9 citation statements)

References 127 publications

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“…Endothelial YAP/TAZ signaling is an important pathway for angiogenesis and tumor vascularization (92), pulmonary fibrosis (93,94), and production of endothelin-1 (95), an endothelium-derived constricting factor (EDCF) that causes pulmonary vasoconstriction and vascular remodeling (96)(97)(98)(99) and RV hypertrophy (100). One of the downstream signaling pathways of Piezo1/2-mediated mechanotransduction is the YAP signaling pathway (101)(102)(103)(104)(105).…”

Section: Discussionmentioning

confidence: 99%

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Wang

Chen

Babicheva

et al. 2021

American Journal of Physiology-Cell Physiology

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Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared to normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

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Section: Discussionmentioning

confidence: 99%

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Wang

Chen

Babicheva

et al. 2021

American Journal of Physiology-Cell Physiology

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“…Transcriptional changes downstream of G protein signaling and YAP/TAZ modulation regulate fibroblast biology in the setting of lung fibrosis (Haak et al, 2020;Zhu et al, 2020). We recently published microarray experiments of lung fibroblasts stimulated with TGFβ after knocking down YAP and TAZ expression by siRNA and reported dramatic changes in genes that regulate cellular contractility (Link et al, 2022).…”

Section: Receptor Specific Effects On Fibrosis Associated Gene Expres...mentioning

confidence: 99%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

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Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and TGF-β1 signaling which together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors which couple to G alpha s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors which couple to G alpha s, in IPF patient-derived fibroblasts compared to non-IPF samples. Of the 14 G alpha s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-β1 signaling, with the β2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and β2 receptor agonists +/-TGF-β1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of β2 receptor agonists was lost, while D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-β1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-β1 signaling.

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“…Activated YAP/TAZ signaling pathway leads to prompting of nuclear transcription factors for TGF-β1, CTGF, type I receptor TGF (TGFB1R), type II receptor TGF (TGFB2R), collagen type I alpha 1 chain (COL1A1), collagen type III alpha 1 chain (COL3A1), tissue inhibitor of metalloproteinase 1(TIMP1) and fibronectin (Noguchi et al 2018 ). Zhu et al ( 2020 ) showed that activation of YAP/TAZ pathway is allied with the development of pulmonary fibrosis and pharmacological targeting of this pathway may attenuate inflammatory-induced pulmonary fibrosis. Selective YAP/TAZ pathway inhibitors such as dopamine type 1 receptor agonists inhibit pulmonary fibrosis by restraining the conversion of pro-fibrotic pulmonary extracellular matrix to fibrotic state (Haak et al 2019 ).…”

Section: Role Of Pirfenidone In Post-covid-19 Pulmonary Fibrosismentioning

confidence: 99%

Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

Al-Kuraishy¹,

Batiha

Faidah

et al. 2022

Inflammopharmacol

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Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fibrosis commonly named post-Covid-19 pulmonary fibrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fibrosis. The precise mechanism of post-Covid-19 pulmonary fibrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fibroblast proliferation, fibroblast migration and myofibroblast conversion. PFN inhibits accumulation and recruitment of inflammatory cells, fibroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-inflammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein effector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription Co-Activator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fibrosis. In conclusion, the anti-inflammatory and anti-fibrotic properties of PFN may attenuate post-Covid-19 pulmonary fibrosis.

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YAP/TAZ affects the development of pulmonary fibrosis by regulating multiple signaling pathways

Cited by 14 publications

References 127 publications

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

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