Endothelin-1 increases CHSY-1 expression in aortic endothelial cells via transactivation of transforming growth factor β type I receptor induced by type B receptor endothelin-1

Seif, Faezeh; Little, Peter J.; Niayesh-Mehr, Reyhaneh; Zamanpour, Masoumeh; Babaahmadi‐Rezaei, Hossein

doi:10.1111/jphp.13081

Cited by 11 publications

(7 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings provide a better understanding of the signaling pathway controlling the length of proteoglycan GAG that promotes lipoprotein binding in the vessel wall and the development of atherosclerosis 43 . Furthermore, endothelin-1 signaling via ETB receptor (endothelin-1 type B receptor) utilizes cytoskeletal rearrangements and Rho (ROCK) kinase, but not map, leading to transactivation signaling of TβRI (transforming growth factor beta type I receptor) and phosphorylation of Smad2C, and increases CHSY-1 levels via this pathway 44 . In addition, a recent study on rat retinal microvascular endothelial cells (rrmec) showed that hyperglycemia in rrmec leads to significantly elevated mRNA levels of GAG biosynthetic enzymes (including extl -1,2,3, ext -1,2, chsy -1,3, and has2,3), and that these elevations may be a compensatory response to overall glycocalyx loss 45 .…”

Section: Discussionmentioning

confidence: 99%

Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms

Zhang,

Li,

Chen

et al. 2023

Sci Rep

View full text Add to dashboard Cite

Aortic dissection (AD) is a life-threatening condition in which the inner layer of the aorta tears. It has been reported that metabolic syndrome (MS) has a close linkage with aortic dissection. However, the inter-relational mechanisms between them were still unclear. This article explored the hub gene signatures and potential molecular mechanisms in AD and MS. We obtained five bulk RNA-seq datasets of AD, one single cell RNA-seq (scRNA-seq) dataset of ascending thoracic aortic aneurysm (ATAA), and one bulk RNA-seq dataset of MS from the gene expression omnibus (GEO) database. Identification of differentially expressed genes (DEGs) and key modules via weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and machine learning algorithms (Random Forest and LASSO regression) were used to identify hub genes for diagnosing AD with MS. XGBoost further improved the diagnostic performance of the model. The receiver operating characteristic (ROC) and precision-recall (PR) curves were developed to assess the diagnostic value. Then, immune cell infiltration and metabolism-associated pathways analyses were created to investigate immune cell and metabolism-associated pathway dysregulation in AD and MS. Finally, the scRNA-seq dataset was performed to confirm the expression levels of identified hub genes. 406 common DEGs were identified between the merged AD and MS datasets. Functional enrichment analysis revealed these DEGs were enriched for applicable terms of metabolism, cellular processes, organismal systems, and human diseases. Besides, the positively related key modules of AD and MS were mainly enriched in transcription factor binding and inflammatory response. In contrast, the negatively related modules were significantly associated with adaptive immune response and regulation of nuclease activity. Through machine learning, nine genes with common diagnostic effects were found in AD and MS, including MAD2L2, IMP4, PRPF4, CHSY1, SLC20A1, SLC9A1, TIPRL, DPYD, and MAPKAPK2. In the training set, the AUC of the hub gene on RP and RR curves was 1. In the AD verification set, the AUC of the Hub gene on RP and RR curves were 0.946 and 0.955, respectively. In the MS set, the AUC of the Hub gene on RP and RR curves were 0.978 and 0.98, respectively. scRNA-seq analysis revealed that the SLC20A1 was found to be relevant in fatty acid metabolic pathways and expressed in endothelial cells. Our study revealed the common pathogenesis of AD and MS. These common pathways and hub genes might provide new ideas for further mechanism research.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms

Zhang,

Li,

Chen

et al. 2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The GPCR agonist, endothelin-1 (ET-1), signals via ET-1 receptors (ET A and ET B ) to transactivate the TGFBR, leading to the phosphorylation of Smad2 carboxyl terminal in human vascular smooth muscle cells [ 129 ], bovine aortic endothelial cells [ 130 , 131 ] and rat alveolar epithelial cells [ 132 ]. Different ET-1 receptors are involved in the transactivation of the two cell types.…”

Section: Transactivation Of Tgfbr By Different Receptor Signaling Pat...mentioning

confidence: 99%

“…Different ET-1 receptors are involved in the transactivation of the two cell types. ET A receptor transactivates TGFBR in rat alveolar epithelial cells [ 132 ], whereas ET B is the responsible receptor in bovine aortic endothelial cells [ 130 ]. In bovine aortic endothelial cells, ET A recruits ROCK to trigger cytoskeleton rearrangement to activate TGFBR [ 130 ].…”

Section: Transactivation Of Tgfbr By Different Receptor Signaling Pat...mentioning

confidence: 99%

Transforming growth factor-β receptors: versatile mechanisms of ligand activation

Chia,

Cao,

Little

et al. 2024

Acta Pharmacol Sin

View full text Add to dashboard Cite

Transforming growth factor-β (TGF-β) signaling is initiated by activation of transmembrane TGF-β receptors (TGFBR), which deploys Smad2/3 transcription factors to control cellular responses. Failure or dysregulation in the TGF-β signaling pathways leads to pathological conditions. TGF-β signaling is regulated at different levels along the pathways and begins with the liberation of TGF-β ligand from its latent form. The mechanisms of TGFBR activation display selectivity to cell types, agonists, and TGF-β isoforms, enabling precise control of TGF-β signals. In addition, the cell surface compartments used to release active TGF-β are surprisingly vibrant, using thrombospondins, integrins, matrix metalloproteinases and reactive oxygen species. The scope of TGFBR activation is further unfolded with the discovery of TGFBR activation initiated by other signaling pathways. The unique combination of mechanisms works in series to trigger TGFBR activation, which can be explored as therapeutic targets. This comprehensive review provides valuable insights into the diverse mechanisms underpinning TGFBR activation, shedding light on potential avenues for therapeutic exploration.

show abstract

“…For experiments, VSMCs were seeded into 35 mm dishes (qRT-PCR and Western blot experiments) at a density of 4 Â 10 5 / well and grown to confluency and then confluent cultures were serum starved for 24 h by incubation in DMEM/F12 medium containing 0.1% (v/v) FBS and 1% penicillin-streptomycin before experimentation. VSMCs were pre-incubated with inhibitors (bosentan (20 μM), 35 SB431542 (10 μM) 36 and SB239063 (20 μM) for 30 min, NAC (10 mM) 37 for 1 h, DPI (20 μM) and apocynin (20 μM) 37 for 2 h and then exposed to ET-1 (100 nM) 13,38 or TGF-β (2 ng/ml). 39 VSMCs used in experiments were between passages 10-20.…”

Section: Culture Of Human Aortic Smooth Muscle Cellsmentioning

confidence: 99%

Endothelin‐1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation

Babaahmadi‐Rezaei

Mohamed

Dayati

et al. 2022

Clin Exp Pharma Physio

Self Cite

View full text Add to dashboard Cite

Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET-1-mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho-Smad2L) regulate GAG synthesising enzymes mRNA expression (C4ST-1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesising enzymes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). ET-1 treatment of human VSMCs resulted in an increase in phospho-Smad2L level. The TGF-β receptor antagonist, SB431542 and the mixed ET A and ET B receptor antagonist bosentan, inhibited ET-1-mediated phospho-Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET-1-mediated phospho-Smad2L levels were inhibited. The gene expression levels of GAG synthesising enzymes post-ET-1 treatment were increased compared to untreated controls (p < 0.01). The ET-mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N-acetyl-L-cysteine (NAC). ET-1-mediated signalling to GAG synthesising enzymes gene expression occurs via transactivation-dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation.

show abstract

Endothelin-1 increases CHSY-1 expression in aortic endothelial cells via transactivation of transforming growth factor β type I receptor induced by type B receptor endothelin-1

Cited by 11 publications

References 32 publications

Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms

Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms

Transforming growth factor-β receptors: versatile mechanisms of ligand activation

Endothelin‐1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation

Contact Info

Product

Resources

About