ArticleMolecular and cellular biochemistry2022
Endothelin-1 mediated glycosaminoglycan synthesizing gene expression involves NOX-dependent transactivation of the transforming growth factor-β receptor.
Article in Molecular and cellular biochemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed, 13 citations in OpenAlex.
- Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling.Acta pharmacologica Sinica · 2025Review
- The vascular microenvironment and its stem cells regulate vascular homeostasis.Frontiers in cell and developmental biology · 2025Review
- Transforming growth factor-β receptors: versatile mechanisms of ligand activation.Acta pharmacologica Sinica · 2024Review
- Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells.International journal of molecular sciences · 2022Article
- Endothelin-1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation.Clinical and experimental pharmacology & physiology · 2022Article
- Endothelin-1 Induced Phosphorylation of Caveolin-1 and Smad2C in Human Vascular Smooth Muscle Cells: Role of NADPH Oxidases, c-Abl, and Caveolae Integrity in TGF-β Receptor Transactivation.International journal of molecular and cellular medicine · 2022Article
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8 authors at 3 institutions in 3 countries.
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Abstract
G protein-coupled receptor (GPCR) agonist endothelin-1 (ET-1) through transactivation of the transforming growth factor (TGF) β receptor (TGFBR1) stimulates glycosaminoglycan (GAG) elongation on proteoglycans. GPCR agonists thrombin and lysophosphatidic acid (LPA) via respective receptors transactivate the TGFBR1 via Rho/ROCK dependent pathways however mechanistic insight for ET-1 transactivation of the TGFBR1 remains unknown. NADPH oxidase (NOX) generates reactive oxygen species (ROS) and is a signalling entity implicated in the pathogenesis of many diseases including atherosclerosis. If implicated in this pathway, NOX/ROS would be a potential therapeutic target. In this study, we investigated the involvement of NOX in ET-1/ET receptor-mediated transactivation of TGFBR1 to stimulate mRNA expression of GAG chain synthesizing enzymes chondroitin 4-O-sulfotransferase 1 (C4ST-1) and chondroitin sulfate synthase 1 (ChSy-1). The invitro model used vascular smooth muscle cells that were treated with pharmacological antagonists in the presence and absence of ET-1 or TGF-β. Proteins and phosphoproteins isolated from treated cells were quantified by western blotting and quantitative real-time PCR was used to assess mRNA expression of GAG synthesizing enzymes. In the presence of diphenyliodonium (DPI) (NOX inhibitor), ET-1 stimulated phospho-Smad2C levels were inhibited. ET-1 mediated mRNA expression of GAG synthesizing enzymes C4ST-1 and ChSy-1 was also blocked by TGBFR1 antagonists, SB431542, broad spectrum ET receptor antagonist bosentan, DPI and ROS scavenger N-acetyl-L-cysteine. This work shows that NOX and ROS play an important role in ET-1 mediated transactivation of the TGFBR1 and downstream gene targets associated with GAG chain elongation. As ROS is involved in GPCR to protein tyrosine kinase receptor transactivation, the NOX/ROS axis presents as the first common biochemical target in all GPCR to kinase receptor transactivation signalling.
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