Endothelin-1 mediated glycosaminoglycan synthesizing gene expression involves NOX-dependent transactivation of the transforming growth factor-β receptor

Babaahmadi‐Rezaei, Hossein; Little, Peter J.; Mohamed, Raafat; Zadeh, Ghorban Mohammad; Kheirollah, Alireza; Mehr, Reyhaneh Niayesh; Kamato, Danielle; Dayati, Parisa

doi:10.1007/s11010-021-04342-8

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…These studies identify the Gαq as a central integrating point for all PAR-1 transactivation-dependent signalling leading to proteoglycan synthesis and GAG chain elongation and a highly specific target for the prevention of atherosclerosis. This would be particularly pertinent if the observation for thrombin/PAR-1 could be extrapolated to other GPCRs such as endothelin [33,34] and LPA [28,35] which are associated with vascular pathology and GAG chain elongation.…”

Section: Discussionmentioning

confidence: 99%

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells

Kamato

Gabr

Kumarapperuma

et al. 2022

IJMS

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Aims: G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-β receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. Main Methods: Using pharmacological and molecular approaches, we studied the role of the G⍺ subunits, G⍺q and G⍺11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. Key Findings: Pan G⍺q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G⍺q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G⍺q members, G⍺q and G⍺11, only the G⍺q was involved in regulating PAR-1 mediated proteoglycan modification. Although G⍺q and G⍺11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles. Significance: Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.

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Section: Discussionmentioning

confidence: 99%

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells

Kamato

Gabr

Kumarapperuma

et al. 2022

IJMS

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“…Additionally, Gialeli et al (2021) found that the TGF‐β signaling pathway activates TGF‐βRI/Smad2, which then stimulates glycosaminoglycan extension on proteoglycans, facilitating the retention of lipoproteins in smooth muscle cells and macrophages and leading to subendothelial lipid accumulation. Moreover, activation of the alternative TGF‐β/Rho/Rho‐kinase (ROCK) pathway initiates lipid oxidation, contributing to lipid deposition (Babaahmadi‐Rezaei, Little, et al, 2022). Therefore, the TGF‐β signaling pathway has a unique capability to promote lipid deposition and trigger AS plaque formation through various downstream targets.…”

Section: Tgf‐β Signaling Pathwaymentioning

confidence: 99%

Modulation of atherosclerosis‐related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives

Liu,

Guo,

Zhang

2024

Phytotherapy Research

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Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt), NF‐E2‐related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator‐activated receptor (PPAR), nucleotide oligo‐structural domain‐like receptor thermoprotein structural domain‐associated protein 3 (NLRP3), silencing information regulator 2‐associated enzyme 1 (Sirt1), nuclear transcription factor‐κB (NF‐κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor‐β (TGF‐β), and Janus kinase‐signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high‐intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

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“…In bovine aortic endothelial cells, ET A recruits ROCK to trigger cytoskeleton rearrangement to activate TGFBR [ 130 ]. However, in human vascular smooth muscle cells, ET-1 stimulates the activation of TGFBR via NOX, resembling the NOX/ROS-mediated activation of TGFBR observed with apocynin [ 133 ]. These studies show that ROCK or NOX signaling pathways are engaged by ET-1 to stimulate TGFBR activation in different cell types.…”

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

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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.

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Endothelin-1 mediated glycosaminoglycan synthesizing gene expression involves NOX-dependent transactivation of the transforming growth factor-β receptor

Cited by 8 publications

References 38 publications

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells

Modulation of atherosclerosis‐related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives

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

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