GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

Mohamed, Raafat; Janke, Reearna; Guo, W.; Cao, Yanshuo; Zhou, Ying; Zheng, Wenhua; Babaahmadi‐Rezaei, Hossein; Xu, Suowen; Kamato, Danielle; Little, Peter J.

doi:10.1530/vb-18-0004

Cited by 19 publications

(22 citation statements)

References 128 publications

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“…The engagement of receptor transactivation markedly expands the range of cellular responses attributable to the index cell surface, usually transmembrane, receptor. The current attributes of transactivation-dependent signalling encompass GPCR transactivation of kinase receptors [25,49,[59][60][61]. Mechanistic studies of GPCR transactivation-dependent signalling define a concrete signalling pathway [23,24,32,49].…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells

Afroz

Kumarapperuma

Nguyen

et al. 2022

Cell. Mol. Life Sci.

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Toll-like receptors (TLRs) recognise pathogen‑associated molecular patterns, which allow the detection of microbial infection by host cells. Bacterial-derived toxin lipopolysaccharide activates TLR4 and leads to the activation of the Smad2 transcription factor. The phosphorylation of the Smad2 transcription factor is the result of the activation of the transforming growth factor-β receptor 1 (TGFBR1). Therefore, we sought to investigate LPS via TLR4-mediated Smad2 carboxy terminal phosphorylation dependent on the transactivation of the TGFBR1. The in vitro model used human aortic vascular smooth muscle cells to assess the implications of TLR4 transactivation of the TGFBR1 in vascular pathophysiology. We show that LPS-mediated Smad2 carboxy terminal phosphorylation is inhibited in the presence of TGFBR1 inhibitor, SB431542. Treatment with MyD88 and TRIF pathway antagonists does not affect LPS-mediated phosphorylation of Smad2 carboxy terminal; however, LPS-mediated Smad2 phosphorylation was inhibited in the presence of MMP inhibitor, GM6001, and unaffected in the presence of ROCK inhibitor Y27632 or ROS/NOX inhibitor DPI. LPS via transactivation of the TGFBR1 stimulates PAI-1 mRNA expression. TLRs are first in line to respond to exogenous invading substances and endogenous molecules; our findings characterise a novel signalling pathway in the context of cell biology. Identifying TLR transactivation of the TGFBR1 may provide future insight into the detrimental implications of pathogens in pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells

Afroz

Kumarapperuma

Nguyen

et al. 2022

Cell. Mol. Life Sci.

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“…G protein-coupled receptors (GPCR) can signal via transactivation of protein tyrosine kinase (PTK) receptors [18] and protein serine (Ser)/threonine (Thr) kinase (PS/TK) receptors, specifically the TGFBR1 [4,[19][20][21][22]. Our lab has led the work in defining the mechanisms of GPCR transactivation of TGFBR1 [21,23]. We have shown that GPCRs promote cytoskeletal rearrangement that activates Rho GTPases and its downstream substrate Rho-associated protein kinase (ROCK) leading to integrin activation.…”

Section: Introductionmentioning

confidence: 99%

Akt acts as a switch for GPCR transactivation of the TGF‐β receptor type 1

et al. 2021

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Transforming growth factor (TGF)‐β signalling commences with the engagement of TGF‐β ligand to cell surface TGF‐β receptors (TGFBR) stimulating Smad2 carboxyl‐terminal phosphorylation (phospho‐Smad2C) and downstream biological responses. In several cell models, G protein‐coupled receptors (GPCRs) transactivate the TGF‐β receptors type‐1 (TGFBR1) leading to phospho‐Smad2C, however, we have recently published that in keratinocytes thrombin did not transactivate the TGFBR1. The bulk of TGFBRs reside in the cytosol and in response to protein kinase B (Akt phosphorylation) can translocate to the cell surface increasing the cell's responsiveness to TGF‐β. In this study, we investigate the role of Akt in GPCR transactivation of the TGFBR1. We demonstrate that angiotensin II and thrombin do not phosphorylate Smad2C in human vascular smooth muscle cells and in keratinocytes respectively. We used Akt agonist, SC79 to sensitise the cells to Akt and observed that Ang II and thrombin phosphorylate Smad2C via Akt/AS160‐dependent pathways. We show that SC79 rapidly translocates TGFBRs to the cell surface thus increasing the cell's response to the GPCR agonist. These findings highlight novel mechanistic insight for the role of Akt in GPCR transactivation of the TGFBR1.

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“…Previous reports indicated that an alternative signaling pathway is critical for a variety of biological responses. The cross-communication between heterologous signaling systems and protein tyrosine kinases (PTKs), such as c-Src, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor (PDGFR), is involved in various cell types, which can activate downstream signaling pathways such as the PI3K/Akt cascade [ 44 , 45 ]. Previous studies have demonstrated that the transactivation of EGFR or PDGFR is involved in proinflammatory cytokines (e.g., IL-1β) and induced several inflammatory mediators, such as MMPs in rat astrocytes [ 19 ] and human keratinocytes [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Brain Protective Effect of Resveratrol via Ameliorating Interleukin-1β-Induced MMP-9-Mediated Disruption of ZO-1 Arranged Integrity

et al. 2022

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In the central nervous system (CNS), the matrix metalloproteinase-9 (MMP-9) is induced by several factors and contributes to CNS disorders, including inflammation and neurodegeneration. Thus, the upregulation of MMP-9 has been considered to be an indicator of inflammation. Interleukin-1β (IL-1β) is an important proinflammatory cytokine which can induce various inflammatory factors, such as MMP-9, in many inflammatory disorders. Several phytochemicals are believed to reduce the risk of several inflammatory disorders, including the CNS diseases. Among them, the resveratrol, a principal phenolic compound of the grape, blueberry, and mulberry peels and Cassia plants, has been shown to possess several medicinal properties, including antioxidative, anti-inflammatory, and antitumor function. Herein, we used mouse-brain microvascular endothelial cells (bMECs) to demonstrate the signaling mechanisms of IL-1β-induced MMP-9 expression via zymographic, RT-PCR, Western blot, reactive oxygen species (ROS) detection, immunofluorescence stain, and promoter reporter analyses. Then we evaluated the effects of resveratrol on IL-1β-induced MMP-9 expression in bMECs and its mechanism of action. We first demonstrated that IL-1β induced MMP-9 expression in bMECs. Subsequently, IL-1β induced MMP-9 expression via ROS-mediated c-Src-dependent transactivation of EGFR, and then activation of the ERK1/2, p38 MAPK, JNK1/2, and NF-κB signaling pathway. Finally, we determined that IL-1β-induced upregulation of MMP-9 may cause the disruption of the arranged integrity of zonula occludens-1 (ZO-1), but this could be inhibited by resveratrol. These data indicated that resveratrol may have antioxidative and brain-protective activities by reducing these related pathways of ROS-mediated MMP-9 expression and tight junction disruption in brain microvascular endothelial cells.

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GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

Cited by 19 publications

References 128 publications

Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells

Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells

Akt acts as a switch for GPCR transactivation of the TGF‐β receptor type 1

Brain Protective Effect of Resveratrol via Ameliorating Interleukin-1β-Induced MMP-9-Mediated Disruption of ZO-1 Arranged Integrity

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