Endothelin-1 (ET-1) stimulates carboxy terminal Smad2 phosphorylation in vascular endothelial cells by a mechanism dependent on ET receptors and <i>de novo</i> protein synthesis

Sharifat, Narges; Zadeh, Ghorban Mohammad; Ghaffari, Mohammad-Ali; Dayati, Parisa; Kamato, Danielle; Little, Peter J.; Babaahmadi‐Rezaei, Hossein

doi:10.1111/jphp.12654

Cited by 23 publications

(21 citation statements)

References 33 publications

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“…ET-1 is a 21-amino-acid peptide with a powerful vasoconstrictor effect in conductive and resistive arteries [41]. The balance between ET-1 and NO provides an endothelial barrier to lipoprotein influx and macrophage recruitment, stimulating cell proliferation and contributing to endothelial dysfunction.…”

Section: Endothelin-1mentioning

confidence: 99%

The emerging role of cell senescence in atherosclerosis

Zheng

Wang

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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Cell senescence is a fundamental mechanism of aging and appears to play vital roles in the onset and prognosis of cardiovascular disease, fibrotic pulmonary disease, liver disease and tumor. Moreover, an increasing body of evidence shows that cell senescence plays an indispensable role in the formation and development of atherosclerosis. Multiple senescent cell types are associated with atherosclerosis, senescent human vascular endothelial cells participated in atherosclerosis via regulating the level of endothelin-1 (ET-1), nitric oxide (NO), angiotensin II and monocyte chemoattractant protein-1 (MCP-1), senescent human vascular smooth muscle cells-mediated plaque instability and vascular calcification via regulating the expression level of BMP-2, OPN, Runx-2 and inflammatory molecules, and senescent macrophages impaired cholesterol efflux and promoted the development of senescent-related cardiovascular diseases. This review summarizes the characteristics of cell senescence and updates the molecular mechanisms underlying cell senescence. Moreover, we also discuss the recent advances on the molecular mechanisms that can potentially regulate the development and progression of atherosclerosis.

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Section: Endothelin-1mentioning

confidence: 99%

The emerging role of cell senescence in atherosclerosis

Zheng

Wang

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…It was originally discovered that Ang II activated the PTK receptors in the fibroblast cells in a process that was termed transactivation . Later, other studies showed that various GPCR agonists such as ET‐1 and thrombin are able to activate other receptors such as PTKR and S/TKR in VSMCs . In 2013, Burch et al .…”

Section: Discussionmentioning

confidence: 99%

“…They also showed that thrombin can mediate the phosphorylation of Smad2C via cytoskeleton/ROCK/integrin axis, leading to activation of the TβRI and phosphorylation of Smad2C (Ser465/467); thrombin via transactivation of these two kinase receptors increases the synthesis of proteoglycans in VSMCs. Our group showed that ET‐1 phosphorylated C‐terminal Smad2 in endothelial cells via transactivation of TβRI but downstream mediators that involved in TβRI transactivation remained unknown …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, any factor that increases the production of proteoglycans, leading to the increased binding and trapping of lipoproteins, will be associated with increased development of atherosclerotic plaques. In our previous study, we reported that ET‐1 via transactivation of TβRI leads to phosphorylation of Smad2C in BAECs, but mechanistic details of this pathway remained unknown. Therefore, in the present study, we identified the effective intermediates of ET receptor to TβRI transactivation and subsequently evaluated protein level of the CHSY‐1 enzyme as target gene in this transactivation pathway.…”

Section: Introductionmentioning

confidence: 99%

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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

Little

Niayesh-Mehr

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives TGF‐β through hyperelongation of glycosaminoglycan (GAG) chains leads to binding of low‐density lipoproteins to the proteoglycans. The vasoactive peptide, endothelin‐1 (ET‐1), plays a key role in the development of atherosclerosis. This study addressed the question whether ET‐1 by activating the Rho kinase and cytoskeletal rearrangement can transactivate the TGF‐β receptor leading to phosphorylation of the transcription factor Smad2 and increased expression of the GAG chain synthesizing enzyme such as chondroitin synthase‐1 (CHSY‐1) in bovine aortic endothelial cells (BAECs). Methods In this study, intermediates in ET‐1‐induced Smad2C phosphorylation and the protein level of CHSY‐1 were identified and quantified by Western blotting. Key findings Endothelin‐1 caused time‐dependent phosphorylation of Smad2C which was inhibited in the presence of the endothelin B receptor antagonist, BQ788. The response to ET‐1 was inhibited by the Rho/ROCK kinase antagonist, Y27632 and by cytochalasin D, an inhibitor of actin polymerization but the ET‐1‐mediated pSmad2C was not inhibited by the matrix metalloproteinase (MMP) inhibitor, GM6001. ET‐1 increased CHSY‐1 protein level, which was inhibited in the presence of BQ788, cytochalasin D and Y27632. Conclusions Endothelin‐1 signalling via the ETB receptor utilizes cytoskeletal rearrangement and Rho kinase but not MMPs leading to TβRI transactivation signalling and phosphorylation of Smad2C and through this pathway increased the level of CHSY‐1.

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“…Since the original observations, this paradigm has recently been expanded to include the transactivation of serine/threonine kinase receptors (S/TKR) notably transforming growth factor (TGF)-β type 1 receptor (TGFBR1). In human vascular smooth muscle cells (VSMCs), treatment with thrombin (12,13) or endothelin-1 (ET-1) (14,15) stimulates carboxy terminal phosphorylation of the transcription factor Smad2. This response was blocked by the TGFBR1 antagonist, SB431542, indicating that the response arises from GPCR transactivation of TGFBR1 (13,14,16,17).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

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Endothelin-1 (ET-1) stimulates carboxy terminal Smad2 phosphorylation in vascular endothelial cells by a mechanism dependent on ET receptors and de novo protein synthesis

Abstract: In BAECs, ET-1 via the ETB receptor is involved in transactivation of the TβRI. The transactivation-dependent response is dependent upon de novo protein synthesis.

Cited by 23 publications

References 33 publications

The emerging role of cell senescence in atherosclerosis

The emerging role of cell senescence in atherosclerosis

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

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

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