Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts

Waters, C; Xu, Shiwen; Denton, Chris; Abraham, David; Pearson, Jeremy D.

doi:10.1002/art.21572

Cited by 24 publications

(13 citation statements)

References 35 publications

(35 reference statements)

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“…However, it should be taken into account that dermal fibroblasts may be a further source of increased serum levels of adhesion molecules. ICAM-1 expression on surface fibroblasts is modulated by ET-1 and inflammatory cytokines, is involved in cell–cell and cell–matrix interactions and plays a key role in regulating inflammatory cells binding to dermal tissue 23 24…”

Section: Discussionmentioning

confidence: 99%

Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension

Iannone

Riccardi

Guiducci

et al. 2008

Annals of the Rheumatic Diseases

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Objectives:To study the expression of adhesion molecules in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH) and the effects of therapy with the endothelin-1 (ET-1) receptor antagonist, bosentan.Methods:In all, 35 patients with SSc and 25 healthy donors (HD) were selected for this study. Of 35 patients, 10 had isolated PAH assessed by Doppler echocardiography and treated with bosentan. Peripheral blood (PB) lymphocytes were isolated by density gradient centrifugation, and the expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and L-selectin on CD3 T cells was assessed by double immunofluorescence and flow-cytometry. As endothelial activation markers, serum soluble P-selectin, platelet/endothelial cell adhesion molecule (PECAM)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and von Willebrand factor (vWF) antigen were assessed by ELISA. In patients with SSc-PAH, T cell subsets and soluble endothelial markers were assessed at baseline and after 6 and 12 months of bosentan therapy.Results:In patients with SSc-PAH, serum soluble ICAM-1, VCAM-1, P-selectin and PECAM-1 levels were higher than in HD at baseline and fell to normal values after 12 months of bosentan therapy. CD3–LFA1 T cells were significantly higher in PAH-SSc at baseline than in HD or SSc and significantly decreased after therapy. CD3–L-selectin T cells were significantly lower in SSc-PAH at baseline than in HD or SSc and rose to normal levels after bosentan therapy.Conclusions:This study confirms that endothelial activation occurs in SSc, and suggests that changes in the T cell/endothelium interplay take place in SSc-associated PAH. Bosentan seems to be able to hamper these changes and restore T cell functions in these patients.

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Section: Discussionmentioning

confidence: 99%

Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension

Iannone

Riccardi

Guiducci

et al. 2008

Annals of the Rheumatic Diseases

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“…However, there is evidence that ET B receptors located on vascular smooth muscle cells may mediate some of the pathological effects of ET-1 [54]. In addition, two studies have shown that the ET B receptor is important for adhesion molecule expression in endothelial and dermal cells [9,10]. In cardiovascular disease the ET B receptor may be upregulated [54,55], which could lead to it playing a greater role in the pathological effects of ET-1.…”

Section: Discussionmentioning

confidence: 99%

“…ET-1 is a potent vasoconstrictor [7], but it is also pro-inflammatory [6], inducing vascular cell adhesion molecule (VCAM-1) expression, leukocyte adherence to endothelial cells, smooth muscle cell proliferation and arterial remodelling in vitro [8,9,10,11] and in vivo [4,5,12,13]. Furthermore, high plasma ET-1 levels correlate with raised soluble VCAM-1 levels in the blood of hypertensive patients and are associated with end organ damage [14,15].…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

et al. 2012

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Endothelin-1 (ET-1) stimulates vascular cell adhesion molecule (VCAM-1) expression, a process associated with arterial remodelling. However, the pathways activated by ET-1 that lead to VCAM-1 expression are not fully understood. It is reported that sphingomyelinases are necessary for VCAM-1 expression in response to cytokines. Our aim was to investigate the role of sphingomyelinases in ET-1-induced VCAM-1 expression. Acid and neutral sphingomyelinase activities were measured in extracts from rat mesenteric small arteries (RMSA). ET-1 (1–100 nmol/l) stimulated neutral but not acid sphingomyelinase. The activation was rapid, peaking within 5 min and transient, returning towards baseline by 10 min and inhibited by BQ-788, GW4869 and SB203580, which are inhibitors of ET_B receptor, neutral sphingomyelinase and p38MAPK, respectively. Both GW4869 and SB203580 are reported to inhibit activation of neutral sphingomyelinase 2 implicating it in the response to ET-1. Accordingly we investigated the expression of this isoform and found it was present in RMSA, predominantly in endothelial cells. Treatment of RMSA with ET-1 (1–100 nmol/l) for 16 h increased VCAM-1 expression, which was inhibited by GW4869 and SB203580. These results indicate that ET-1 stimulates arterial VCAM-1 expression through p38MAPK-dependent activation of neutral sphingomyelinases. This suggests a role for sphingolipids in ET-1-induced vascular inflammation in cardiovascular disease.

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“…ET B receptors, like ET A receptors, contribute to the pro-inflammatory action of ET-1: activation of the ubiquitous inflammatory mediator nuclear factor NFkB, increased vascular permeability, neutrophil adhesion, and cytokine release [Loomis et al, 2005;Waters et al, 2006;Wilson et al, 2001]. In transgenic mice, conditional cardiac overexpression of ET-1 in cardiac myocytes caused activation of NFkB, upregulation of the cytokines TNF-a, interleukin-1, interleukin-6, and interferon-g, and early death.…”

Section: Inflammationmentioning

confidence: 98%

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

Clozel¹,

Flores²

2006

Drug Development Research

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Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ET A and ET B , and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ET A antagonism or dual ET A and ET B receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ET B receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ET B receptors, as compared to the physiological state, creating a situation where both ET A and ET B receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ET A /ET B receptor antagonism may be necessary to obtain maximal efficacy. Drug Dev. Res. 67:825-834, 2006.

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Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts

Cited by 24 publications

References 35 publications

Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension

Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension

Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

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