Inflammatory responses after endothelin B (ETB) receptor activation in human monocytes: New evidence for beneficial anti-inflammatory potency of ETB-receptor antagonism

Juergens, Uwe R.; Racké, Kurt; Uen, Sakir; Haag, Susanne; Lamyel, F.; Stöber, Meinolf; Gillissen, Adrian; Novak, Natalija; Vetter, Hans

doi:10.1016/j.pupt.2007.12.005

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…Endothelin-1 (ET-1), a potent vasoconstrictor, stimulates inflammation through increased NFkB activation, oxidative stress and pro-inflammatory cytokines via the activation of the ET A receptor (Loomis et al, 2005; Yeager et al, 2012) while the activation of the ET B receptor subtype may exert anti-inflammatory actions (Juergens et al, 2008). Elevation of ET-1 has been well documented in patients and experimental models in diabetes (Matsumoto et al, 2004; Takahashi et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

Ward

Ergul

2016

Life Sciences

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Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25 mM), low (5.5 mM) and high (50 mM) glucose conditions with and without palmitate (200 μM) in the presence and absence of 10 μM bosentan for 24 hours. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored.

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Section: Introductionmentioning

confidence: 99%

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

Ward

Ergul

2016

Life Sciences

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“…The small vasoactive peptide endothelin-1 (ET-1) has been shown to mediate the vascular remodeling of PAH by promoting vasoconstriction, smooth muscle proliferation (43), protein synthesis (5), and production of a variety of cytokines and growth factors (18). ET-1 activates a complex cascade of intracellular events by binding to its specific receptors, endothelin receptor A (ET A ) and endothelin receptor B (ET B ).…”

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confidence: 99%

BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

Talati¹,

West²,

Blackwell³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.

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“…The ET B signaling through protein kinases is markedly reduced in pulmonary artery smooth muscle cells in PAH patients carrying a BMPR 2 mutation [22]. Inflammation increases the ET B receptor expression and activation mediated by elevated ET concentration [23]. This data demonstrates that endothelin plays a role in the development and progression of PAH.…”

Section: Introductionmentioning

confidence: 69%

Macitentan for the treatment of pulmonary arterial hypertension

Sood¹

2014

Expert Opinion on Pharmacotherapy

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Macitentan is a more potent ERA and has been shown to delay progression of the disease. It does not appear to have any significant hepatotoxicity and has a convenient once-a-day dosing. In the large event driven trial, macitentan significantly reduced morbidity in patients with PAH. It was safe and well tolerated and the benefit was seen in treatment-naïve patients and those already receiving PAH therapy.

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Inflammatory responses after endothelin B (ETB) receptor activation in human monocytes: New evidence for beneficial anti-inflammatory potency of ETB-receptor antagonism

Cited by 21 publications

References 34 publications

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

Macitentan for the treatment of pulmonary arterial hypertension

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