Activation of ET<sub>B</sub> receptors regulates the abundance of ET‐1 mRNA in vascular endothelial cells

Farhat, Nada; Matouk, Charles; Mamarbachi, Aida M.; Marsden, Philip A.; Allen, Bruce G.; Thorin, Éric

doi:10.1038/bjp.2008.25

Cited by 21 publications

(13 citation statements)

References 60 publications

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“…In this regard, CSE was able to increase supernatant ET levels that were consequently suppressed by bosentan and BQ123 and, to a lesser extent, by BQ788. These results are apparently in contrast with previous reports where exposure to BQ788 and bosentan increased ET-1 mRNA in endothelial cells [27]. This effect was explained because extracellular levels of ET-1 are cleared via endocytosis of ETB; thus, its blockade impedes extracellular ET-1 clearance, inducing ET-1 upregulation.…”

Section: Discussioncontrasting

confidence: 98%

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Milara

Gabarda²,

Juan³

et al. 2011

Eur Respir J

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The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients.This study examined the effect of cigarette smoke (CS) on ET receptor A (ETA) and B (ETB) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences.CS extract (CSE) increased ETA and ETB expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ETA antagonist BQ123 and the ETB antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ETA and ETB than those of nonsmoker patients.These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.KEYWORDS: Bosentan, cigarette smoke, endothelin receptor, human pulmonary artery smooth muscle cells, precision-cut lung slice P ulmonary hypertension (PH) is a relatively common form of cigarette smoke (CS)-induced lung disease. PH develops in ,6% of subjects with chronic obstructive pulmonary disease (COPD) but is present in ,40% of patients with a forced expiratory volume in 1 s of ,1 L [1, 2]. The pathogenesis of PH in COPD is unclear. Current studies suggest that PH is caused by the direct effects of CS on the intrapulmonary vessels by the secretion of a number of vasoconstrictive/proliferative peptides, such as endothelin (ET) or vascular endothelial growth factor, which subsequently contribute to vascular remodelling and the development of PH [3]. The circulating levels of ET-1 are elevated after exposure to CS in humans [4] and it has been shown that ET-1 correlates with pulmonary systolic pressure in COPD patients with PH [5], suggesting that ET-1 is involved in CS-induced vascular remodelling. ET-1 activates two receptors, ETA and ETB, which are located in pulmonary artery smooth muscle cells (PASMCs), whilst exclusively ETB are present in endothelial cells. Both ETA and ETB mediate proliferation and contractility in PASMCs from small pulmonary arteries, while endothelial ETB mediates vasodilation in normal pulmonary arteries. ETB upregulation has been observed in human blood vessels from patients with ischaemic heart disease [6], hypertension [7] and severe PH [8]. More recently, it has been shown that CS extract (CSE) induces ETA and ETB overexpression in resistant cerebral arteries from rats by a mechanism implicating the activation of the intracellular m...

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Section: Discussioncontrasting

confidence: 98%

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Milara

Gabarda²,

Juan³

et al. 2011

Eur Respir J

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“…In endothelial cells, ET-1 production is regulated at the level of transcription, mRNA stability, and maturation of the ET precursor protein, preproendothelin. Whereas extracellular ET-1 reduces the cellular content of ET-1 mRNA in endothelial cells [74], Ang II, oxidized LDL, insulin, isoproterenol, thrombin, TGFβ, TNFα, verotoxin, and VEGF increase ET-1 mRNA abundance [75][76][77]. The best characterized intracrine signalling system is that of peptidergic agonist, Ang II.…”

Section: Discussionmentioning

confidence: 99%

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Merlen¹,

Farhat²,

Luo³

et al. 2013

Journal of Molecular and Cellular Cardiology

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Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca 2+ signalling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei. Furthermore, in both cardiac myocytes and aortic endothelial cells, endocytosed ET:ETB complexes translocated to lysosomes and not the nuclear envelope. Although ETA and ETB can form heterodimers, the presence or absence of ETA did not alter ETB trafficking. Treatment of isolated nuclei with * Abbreviations: The abbreviations used are: 2-APB, 2-aminoethoxydiphenyl borate; A, Angiotensin II; αAR, α-adrenergic receptor;[Ca 2+ ] n , nucleoplasmic free calcium concentration; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; DMNB, 4,5-dimethoxynitrobenzyl group; DNA, deoxyribonucleic acid; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DTT, dithiothreitol; ECE1-a, endothelin converting enzyme 1a; cET-1, caged ET-1; caged ET-1, [Trp-ODMNB 21 ]ET-1; ET-1, endothelin 1; ET-2, endothelin 2; ET-3, endothelin 3; ETA, endothelin type A receptor; ETB, endothelin type B receptor; ETR, endothelin receptor; GPCR, G protein-coupled receptor; HDAC5; histone deacetylase 5; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate receptor; ISO, isoproterenol; MEF2, myocyte enhancing factor-2; PBS, phosphate buffered saline; PMSF, phenylmethanesulphonylfluoride; PNGase F, peptide N-glycosidase F; qPCR, quantitative real-time polymerase chain reaction; RNA, ribonucleic acid; RyR, ryanodine receptor; TCA, trichloroacetic acid; TFA, trifluoroacetic acid; TX-100, Triton X-100. Address correspondence to: Bruce G. Allen, Montreal Heart Institute, 5000 Belanger St,. Montréal, Québec, Canada, H1T 1C8., Telephone: (514) ] n whereas extracellular application of ETA and ETB receptor antagonists did not. These data suggest that 1) the endothelin receptor in the cardiac nuclear membranes is ETB, 2) ETB traffic directly to the nuclear membrane after biosynthesis, 3) exogenous endothelins are not ligands for ETB on nuclear membranes, and 4) ETB associated with the nuclear membranes regulate nuclear Ca 2+ signalling.

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“…The potency of ET-1 is unequaled, with the exception of urotensin II (À log[EC 50 ] ¼ 9.5; Douglas et al, 2000). ET-1 elicits its effects through two receptors (http://www.iuphar.org/): ET A receptors, located in vascular smooth muscle cells (VSMC) and cardiomyocytes, mediate contraction, whereas ET B receptors, located on vascular endothelial cells (EC), mediate dilation and ET-1 uptake, and regulate ET-1 production (Arai et al, 1990;Barton & Yanagisawa, 2008;Brunner et al, 2006;Callera et al, 2007;Dupuis et al, 1997;Farhat et al, 2008;Komukai et al, 2010;Rubanyi & Polokoff, 1994;Sakurai et al, 1990;Sanchez et al, 2002). Additionally, ET B receptors can also be expressed on VSMC and elicit contractions (Sanchez et al, 2002;Teerlink et al, 1994).…”

Section: Cardiovascular Physiology Of Etmentioning

confidence: 99%

The Cardiovascular Physiology and Pharmacology of Endothelin-1

Thorin

Clozel

2010

Advances in Pharmacology

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One year after the discovery in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21 amino acids) peptide were quickly determined in humans and it was reported that in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then recognized as a likely mediator of pathological vasoconstriction in human. The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of bosentan, which entered clinical development in 1993, and was offered to patients with pulmonary arterial hypertension in 2001. In this report, we discuss the physiological and pathophysiological role of endothelium-derived ET-1, the pharmacology of its two receptors, focusing on the regulation of the vascular tone and as much as possible in humans. The coronary bed will be used as a running example, but references to the pulmonary, cerebral, and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of NO and ET-1, in which the implication of the ET(B) receptor may be central.

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Activation of ET_B receptors regulates the abundance of ET‐1 mRNA in vascular endothelial cells

Cited by 21 publications

References 60 publications

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

The Cardiovascular Physiology and Pharmacology of Endothelin-1

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Activation of ETB receptors regulates the abundance of ET‐1 mRNA in vascular endothelial cells

Cited by 21 publications

References 60 publications

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

The Cardiovascular Physiology and Pharmacology of Endothelin-1

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Activation of ET_B receptors regulates the abundance of ET‐1 mRNA in vascular endothelial cells