Endothelin-2 synthesis is stimulated by the type-1 tumour necrosis factor receptor and cAMP: comparison with endothelin-converting enzyme-1 expression

Lambert, GL; Barker, Stewart; Lees, DM; Corder, Roger

doi:10.1677/jme.0.0240273

Cited by 8 publications

(2 citation statements)

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“…4B). To determine where endothelin-converting enzyme 1 (ECE-1), an enzyme implicated in the processing of big EDN2 to mature EDN2 [37], is expressed in retina, we used immunofluorescence staining. We found that ECE-1 was expressed in Müller cell bodies and radial fibres (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

et al. 2013

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Expression of the Endothelin-2 (Edn2) mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of Edn2 in mutant PR survival, we generated Edn2−/− mice carrying homozygous Pde6brd1 alleles or the Tg(RHO P347S) transgene. In the Edn2−/− background, PR survival increased 110% in Pde6brd1/rd1 mice at post-natal (PN) day 15, and 60% in Tg(RHO P347S) mice at PN40. In contrast, PR survival was not increased in retinal explants of Pde6brd1/rd1; Edn2−/− mice. This finding, together with systemic abnormalities in Edn2−/− mice, suggested that the increased survival of mutant PRs in the Edn2−/− background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5-Edn2 cDNA vector to restore Edn2 expression in Pde6brd1/rd1; Edn2−/− PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5-Edn2 into Pde6brd1/rd1 retinas, by 31% at PN15. Together, these findings suggest that increased Edn2 expression is protective to mutant PRs. To begin to elucidate Edn2-mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in Tg(RHO P347S) retinas, including Fgf2. Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2−/− retinas. Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

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Section: Resultsmentioning

confidence: 99%

Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

et al. 2013

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“…(1991) demonstrated an inhibitory effect of epidermal growth factor in the production of ET‐2 but not ET‐1 in renal adenocarcinoma cells. Lambert et al . (1998; 2000) explored compounds regulating expression of ET‐2 mRNA and secretion of the peptide in human renal adenocarcinoma cell lines.…”

Section: Regulation Of Et Genesmentioning

confidence: 99%

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

Ling

Maguire

Davenport

2012

British J Pharmacology

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Endothelin-2 [ET-2; also known as vasoactive intestinal contractor (VIC), in rodents] differs from endothelin-1 (ET-1) by only two amino acids, and unlike the third isoform, endothelin-3 (ET-3), it has the same affinity as ET-1 for both ETA and ETB receptors. It is often assumed that ET-2 would mimic the actions of the more abundant ET-1 and current pharmacological interventions used to inhibit the ET system would also block the actions of ET-2. These assumptions have focused research on ET-1 with ET-2 studied in much less detail. Recent research suggests that our understanding of the ET family requires re-evaluation. Although ET-2 is very similar in structure as well as pharmacology to ET-1, and may co-exist in the same tissue compartments, there is converging evidence for an important and distinct ET-2 pathway. Specifically is has been demonstrated that ET-2 has a key role in ovarian physiology, with ET-2-mediated contraction proposed as a final signal facilitating ovulation. Furthermore, ET-2 may also have a pathophysiological role in heart failure, immunology and cancer. Comparison of ET-2 versus ET-1 mRNA expression suggests this may be accomplished at the level of gene expression but differences may also exist in peptide synthesis by enzymes such as endothelin converting enzymes (ECEs) and chymase, which may allow the two pathways to be distinguished pharmacologically and become separate drug targets. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi. org/ 10.1111/bph.2013.168.issue-2 Abbreviations ECE-1, endothelin converting enzyme 1; ECE-2, endothelin converting enzyme 2; ELISA, enzyme-linked immunosorbent assay; HIFs, hypoxia-inducible factors; MEK1/2, mitogen-activated protein kinase kinase; MMP-2, matrix metallopeptidase 2; MMP-9, matrix metallopeptidase 9; NEP, neutral endopeptidase; PRKO, progesterone receptor knockout; PMA, phorbol 12-myristate 13 acetate; VIC, vasoactive intestinal contractor IntroductionThe existence of a peptidic endothelium-derived constricting factor was originally proposed in 1985 by Hickey et al. (Hickey et al., 1985) but was identified and named endothelin (ET) by colleagues in 1988 (Yanagisawa et al., 1988). The peptide was renamed ET-1 to reflect the subsequent discovery a year later of human genes encoding two further members of the family, ET-2 and ET-3 (Inoue et al., 1989). The ET peptides act by activating two G-protein couples receptors, ETA and ETB. (Davenport, 2002;Alexander et al., 2011) ET-3 is the only endogenous isoform that distinguishes between the two receptors, having the same affinity at ETB as ET-1 and ET-2 but, at physiological concentrations, has much lower or little affinity for ETA. The established dogma is that ET-2 has the same affinity for both ETA and ETB receptors as ET-1. It is often assumed that ET-2 would mimic the actions of the more abundant peptide, and current pharmacological interventions used to inhibit the ET system would also block the actions o...

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Endothelin und Endothelin‐Rezeptorantagonisten. Wirkungen, Nebenwirkungen und Interaktionen

Dahse

Nieber

2010

Pharmazie in unserer Zeit

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Die Substanzklasse der ET‐Rezeptorantagonisten hat die Therapiemöglichkeiten der PAH erweitert. Die therapieresistente Hypertonie scheint dagegen keine viel versprechende Indikation zu sein. Ein Problem stellt die Lebertoxizität dar. Obwohl bei den selektiven Antagonisten geringer ausgeprägt, sind regelmäßige Kontrolluntersuchungen erforderlich. Ebenfalls nicht ausreichend geklärt ist die Embryotoxizität. Deshalb muss eine Schwangerschaft vor und während der Behandlung mit ET‐Rezeptorantagonisten unbedingt ausgeschlossen werden. Es bleibt abzuwarten, wann weitere ET‐Rezeptorantagonisten mit verbesserter Nutzen‐Risiko‐Relation auf den Markt kommen. Begonnen hat auch die Entwicklung von selektiven ETB‐Rezeptoragonisten. Die intravenös applizierbare Substanz SPI 1620 befindet sich derzeit in Phase‐I‐ und Phase‐II‐Studien als Adjuvans zur Chemotherapie. Auch hier wird die Zukunft zeigen, wie effektiv diese Substanzen sind.

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Endothelin-2 synthesis is stimulated by the type-1 tumour necrosis factor receptor and cAMP: comparison with endothelin-converting enzyme-1 expression

Cited by 8 publications

References 42 publications

Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

Endothelin und Endothelin‐Rezeptorantagonisten. Wirkungen, Nebenwirkungen und Interaktionen

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