title: Tweak up-regulates endothelin-1 system in mouse and human endothelial cells.
abstract: To analyse the ability of TWEAK to modify the endothelin system, particularly endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1), studying the intracellular mechanisms implied. TNF-like weak inducer of apoptosis (TWEAK) is a member of TNF superfamily; it has different biological functions such as inflammation, angiogenesis, proliferation, and apoptosis. TWEAK and fibroblast growth-factor-inducible 14 are expressed in different cell types, including endothelial and smooth muscle cells. Despite their presence in endothelial cells, the effect of TWEAK on endothelial function is incompletely defined.
  
  
  
  In cells, TWEAK induced protein (Western blot) and mRNA (quantitative polymerase chain reaction) expression of ECE-1. Results were related to transcriptional changes, as ECE-1 promoter activity (transfection assays) was also increased. Transfections with serial deletions of ECE-1 promoter suggest a potential role for AP-1 and NFkB, which were confirmed by electrophoretic mobility shift assays. When AP-1 or NFkB activations were inhibited by specific inhibitors of AP-1, PD-98059 (Erk1/2 inhibitor), or SP-600125 (JNK inhibitor), and also with an inhibitor of NFKB and PDTC, TWEAK effect was partially blocked in both cases, suggesting that both transcription factors are implied in ECE-1 regulation. Moreover, the endothelial changes induced by TWEAK were also tested in vivo, using 3-month-old male CD-1 mice treated with TWEAK 10 µg/kg body weight for 24 h, finding similar effects, a rise in ET-1 production (enzyme-linked immunosorbent assay), and ECE-1 expression in aorta and lung tissues. Mice showed slight hypertension after 4 h of treatment, which disappeared at 24 h.
  
  
  
  In pathological situations such as chronic inflammation, TWEAK could be more harmful through this effect at endothelial level. Pharmacological blockade of this cytokine could prevent the haemodynamic and structural changes related to an increased ET-1 synthesis.
authors.affiliation: Research Unit, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.|Nephrology Section, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martínez-Miguel
authors.affiliation: Research Unit, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Medrano-Andrés
authors.affiliation: Biology of System Department, Alcala Universtity, Alcalá de Henares, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera-Merino
authors.affiliation: Nephrology, IIS-Fundación Jiménez Díaz, IRSIN, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Biology of System Department, Alcala Universtity, Alcalá de Henares, Madrid, Spain.|Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
authors.affiliation: Research Unit, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.|Nephrology Section, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.|Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
authors.affiliation: Research Unit, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; slorgil@salud.madrid.org.|Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: López-Ongil
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000494:pharmacology* / Q000633:toxicity; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D048069:Tumor Necrosis Factors; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes
keywords: Blood pressure; Endothelial cells; Endothelin-converting enzyme-1; TWEAK